Treatment of limited-stage small-cell lung cancer with pd-l1 inhibitors

Abstract

The disclosure relates to methods of treating limited stage small-cell lung cancer.

Description

[0001] TREATMENT OF LIMITED-STAGE SMALL-CELL LUNG CANCER WITH PD-L1 INHIBITORS

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 575,596, filed April 5, 2024, U.S. Provisional Application No. 63 / 644,237, filed May 8, 2024, U.S. Provisional Application No. 63 / 648,384, filed May 16, 2024, and U.S. Provisional Application No. 63 / 752,269, filed January 31, 2025, the disclosures of each of which are incorporated by reference in their entirety.

[0004] SEQUENCE LISTING

[0005] This application contains a sequence listing which is submitted electronically and is hereby incorporated by reference in its entirety. The sequence listing submitted herewith is contained in the XML file created March 20, 2025 entitled “24-0427-WO_Sequence- Listing.xml” and is 20,480 bytes in size.

[0006] FIELD OF THE DISCLOSURE

[0007] The disclosure relates to methods of treating limited-state small-cell lung carcinoma (LS-SCLC) in patients.

[0008] BACKGROUND OF THE DISCLOSURE

[0009] Small-cell lung cancer (SCLC), which accounts for approximately 14% of newly diagnosed lung cancers, is an aggressive disease characterized by rapid growth and early metastases. For limited stage (LS)-SCLC, which accounts for approximately 30% of SCLC diagnoses, the prognosis remains poor despite curative-intent concurrent chemoradiation therapy (CRT) with median overall survival (OS) around two years; no new systemic treatment has become available for LS-SCLC in several decades.

[0010] Immunotherapy, in particular checkpoint inhibitors targeting both programmed cell death 1 (PD-1) and cytotoxic T-lymphocytes-associated antigen-4 (CTLA-4), has been in development in SCLC for several years now. At the time of study inception in 2018, data were available from several key AstraZeneca-sponsored studies suggesting that durvalumab monotherapy is efficacious in the post-chemoradiation therapy setting in locally advanced non-small cell lung cancer (NSCLC) and is also active in pre-treated extensive-stage smallcell lung cancer (ES)-SCLC.

[0011] For example, the PACIFIC study (NCT02125461, targeting patients with locally advanced NSCLC) demonstrated that the addition of durvalumab as consolidation treatment post platinum-based chemoradiation therapy significantly improves progression-free survival (PFS; improved median PFS from 5.6 to 16.8 months, hazard ratio [HR] of 0.52, 95% confidence interval [CI]: 0.42, 0.65, p<0.0001) (Antonia et al 2017) and subsequently the study also demonstrated a statistically significant improvement in OS; (HR of 0.68; 99.73% CI: 0.47, 0.997, p=0.00251 (Antonia et al 2018) with manageable toxicities. In a Phase I / IB Study CD-ON-MEDI4736-1108 (hereafter referred to as Study 1108 (NCT01693562)), durvalumab monotherapy showed encouraging activity in patients with pre-treated ES-SCLC, with an objective response rate (ORR) of 9.5%, a median OS of 4.8 months (95% CI: 1.3, 10.8), and a 1-year survival rate of 27.6% (95% CI: 10.2%, 48.4%).

[0012] Additional data from later line studies in patients with ES-SCLC (extensive stage SCLC) suggest that treatment with durvalumab in combination with tremelimumab may provide additional benefits to durvalumab alone, when administered as a pretreatment in ES- SCLC patients. Similar data were published for other drugs of the same class (i.e., nivolumab in combination with ipilimumab). In a Phase I / II study (D4190C00010; hereafter referred to as Study 10 (NCT02261220)), durvalumab in combination with tremelimumab demonstrated clinical activity in heavily pre-treated ES-SCLC with an ORR of 13.3%, a median OS of 7.9 months (95% CL 3.2, NR), and a 1-year survival rate of 41.7% (95% CL 23.3%, 59.2%). The CHECKMATE-032 study (NCT01928394), conducted in patients with recurrent SCLC, reported ORRs of 10% and 23% in patients with nivolumab monotherapy and combination nivolumab and ipilimumab therapy, respectively, as well as median PFS of 1.4 months (95% CL 1.2, 2.2 months) and 2.6 months (95% CI: 1.4, 4.1 months) with nivolumab monotherapy and nivolumab and ipilimumab combination therapy, respectively, median OS of 4.1 months (95% CL 3.1, 9.1 months) and 7.9 months (95% CI: 3.6, 14.2 months), respectively (Antonia 2016).

[0013] Response rates for concurrent chemoradiation therapy (CRT) in LS-SCLC are approximately 90%, but the majority of patients eventually progress, with median PFS of 10 to 15 months and median OS of 15 to 30 months (Faivre-Finn et al 2017, Granberg et al 2016, Seckl et al 2017). Therefore, there is still a significant unmet medical need for additional treatment options for this patient population .

[0014] SUMMARY OF THE DISCLOSURE

[0015] The disclosure generally relates to methods for treating limited-stage small-cell lung cancer patients (LS-SCLC). Surprisingly, patients with LS-SCLC benefit from treatment with a PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, such as durvalumab), optionally together with a CTLA-4 inhibitor (e.g., an anti-CTLA4 antibody, such as tremelimumab), following treatment with chemoradiation therapy (e,g, concurrent chemoradiation therapy). As shown in the Examples, this treatment regimen significantly improves progression free survival and overall survival in this patient population compared to patients only treated with chemoradiation therapy. Thus, the disclosure demonstrates that treatment of LS-SCLC with a therapy comprising a PD-Ll inhibitor (e.g., an anti-PD-Ll antibody, such as durvalumab) and / or a CTLA-4 inhibitor (e.g., an anti-CTLA4 antibody, such as tremelimumab) following chemoradiation therapy can improve progression free survival and / or overall survival.

[0016] In one aspect, the disclosure provides a method of treating a patient having limitedstage small-cell lung cancer (LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein the patient having LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In an embodiment, the PD-L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In an embodiment, the CTLA-4 inhibitor is tremelimumab.

[0017] In another aspect, the disclosure provides a method for improving progression free survival (PFS) and / or overall survival (OS) in a patient having limited-stage small-cell lung cancer (LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein prior to administering to the patient, the LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In an embodiment, the PD-L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In an embodiment, the CTLA-4 inhibitor is tremelimumab.

[0018] In another aspect, the disclosure relates to treatments comprising a PD-L1 inhibitor for use in treating limited-stage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy in a patient in need thereof. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (C SI 001), or BMS-936559. In an embodiment, the PD-L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In an embodiment, the CTLA-4 inhibitor is tremelimumab. In another aspect, the disclosure relates to use of a treatment comprising a PD-L1 inhibitor for the manufacture of a medicament for treating limited-stage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy in a patient in need thereof. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In an embodiment, the PD-L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In one embodiment, the CTLA-4 inhibitor is tremelimumab.

[0019] In any embodiment referred to herein, the chemoradiation therapy may be concurrent chemoradiation therapy.

[0020] These and other features and advantages of the disclosure will be more fully understood from the following detailed description taken together with the accompanying claims. It is noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the description.

[0021] BRIEF DESCRIPTION OF THE DRAWINGS / FIGURES

[0022] The accompanying drawings are included to provide a further understanding of the methods and compositions of the disclosure. The drawings merely illustrate one or more embodiments of the disclosure, and together with the description serve to explain the principles and operation of the disclosure.

[0023] FIG. 1 shows a schematic of the overall study design (BID = Twice daily; CR = Complete response; CRT = Chemoradiation therapy; D = Durvalumab; EP = Etoposide and cisplatin chemotherapy; LS-SCLC = Limited stage small-cell lung; PCI = Prophylactic cranial irradiation; PD = Progressive disease; PR = Partial response; PS = Performance status; QD = Once daily; R = Randomization; RT = Radiotherapy; SD = Stable disease).

[0024] FIG. 2A and 2B Overall Survival (OS) in the Intention-to-Treat Population. Overall survival was defined as the time from date of randomization until death from any cause. FIG. 2A shows Kaplan-Meier curves for overall survival (OS). Tick marks indicate censored observations, and vertical dashed lines indicate the times of landmark OS analyses. Median values with corresponding 95% Cis were derived based on the Brookmeyer-Crowley method with log-log transformation. *The significance level for testing OS at this interim was 0.01679 (2 sided) at the overall 4.5% level allowing for strong alpha control across interim and final analysis timepoints. The hazard ratio and 98.321% and 95% confidence intervals were calculated from a stratified Cox proportional hazards model. FIG. 2B shows OS in prespecified subgroups. The hazard ratios and 95% confidence intervals for subgroups were calculated from a stratified Cox proportional hazards model for the intention-to-treat population and from an unstratified Cox proportional hazards model with treatment as the only covariate for each subgroup. Size of circle is proportional to number of events across both groups. NC, not calculated due to fewer than 10 events in each subgroup.

[0025] FIG. 3A and 3B Progression-Free Survival (PFS) in the Intend on-to-Treat Population. Progression-free survival was defined as the time from date of randomization to date of objective disease progression or death from any cause in the absence of progression. *Of the 139 and 169 patients in the durvalumab and placebo groups who had progressed or died, 126 and 158 had RECIST progression and 13 and 11 died in the absence of disease progression, respectively. FIG. 3 A shows Kaplan-Meier curves for progression-free survival (PFS), defined according to the Response Evaluation Criteria in Solid Tumors, version 1.1, and assessed by means of blinded independent central review. Tick marks indicate censored observations, and dashed vertical lines indicate the times of landmark PFS analyses. Median values with corresponding 95% Cis were derived based on the Brookmeyer-Crowley method with log-log transformation, f The significance level for testing PFS at this interim analysis was 0.00184 (2-sided) at the 0.5% level and 0.02805 (2-sided) at the overall 5% level. Statistical significance for PFS was achieved through the alpha-recycling multiple testing procedure framework and testing at the 5% (2-sided) alpha level (adjusted for an interim and final analysis). The hazard ratio and 99.816%, 97.195%, and 95% confidence intervals were calculated from a stratified Cox proportional hazards model. FIG. 3B shows PFS in prespecified subgroups. The hazard ratios and 95% confidence intervals for subgroups were calculated from a stratified Cox proportional hazards model for the intention-to-treat population and from an unstratified Cox proportional hazards model with treatment as the only covariate for each subgroup. Size of circle is proportional to number of events across both groups.

[0026] FIG. 4 ADRIATIC Study Design and Dual Primary, Alpha-Controlled Secondary, and Other Secondary End Points. *cCRT and PCI, if received per local standard of care, had to be completed 1 42 days before randomization and treatment start, f 3 cycles of chemotherapy were permitted if disease control was achieved and no additional benefit was expected from an additional cycle, as determined by the investigator. {Randomization stratified by disease stage (I / II vs. Ill) and receipt of PCI (yes vs. no). The first 600 patients were randomized in a 1 : 1 : 1 ratio between the three arms; subsequently, an additional 130 patients were randomized in a 1 : 1 ratio between the durvalumab and placebo arms. BICR, blinded independent central review; BID, twice daily; cCRT, concurrent chemoradiotherapy; D, durvalumab; LS-SCLC, limited-stage small-cell lung cancer; ORR, objective response rate; OS, overall survival; PCI, prophylactic cranial irradiation; PFS, progression-free survival; PS, performance status; Q4W, every 4 weeks; QD, once daily; RECIST vl. l, Response Evaluation Criteria in Solid Tumors, version 1.1; RT, radiotherapy; T, tremelimumab; WHO, World Health Organization.

[0027] FIG. 5 CONSORT Flow Diagram Showing Patient Disposition. Data cut-off date: January 15, 2024. *Patients were randomized but did not meet the dosing window from randomization to first dose; the patient in the durvalumab group withdrew consent and was not followed, and the patient in the placebo group remained in study follow-up and subsequently died. '''One patient randomly assigned to the durvalumab group received tremelimumab in addition to durvalumab and will be included in the durvalumab plus tremelimumab group of the safety population. Patients who were recorded on the electronic case report form as having ‘maximum cycle of immunotherapy reached’ - i.e. completed 24 months of treatment. ^Patients could receive more than one therapy class.

[0028] FIG. 6 Duration of Exposure to Durvalumab or Placebo in the Safety Population. Distribution curves showing proportions of patients still receiving treatment according to duration of exposure. Tick marks indicate times at which patients stopped treatment. SD, standard deviation. *One patient randomly assigned to the durvalumab group received tremelimumab in addition to durvalumab and will be included in the durvalumab plus tremelimumab group of the safety population.

[0029] FIG. 7 Duration of Response in Responding Patients Receiving Durvalumab or Placebo. Duration of response was defined as the time from the date of first documented response until the first date of documented progression or death in the absence of disease progression, per the Response Evaluation Criteria in Solid Tumors, version 1.1, and assessed by means of blinded independent central review. The figure shows Kaplan-Meier curves for duration of response, with tick marks indicating censored observations and vertical dashed lines indicating the times of landmark analyses. FIG. 8 shows a schematic for the ADRIATIC study design. *cCRT and PCI treatment, if received per local standard of care, must have been completed within 1-42 days prior to randomization, flf disease control was achieved and no additional benefit was expected with an additional cycle of chemotherapy, in the opinion of the investigator. {The first 600 patients were randomized in a 1 : 1 : 1 ratio to the 3 treatment arms; subsequent patients were randomized 1 : 1 to either durvalumab or placebo. BICR, blinded independent central review; BID, twice daily; CT, chemotherapy; D, durvalumab; ORR, objective response rate; PBO, placebo; PD, progressive disease; Q4W, every 4 weeks; QD, once daily; RECIST, Response Evaluation Criteria in Solid Tumors; RT, radiotherapy; T, tremelimumab; WHO PS, World Health Organization performance status.

[0030] FIG. 9 shows baseline characteristics for the ADRIATIC study participants. *Based on the first cycle of chemotherapy. AICC, American loint Committee on Cancer; CR, complete response; PR, partial response; SD, stable disease.

[0031] FIG. 10 shows patient disposition for the ADRIATIC study. DCO = data cut-off; * DCO date of lanuary 15, 2024.

[0032] FIG. 11 shows the overall survival for the ADRIATIC study. OS was analysed using a stratified log-rank test adjusted for receipt of PCI (yes vs no). The significance level for testing OS at this interim analysis was 0.01679 (2-sided) at the overall 4.5% level, allowing for strong alpha control across interim and final analysis timepoints. CI, confidence interval; HR, hazard ratio; NE, not estimable.

[0033] FIG. 12 shows the overall survival subgroup analysis for the ADRIATIC study. *End of chemotherapy or radiotherapy, whichever was latest. ITT analysis stratified, subgroup analyses unstratified. Not all prespecified subgroups are included in the plot. Size of circle is proportional to number of events across both arms.

[0034] FIG. 13 shows the progression-free survival (PFS) for the ADRIATIC study. *By BICR per RECIST, vl .1. PFS was analysed using a stratified log-rank test adjusted for TNM stage (stage VII vs III) and receipt of PCI (yes vs no). The significance level for testing PFS at this interim analysis was 0.00184 (2-sided) at the 0.5% level, and 0.02805 (2-sided) at the overall 5% level. Statistical significance for PFS was achieved through the recycling MTP framework and testing at the 5% (2-sided) alpha level (adjusted for an interim and final analysis).

[0035] FIG. 14 shows the progression-free survival subgroup analysis for the ADRIATIC study. *End of chemotherapy or radiotherapy, whichever was latest. ITT analysis stratified, subgroup analyses unstratified. Not all prespecified subgroups are included in the plot. Size of circle is proportional to number of events across both arms.

[0036] FIG. 15 shows safety summary for the ADRIATIC study. *Assessed by investigator, f Defined as an AE of special interest (excluding infusion related / hypersensitivity / anaphylactic reaction) that is consistent with an immune-mediated mechanism that required treatment with systemic corticosteroids, other immunosuppressants, or endocrine therapy. {Causes of death were encephalopathy and pneumonitis.

[0037] FIG. 16 shows a summary of the most frequent adverse events (AE) for the ADRIATIC study. *Occurring in >10% of patients in either treatment arm.

[0038] FIG. 17 shows a summary of pneumonitis in patients for the ADRIATIC study. *Includes the preferred terms of immune-mediated lung disease, interstitial lung disease, pneumonitis, radiation fibrosis - lung, and radiation pneumonitis. Events are included irrespective of etiology and AE management.

[0039] DETAILED DESCRIPTION OF THE DISCLOSURE

[0040] In a general sense, the disclosure relates to methods for treating limited-stage smallcell lung cancer (LS-SCLC) that has responded to or has been stabilized after one or more therapies such as chemotherapy, radiation therapy, and chemoradiation therapy. As described herein, while current standard of care for LS-SCLC (e.g., concurrent chemoradiation therapy (CRT)) provides disease response rates of about 90%, the disease in a majority of patients will eventually progress (median PFS of 10 to 15 months and median OS of 15 to 30 months). Surprisingly, the data presented herein illustrates that methods that comprises a therapy comprising a PD-L1 inhibitor can improve PFS and / or OS in a patient who has LS- SCLC.

[0041] Thus, the disclosure generally provides methods for treating limited-stage small-cell lung cancer patients (LS-SCLC). As the disclosure and supporting data demonstrates, methods that comprise treatment of LS-SCLC with a therapy comprising a PD-L1 inhibitor and / or a CTLA-4 inhibitor and / or chemotherapy can improve progression free survival and / or overall survival at least relative to the current standard of care.

[0042] As utilized in accordance with the disclosure, unless otherwise indicated, all technical and scientific terms shall be understood to have the same meaning as commonly understood by one of ordinary skill in the art. The following references provide one of skill with a general definition of many of the terms used in this disclosure: Singleton et al., Dictionary of Microbiology and Molecular Biology (2nd ed. 1994); The Cambridge Dictionary of Science and Technology (Walker ed., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et al. (eds.), Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionary of Biology (1991). As used herein, the following terms have the meanings ascribed to them below, unless specified otherwise.

[0043] As used herein, the terms "comprise" and "include" and variations thereof (e.g., "comprises," "comprising," "includes," and "including") will be understood to indicate the inclusion of a stated component, feature, element, or step or group of components, features, elements or steps but not the exclusion of any other component, feature, element, or step or group of components, features, elements, or steps. Any of the terms "comprising," "consisting essentially of," and "consisting of may be replaced with either of the other two terms, while retaining their ordinary meanings.

[0044] Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise.

[0045] Percentages disclosed herein can vary in amount by ±10, 20, or 30% from values disclosed and remain within the scope of the contemplated disclosure.

[0046] Unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values herein that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0047] As used herein, ranges and amounts can be expressed as "about" a particular value or range. The term "about" also includes the exact amount. For example, "about 5%" means "about 5%" and also "5%." The term "about" can also refer to ± 10% of a given value or range of values. Therefore, about 5% also means 4.5% - 5.5%, for example. Additionally, "about" or "comprising essentially of' can mean a range of up to ±10%. When particular values or compositions are provided in the application and claims, unless otherwise stated, the meaning of "about" or "comprising essentially of' should be assumed to be within an acceptable error range for that particular value or composition. Unless otherwise clear from context, all numerical values provided herein are modified by the term "about."

[0048] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0049] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written left to right in 5' to 3' orientation. Amino acid sequences are written left to right in amino to carboxy termini orientation. The headings provided herein are not limitations of the various aspects of the disclosure, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0050] As used herein, the terms "or" and "and / or" can describe multiple components in combination or exclusive of one another. For example, "x, y, and / or z" can refer to "x" alone, "y" alone, "z" alone, "x, y, and z," "(x and y) or z," "x or (y and z)," or "x or y or z."

[0051] As used herein, the terms "treat," "treatment," or "treating" when used in the context of treating cancer refer to reducing disease pathology, reducing or eliminating disease symptoms, promoting increased survival rates, and / or reducing discomfort. For example, treating can refer to the ability of a therapy when administered to a subject, to reduce disease symptoms, signs, or causes. Treating also refers to mitigating or decreasing at least one clinical symptom and / or inhibition or delay in the progression of the condition and / or prevention or delay of the onset of a disease or illness.

[0052] As used herein, the terms "subject," "individual," or "patient," refer to any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammalian subjects include, for example, humans, non-human primates, dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, bears, and so on. The term "patient" may refer to a human.

[0053] In an aspect, the disclosure provides a method of treating a patient having limitedstage small-cell lung cancer (LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein the patient having LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In an embodiment, the PD-L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In one embodiment, the CTLA-4 inhibitor is tremelimumab.

[0054] In another aspect, the disclosure provides a method for improving progression free survival (PFS) and / or overall survival (OS) in a patient having limited-stage small-cell lung cancer (LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein prior to administering to the patient, the LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In an embodiment, the PD-L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In one embodiment, the CTLA-4 inhibitor is tremelimumab.

[0055] In another aspect, the disclosure relates to treatments comprising a PD-L1 inhibitor for use in treating limited-stage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy in a patient in need thereof. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (C SI 001), or BMS-936559. In an embodiment, the PD-L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In one embodiment, the CTLA-4 inhibitor is tremelimumab.

[0056] In another aspect, the disclosure relates to use of a treatment comprising a PD-L1 inhibitor for the manufacture of a medicament for treating limited-stage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy in a patient in need thereof. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In an embodiment, the PD- L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In one embodiment, the CTLA-4 inhibitor is tremelimumab.

[0057] In another aspect, this disclosure provides methods for reducing risk of disease progression in a patient having limited-stage small-cell lung cancer (LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein prior to administering to the patient, the LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In an embodiment, the PD-L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In one embodiment, the CTLA-4 inhibitor is tremelimumab.

[0058] In another aspect, this disclosure provides methods for increasing duration of disease response or stable disease in a patient having limited-stage small-cell lung cancer (LS- SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein prior to administering to the patient, the LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. In certain embodiments, the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In an embodiment, the PD- L1 inhibitor is durvalumab. In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In one embodiment, the CTLA-4 inhibitor is tremelimumab.

[0059] As used herein, the term "responsive" refers to a patient that achieves a response, i.e. a patient where the cancer is eradicated, reduced or improved, and thus an indication that the treatment is successful.

[0060] As used herein, the term "improvement" refers to a patient that achieves an increase in time of survival following the treatment as disclosed herein. In some embodiments, an improvement refers to an improvement or increase in PF S or OS compared to standard of care or a platinum based chemoradiation therapy regimen. In some embodiments, an improvement refers to an improvement or increase in OS of at least about 20 months, 21 months, 22 months, 23 months, 24 months, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, the methods disclosed herein result in an OS of at least about 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, or 60 months. In some embodiments, an improvement refers to an improvement or increase in PFS of at least about 5 months, 6 months, 7 months, 8 months, 9 months, or more compared to standard of care or a platinum based chemoradiation therapy regimen. In some embodiments, the methods disclosed herein result in a PFS of at least about 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, or 20 months. In some embodiments of the methods disclosed herein, the an improvement refers to an improvement or increase in one or more of: objective response rate (ORR), time from randomization to second progression (PFS2), progression-free survival at 18 months following randomization (PFS 18a), progression-free survival at 24 months following randomization (PFS24a), proportion of patients alive at 24 months from randomization (OS24), proportion of patients alive at 36 months from randomization (OS36), and time to death or distant metastasis (TTDM) using Blinded Independent Central Review (BICR) assessments according to RECIST 1.1. In some embodiments, an improvement refers to an improvement or increase in PFS18 rate of at least about 10%, 11%, 12%, 13%, 14%, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in PFS24 rate of at least about 10%, 11%, 12%, 13%, 14%, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in OS24 rate of at least about 8%, 9%, 10%, 11%, 12%, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in OS36 rate of at least about 8%, 9%, 10%, 11%, 12%, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, the improvement is a statistically significant and / or a clinically meaningful improvement. In an embodiment, treatment with durvalumab results in a statistically significant and clinically meaningful improvement in overall survival (OS) and / or progression-free survival (PFS) in patients with limited-stage small cell lung cancer (LS-SCLC) who had not progressed following concurrent chemoradiotherapy (cCRT) compared to placebo after cCRT.

[0061] In certain embodiments, a complete response (CR) refers to the disappearance of all target lesions since baseline, and any pathological lymph nodes selected as target lesions must have a reduction in short axis diameter to <10 mm. In certain embodiments, a partial response (PR) refers to an at least 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. In certain embodiments, stable disease (SD), refers to neither sufficient decrease in sum of diameters to qualify for partial response, nor sufficient increase to qualify for progression of disease. A "non-responder" or "refractory" patient includes patients for whom the cancer does not show reduction or improvement after the chemotherapy, radiation therapy, chemoradiation therapy, and / or treatment with a PD-L1 inhibitor and / or tremelimumab. In certain embodiments, progression of disease (PD), refers to an at least 20% increase in the sum of diameters of target lesions, taking as reference the smallest previous sum of diameters (nadir) - this includes the baseline sum if that is the smallest on study (in addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm from nadir).

[0062] In an aspect, this disclosure provides methods of treating a patient identified as having limited-stage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. Limitedstage small-cell lung cancer (LS-SCLC) refers to small-cell lung cancer that can be encompassed within a radical radiation portal. LS-SCLC is only on one side of a patient’s chest and can therefore be treated with a single radiation field. LS-SCLC generally includes cancers that are only in one lung, and that might also have reached the lymph nodes on the same side of the chest. In some embodiments, the patient’s LS-SCLC is histologically or cytologically documented limited-stage SCLC (Stage I-III SCLC [T any, N any, M0] according to the American Joint Committee on Cancer Staging Manual [AJCC Cancer Staging Manual, 8thEdition] or the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology [IASLC Staging Manual in Thoracic Oncology 2016]), i.e., patients whose disease can be encompassed within a radical radiation portal. In some embodiments, the patient’s LS-SCLC can be encompassed within a radical radiation portal. Patients who are Stage I or II must be medically inoperable as determined by an investigator. In some embodiments, the patient’s LS-SCLC has a World Health Organization (WHO) / Eastem Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at enrollment and randomization.

[0063] In some embodiments, the patient with LS-SCLC has received a platinum-based chemotherapy concurrent with radiation therapy. In some embodiments, the patient with LS- SCLC has received about 4 cycles of a platinum-based chemotherapy concurrent with radiation therapy that was completed about 1 to about 42 days prior to the first dose of a PD- L1 inhibitor and / or tremelimumab. In some embodiments, the patient with LS-SCLC has received about 4 cycles of a platinum-based chemotherapy concurrent with radiation therapy that was completed about 1 to about 42 days prior to the first dose of durvalumab and / or tremelimumab. In some embodiments, the patient with LS-SCLC has received a platinumbased chemotherapy and etoposide (for example, via IV). In some embodiments, the patient with LS-SCLC has received radiation therapy comprising a total dose of radiation of: (1) 60 Gy to 66 Gy over 6 weeks for standard once daily (QD) radiation schedules, or (2) 45 Gy over 3 weeks for hyperfractionated twice daily (BID) radiation schedules (for example, with a mean lung does of <20 Gy and / or V20 <35%; or heart dose of V50 <25%). In some embodiments, the radiation therapy must have commenced no later than the end of Cycle 2 of the chemotherapy. In some embodiments, the patient can receive 3 cycles of a platinumbased chemotherapy concurrent with radiation therapy. In some embodiments, the patient has achieved complete remission (CR), partial response (PR), or stable disease (SD) and not have progressed following a platinum-based chemotherapy concurrent with radiation therapy. In some embodiments, the patient has received prophylactic cranial irradiation (PCI). In some embodiments, the patient has not received prophylactic cranial irradiation (PCI).

[0064] Programmed Death Ligand 1 ("PD-L1") is part of a complex system of receptors and ligands that are involved in controlling T-cell activation. Its normal function is to regulate the balance between T-cell activation and tolerance through interaction with its two receptors: programmed death 1 (also known as PD-1 or CD279) and CD80 (also known as B7-1 or B7.1). PD-L1 is also expressed by tumors and acts at multiple sites to help tumors evade detection and elimination by the host immune system. PD-L1 is expressed in a broad range of cancers with a high frequency.

[0065] Programmed Death- 1 ("PD-1") is an approximately 31 kD type I membrane protein member of the extended CD28 / CTLA-4 family of T cell regulators. PD-1 is expressed on activated T cells, B cells, and monocytes, where it serves as a receptor responsible for downregulation of the immune system following activation by binding of PD-L1 or PD-L2. This process is exploited in many tumors via the over-expression of PD-L1, leading to a suppressed immune response.

[0066] As used herein, the terms "PD-L1 inhibitor" and "anti-PD-Ll binding protein" refer to polypeptides, binding proteins, antibodies, or antigen-binding fragments thereof that selectively bind a PD-L1 polypeptide. In some embodiments, a PD-L1 inhibitor can be an anti-PD-Ll antibody. Exemplary anti-PD-Ll antibodies are described, for example, in U.S. Patent Nos. 8,779,108 and 9,493,565, which are incorporated herein by reference. In some embodiments, the anti-PD-Ll antibody is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. In some embodiments, the anti-PD-Ll antibody is durvalumab.

[0067] As used herein, the term "durvalumab" refers to an antibody that selectively binds PD-L1 and blocks the binding of PD-L1 to the PD-1 and CD80 receptors. The durvalumab antibody is disclosed in U.S. Patent No. 9,493,565 (referred to as "2.14H9OPT"), which is incorporated by reference herein in its entirety. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation in the constant domain of the IgGl heavy chain that reduces binding to the complement component Clq and the Fey receptors responsible for mediating antibody-dependent cell-mediated cytotoxicity ("ADCC"). In certain embodiments, the triple mutation refers to the IgGl Fc region comprising a L234F / L235E / P331S triple mutation (EU numbering; see also US 9,493,565). Durvalumab can relieve PD-L1 -mediated suppression of human T-cell activation in vitro and inhibits tumor growth in a xenograft model via a T-cell dependent mechanism. Amino acid sequences of durvalumab are as follows: _

[0068] In some embodiments, the method further comprises administering a CTLA-4 inhibitor. In certain embodiments, the CTLA-4 inhibitor is tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab. In an embodiment, the methods disclosed herein further comprise treatment with tremelimumab. The term "tremelimumab" as used herein refers to an antibody that selectively binds a CTLA-4 polypeptide, can be an inhibitor of CTLA-4, and can prevent binding of CTLA-4 to its ligands of the B7 family of molecules (e.g. B7-1 or B7-2), as disclosed in U.S. Patent No. 6,682,736 and 8,491,895 (referred to as "clone 11.2.1"), which is incorporated by reference herein in its entirety. Tremelimumab is specific for human CTLA-4, with no cross-reactivity to related human proteins. Tremelimumab blocks the inhibitory effect of CTLA-4, and therefore enhances T-cell activation. Tremelimumab shows minimal specific binding to Fc receptors, does not induce natural killer (NK) ADCC activity, and does not deliver inhibitory signals following plate- bound aggregation.

[0069] In some embodiments, the patient having LS-SCLC has responded to or has been stabilized by chemotherapy concurrent with radiation therapy.

[0070] As used herein, the term "chemotherapy" refers to one or more chemotherapeutic agents that can be used to treat a patient diagnosed with a small-cell lung carcinoma. The term "chemotherapeutic agent" refers to a chemical compound that is selectively destructive or selectively toxic to malignant cells and tissues. In some embodiments, chemotherapy can refer to a platinum-based chemotherapy.

[0071] As used herein, the term "platinum-based chemotherapy" refers to chemotherapy drugs that contain the element platinum. Platinum-based chemotherapy has been used to treat many different types of cancer. In some embodiments, a platinum-based chemotherapy refers to chemotherapy treatment comprising comprises at least one of one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin. In some embodiments, a platinum-based chemotherapy can also refer to chemotherapy treatment comprising at least one or more of triplatin tetranitrate, phenanthriplatin, picoplatin, and satraplatin. In certain embodiments, a platinumbased chemotherapy further comprises etoposide. In certain embodiments, a platinum-based chemotherapy comprises cisplatin and etoposide. In certain embodiments, a platinum-based chemotherapy comprises carboplatin and etoposide. In some embodiments, a platinum-based chemotherapy is administered concurrent with radiotherapy (cCRT).

[0072] As used herein, the terms "radiation therapy" or "radiotherapy" or "RT" refer to cancer treatment that uses high doses of radiation to kill cancer cells. In some embodiments, radiation therapy comprises a total dose of radiation of: (1) 60 Gy to 66 Gy over 6 weeks for standard once daily (QD) radiation schedules, or (2) 45 Gy over 3 weeks for hyperfractionated twice daily (BID) radiation schedules. In some embodiments, the radiation therapy commences no later than the end of Cycle 2 of the chemotherapy. In some embodiments, radiation therapy comprises prophylactic cranial irradiation (PCI). In some embodiments, radiation therapy comprises concurrent radiation therapy (for example, a platinum-based chemotherapy administered concurrent with radiotherapy).

[0073] In some embodiments, the PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, an anti-PD- 1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) can be administered once every four weeks while providing benefit to the patient. In further embodiments, the patient is administered additional follow-on doses. Follow-on doses can be administered at various time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and / or other factors, including the judgment of the attending physician.

[0074] In some embodiments, the PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, an anti-PD- 1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) can be administered once every three weeks while providing benefit to the patient. In further embodiments, the patient is administered additional follow-on doses. Follow-on doses can be administered at various time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and / or other factors, including the judgment of the attending physician.

[0075] In some embodiments, multiple doses of a PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, an anti-PD-1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) are administered to the patient. In some embodiments, at least three doses, at least four doses, at least five doses, at least six doses, at least seven doses, at least eight doses, at least nine doses, at least ten doses, at least fifteen doses, at least twenty-four doses, or more than at least twenty doses can be administered to the patient. In some embodiments, the PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, an anti-PD-1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) is administered over a two-week period, over a four-week treatment period, over a six-week treatment period, over an eight-week treatment period, over a twelve-week treatment period, over a twenty-four-week treatment period, over a one-year treatment period, or more than over a one-year treatment period.

[0076] In some embodiments, the interval between doses (e.g., of the PD-L1 inhibitor and / or the CTLA-4 inhibitor) can be every four weeks (Q4W). In some embodiments, the intervals between doses can be every two months. In some embodiments, the interval between doses can be every three weeks (Q3W). In some embodiments, the intervals between doses can be every two months. In some embodiments, the interval between doses can be every two weeks (Q2W). In some embodiments, the interval between doses can be from every two weeks (Q2W) to every four weeks (Q4W).

[0077] In some embodiments, the PD-L1 inhibitor and the CTLA-4 inhibitor are administered on the same day. In some embodiments, the PD-L1 inhibitor and the CTLA-4 inhibitor are administered on sequentially or simultaneously.

[0078] In some embodiments, the amount of the PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, an anti-PD-1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) administered to a patient will be in the range of about 0.01 to about 50 mg / kg of patient body weight, whether by one or more administrations. In some embodiments, the amount of the PD-L1 inhibitor (e.g., an anti-PD-Ll antibody) administered to a patient is in the range of about lOmg / kg to about 20 mg / kg of patient body weight. In some embodiments, the PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, an anti-PD-1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) is administered at about 0.01 mg / kg to about 50 mg / kg, about 0.01 mg / kg to about 45 mg / kg, about 0.01 mg / kg to about 40 mg / kg, about 0.01 mg / kg to about 35 mg / kg, about 0.01 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 25 mg / kg, about 0.01 mg / kg to about 20 mg / kg, about 0.01 mg / kg to about 15 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 5 mg / kg, about 0.2 mg / kg to about 0.8 mg / kg, or about 0.01 mg / kg to about 1 mg / kg administered daily, weekly, every two weeks, every three weeks, or monthly, for example. In some embodiments, the PD-L1 inhibitor (e.g., an anti- PD-Ll antibody, an anti-PD-1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) is administered at about 0.1 mg / kg to about 1.0 mg / kg. However, other dosage regimens may be useful. In one embodiment, the PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, an anti- PD-1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) described herein is administered to a human at a dose of about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, or about 1800 mg daily, weekly, every two weeks, every three weeks, or monthly. In some embodiments, the PD-L1 inhibitor (e.g., an anti-PD-Ll antibody, an anti-PD-1 antibody, or an anti-PD-l / CTLA-4 bispecific antibody) is administered intravenously daily, every two days, every three days, every four days, every five days, every six days, weekly, every two weeks, every three weeks, or monthly. The dose may be administered as a single dose or as multiple doses (e.g., 2 or 3 doses), such as infusions.

[0079] In some embodiments, the LS-SCLC treatment comprises administering an effective amount of a PD-L1 inhibitor once about every 21 to 35 days for up to about 3 to 6 cycles and then an effective amount of a PD-L1 inhibitor once about every 21 to 35 days for up to about an additional 10, 20, 30, 40, or 50 cycles or until clinical / RECIST 1.1-defined radiological progression, until intolerable toxicity (for example, grade 2 or higher), or for a maximum of 24 months, whichever occurs first. In some embodiments LS-SCLC treatment in patients with grade 2 or higher toxicity can be discontinued. In some embodiments, the LS-SCLC treatment comprises administering an effective amount of a PD-L1 inhibitor once about every four weeks (Q4W) for about 4 cycles and then an effective amount of a PD-L1 inhibitor once about every four weeks (Q4W) for up to about 10, 20, 30, 40, or 50 cycles, or until clinical / RECIST 1.1 -defined radiological progression, until intolerable toxicity (for example, grade 2 or higher), or for a maximum of 24 months, whichever occurs first. In some embodiments LS-SCLC treatment in patients with grade 2 or higher toxicity can be discontinued. If a patient's weight falls to 30 kg or below (<30 kg), then the patient should receive weight-based dosing equivalent to about 20 mg / kg of an effective amount of a PD-L1 inhibitor (or placebo) about Q3W or about Q4W until the weight improves to >30 kg, at which point the patient should start receiving an effective amount of a PD-L1 inhibitor (or placebo) about Q3W or about Q4W.

[0080] In some embodiments, the LS-SCLC treatment comprises administering about 1000 mg to about 2000 mg durvalumab once about every 21 to 35 days for up to about 3 to 6 cycles and then about 1000 mg to about 2000 mg durvalumab once about every 21 to 35 days for up to about an additional 10, 20, 30, 40, or 50 cycles or until clinical / RECIST 1.1-defined radiological progression, until intolerable toxicity (for example, grade 2 or higher), or for a maximum of 24 months, whichever occurs first. For example, in some embodiments patients with grade 2 or higher toxicity can be discontinued. In some embodiments, the LS-SCLC treatment comprises administering about 1500 mg durvalumab once about every four weeks (Q4W) for about 4 cycles and then about 1500 mg durvalumab once about every four weeks (Q4W) for up to about an additional 10, 20, 30, 40, or 50 cycles, or until clinical / RECIST 1.1-defined radiological progression, until intolerable toxicity, or for a maximum of 24 months, whichever occurs first. In some embodiments LS-SCLC treatment in patients with grade 2 or higher toxicity can be discontinued. If a patient's weight falls to 30 kg or below (<30 kg), then the patient should receive weight-based dosing equivalent to about 20 mg / kg of durvalumab (or placebo) about Q3W or about Q4W until the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of durvalumab about 1500 mg (or placebo) about Q3W or about Q4W.

[0081] In some embodiments, durvalumab can be provided as a 500-mg vial solution for infusion after dilution. In some embodiments, the solution contains 50 mg / mL durvalumab, 26 mM histidine / histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% w / v polysorbate 80; it has a pH of 6.0 and density of 1.054 g / mL. In certain embodiments, a dose of about 1500 mg (for patients >30 kg in WT) can be administered using an IV bag containing 0.9% (w / v) saline or 5% (w / v) dextrose, with a final durvalumab concentration ranging from 1 to 15 mg / mL and delivered through an IV administration set with a 0.2- or 0.22-pm filter. If patient weight falls to <30 kg, weight-based dosing at 20 mg / kg can be administered using an IV bag selected such that the final concentration is within 1 to 15 mg / mL. In some embodiments, a standard infusion time is 1 hour (±10 mins); however, if there are interruptions, the total allowed time must not exceed 8 hours at room temperature.

[0082] In some embodiments, the LS-SCLC treatment further comprises administering about 50 mg to about 100 mg tremelimumab once about every 21 to 35 days for up to about 3 to 6 cycles. In some embodiments, the LS-SCLC treatment comprises administering about 75 mg tremelimumab once about every four weeks (Q4W) for about 4 cycles. If a patient's weight falls to 30 kg or below (<30 kg), the patient should receive weight-based dosing equivalent to about 1 mg / kg of tremelimumab (or placebo) about Q3W or about Q4W until the weight improves to >30 kg, at which point the patient should start receiving the fixed dosing of tremelimumab about 75 mg (or placebo) about Q3W or about Q4W.

[0083] In some embodiments, tremelimumab can be provided as a 400-mg vial solution or 25-mg vial for infusion after dilution. The tremelimumab solution contains 20 mg / mL tremelimumab, 20 mM histidine / histidine hydrochloride, 222 mM trehalose dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% weight / volume (w / v) polysorbate 80; it has a pH of 5.5 and density of 1.034 g / mL. The label-claim volume is 20 mL for the 400-mg vial and 1.25 mL for the 25-mg vial. In certain embodiments, a dose of about 75 mg tremelimumab (for patients >30 kg in WT) can be administered using an IV bag containing 0.9% (w / v) saline or 5% (w / v) dextrose, with a final tremelimumab concentration ranging from 0.1 to 10 mg / mL and delivered through an IV administration set with a 0.2- or 0.22-pm filter. If patient weight falls to <30 kg, weight-based dosing at 1 mg / kg tremelimumab can be administered using an IV bag selected such that the final concentration is within 0.1 to 10 mg / mL. In some embodiments, a standard infusion time is 1 hour (±10 mins); however, if there are interruptions, the total allowed time must not exceed 8 hours at room temperature.

[0084] In certain embodiments, the LS-SCLC treatment refers to a combination therapy comprising a PD-L1 inhibitor and tremelimumab. In some embodiments, the combination therapy of the PD-L1 inhibitor in combination with tremelimumab comprises durvalumab (1500 mg IV) Q4W in combination with tremelimumab (75 mg IV) Q4W for 4 cycles each, followed by durvalumab 1500 mg Q4W, wherein the first durvalumab monotherapy of 1500 mg dose Q4W is 4 weeks after the final dose of durvalumab in combination with tremelimumab. In certain embodiments, the LS-SCLC treatment refers to a combination therapy comprising durvalumab and tremelimumab. In some embodiments, the combination therapy of durvalumab in combination with tremelimumab comprises durvalumab (1500 mg IV) Q4W in combination with tremelimumab (75 mg IV) Q4W for 4 cycles each, followed by durvalumab 1500 mg Q4W, wherein the first durvalumab monotherapy of 1500 mg dose Q4W is 4 weeks after the final dose of durvalumab in combination with tremelimumab.

[0085] The terms "administration" or "administering" as used herein refer to providing, contacting, and / or delivering a compound or compounds by any appropriate route to achieve the desired effect. Administration may include, but is not limited to, oral, sublingual, parenteral (e.g., intravenous, subcutaneous, intracutaneous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, or intracranial injection), transdermal, topical, buccal, rectal, vaginal, nasal, ophthalmic, via inhalation, and implants.

[0086] As used herein, the term "Standard of care" (SoC) can refer to one or more of a standard-of-care treatment for LS-SCLC comprising thoracic radiotherapy (once daily with a total dose of 60 to 66 Gy or twice daily with a total dose of 45 Gy) combined with 4 cycles of either cisplatin or carboplatin and etoposide chemotherapy (Friih et al 2013, NCCN 2017). In addition, SoC can comprise prophylactic cranial irradiation (PCI; for patients that respond to initial therapy). In some embodiments, a standard of care treatment comprises a platinumbased chemotherapy, concurrent with radiotherapy. In some embodiments, a standard of care treatment comprises a platinum-based chemotherapy with etoposide. In some embodiments, a standard of care treatment comprises a platinum-based chemotherapy with etoposide and concurrent with radiotherapy.

[0087] In certain embodiments, the patient has LS-SCLC that has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. As used herein, the term "stabilized" refers to a patient with "stable disease" (SD) or tumors and / or target lesions that demonstrate neither sufficient shrinkage to qualify for partial response (i.e., at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter) nor sufficient increase to qualify for progressive disease (i.e., at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions), taking as reference the smallest sum longest diameter since the treatment started. In some embodiments, stable disease covers a wide range of sum of the longest diameter changes that encompass about a 30% decrease in sum of the longest diameter up to about a 20% increase from nadir. Stable disease is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started. The clinical relevance of the duration of stable disease can vary for different tumor types and grades.

[0088] In some embodiments, the methods as disclosed herein result in improvement in one or more of progression-free survival (PFS) and overall survival (OS) compared to a standard of care. In certain embodiments, the methods results in improvement in one or more of PFS and OS compared to a platinum-based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in OS of at least about 20 months, 21 months, 22 months, 23 months, 24 months, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, the methods disclosed herein result in an OS of at least about 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, or 60 months. In some embodiments, the methods disclosed herein result in an OS of at least about 56 months. In some embodiments, an improvement refers to an improvement or increase in OS of at least about 22 months compared to standard of care or a platinum based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in PFS of at least about 5 months, 6 months, 7 months, 8 months, 9 months, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, the methods disclosed herein result in a PFS of at least about 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, or 20 months. In some embodiments, the methods disclosed herein result in a PFS of at least about 16 months. In some embodiments, an improvement refers to an improvement or increase in PFS of at least about 7 months compared to standard of care or a platinum based chemotherapy. In some embodiments, the improvement is a statistically significant and / or a clinically meaningful improvement.

[0089] In some embodiments of the methods disclosed herein, the treatment results in an improvement in progression-free survival (PFS) as compared to a standard of care. In some embodiments of the methods disclosed herein, the method results in an improvement in overall survival (OS) as compared to a standard of care. In some embodiments, an improvement refers to an improvement or increase in OS of at least about 20 months, 21 months, 22 months, 23 months, 24 months, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, the methods disclosed herein result in an OS at least about 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, or 60 months. In some embodiments, the methods disclosed herein result in an OS of at least about 56 months. In some embodiments, an improvement refers to an improvement or increase in OS of at least about 22 months compared to standard of care or a platinum based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in PFS of at least about 5 months, 6 months, 7 months, 8 months, 9 months, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, the methods disclosed herein result in a PFS of at least about 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, or more. In some embodiments, the methods disclosed herein result in a PFS of at least about 16 months. In some embodiments, an improvement refers to an improvement or increase in PFS of at least about 7 months compared to standard of care or a platinum based chemotherapy. In some embodiments, the improvement is a statistically significant and / or a clinically meaningful improvement.

[0090] In some embodiments of the methods disclosed herein, the treatment results in an improvement one or more of objective response rate (ORR), time from randomization to second progression (PFS2), progression-free survival at 18 months following randomization (PFS 18a), progression-free survival at 24 months following randomization (PFS24a), proportion of patients alive at 24 months from randomization (OS24), proportion of patients alive at 36 months from randomization (OS36), and time to death or distant metastasis (TTDM) using Blinded Independent Central Review (BICR) assessments according to RECIST 1.1. In some embodiments, an improvement refers to an improvement or increase in PFS18 rate of at least about 10%, 11%, 12%, 13%, 14%, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in PFS24 rate of at least about 10%, 11%, 12%, 13%, 14%, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in OS24 rate of at least about 8%, 9%, 10%, 11%, 12%, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, an improvement refers to an improvement or increase in OS36 rate of at least about 8%, 9%, 10%, 11%, 12%, or more compared to standard of care or a platinum based chemotherapy. In some embodiments, the methods disclosed herein result in a PFS 18 rate of at least about 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, or 53%. In some embodiments, the methods disclosed herein result in a PFS 18 rate of at least about 48%. In some embodiments, the methods disclosed herein result in a PFS24 rate of at least about 46%. In some embodiments, the methods disclosed herein result in a OS24 rate of at least about 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, or 73%. In some embodiments, the methods disclosed herein result in a OS24 rate of at least about 68%. In some embodiments, the methods disclosed herein result in a OS36 rate of at least about 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, or 61%. In some embodiments, the methods disclosed herein result in a OS36 rate of at least about 56%.

[0091] In some embodiments of the methods disclosed herein, the treatment results in a reduced the rate of extra-thoracic (ET) metastases and prolonged time to progression for intra-thoracic (IT; any lesion within lungs) and / or extra-thoracic (ET; lesions outside the lung, including chest wall / diaphragm) metastases, including brain / CNS metastases.

[0092] In some embodiments of the methods disclosed herein, the treatment results in reduced brain and / or central nervous system (CNS) metastases regardless of prophylactic cranial irradiation (PCI) use.

[0093] In some embodiments, the improvement is a statistically significant and / or a clinically meaningful improvement.

[0094] As used herein, the terms "progression-free survival" or "PFS" refer to progression- free survival (per RECIST 1.1, as assessed by BICR), and refer to the time from the date of randomization until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the patient withdraws from therapy or receives another anticancer therapy prior to progression (i.e., date of event or censoring - date of randomization + 1). Patients who have not progressed or died at the time of analysis will be censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment. However, if the patient progresses or dies after 2 or more missed visits, the patient will be censored at the time of the latest evaluable RECIST 1.1 assessment prior to the 2 missed visits (NE is not considered a missed visit). If the patient has no evaluable visits or does not have baseline data, they will be censored at Day 1 unless they die within 2 visits of baseline, then they will be treated as an event with date of death as the event date. The PFS time is derived from scan / assessment dates and not visit dates.

[0095] RECIST 1.1 assessments / scans contributing toward a particular visit may be performed on different dates. The following rules are applied: For BICR assessments, the date of progression is determined based on the earliest scan dates of the component that triggered the progression for the adjudicated reviewer selecting PD or of the reviewer who read baseline first if there is no adjudication. For Investigator assessments, the date of progression is determined by the earliest of the RECIST assessment / scan dates of the component that indicates progression. When censoring a patient for PFS, the patient is censored at the latest of the scan dates contributing to a particular overall visit assessment. As used herein, the terms "PFS18" and "PFS24" refer to progression-free survival at 18 months, and progression-free survival at 24 months, respectively. The PFS18 and PFS24 are defined as the Kaplan-Meier estimate of PFS (per RECIST 1.1 as assessed by BICR) at 18 months and 24 months, respectively.

[0096] Time from randomization to second progression (also call "PFS2") is defined as the time from the date of randomization to the earliest of the progression event subsequent to first subsequent therapy or death. The date of second progression is recorded by the Investigator at each assessment and defined according to local standard clinical practice and may involve any of the following: objective radiological imaging, symptomatic progression, or death. Patients alive and for whom a second disease progression has not been observed should be censored at the last time known to be alive and without a second disease progression, that is, censored at the latest of the PFS or PFS2 assessment date if the patient has not had a second progression or death.

[0097] As used herein, the terms "overall survival" and "OS" refer to the time from the date of randomization until death due to any cause regardless of whether the subject withdraws from randomized therapy or receives another anticancer therapy. Any patient not known to have died at the time of analysis will be censored based on the last recorded date on which the patient was known to be alive. Survival calls are made following the date of data cut-off (DCO) for the analysis (these contacts should generally occur within 7 days of the DCO). If patients are confirmed to be alive, or if the death date is post the DCO date, these patients are censored at the date of DCO. Death dates may be found by checking publicly available death registries. The proportion of patients alive at 24 months (OS24) and 36 months (OS36) after randomization is defined as the Kaplan-Meier estimate of OS at 24 months and 36 months after randomization, respectively.

[0098] As used herein, the terms "objective response rate" or "ORR" refer to the number (%) of patients with at least 1 visit response of CR or PR (i.e., unconfirmed response). Data obtained up until progression, or the last evaluable assessment in the absence of progression, are included in the assessment of ORR. Patients who go off treatment without progression, receive a subsequent therapy, and then respond are included as responders in the ORR.

[0099] As used herein, the terms "time to death or distant metastasis" or "TTDM" refer to the time from the date of randomization until the first date of distant metastasis or death in the absence of distant metastasis. Distant metastasis is defined as any new lesion that is outside of the radiation field according to RECIST 1.1 or proven by biopsy. Patients who have not developed distant metastasis or died at the time of analysis are censored at the time of the latest date of assessment from their last evaluable RECIST 1.1 assessment. However, if the patient has distant metastasis or dies after 2 or more missed visits, the patient is censored at the time of the latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. If the patient has no evaluable visits or does not have baseline data, he / she is censored at Day 1 unless they die within 2 visits of baseline.

[0100] In some embodiments of the methods disclosed herein, the patient's tumor PD-L1 status of the LS-SCLC is determined prior to treatment. In some embodiments, the LS-SCLC of the patients has a PD-L1 tumor cell expression <1%. In some embodiments, the LS-SCLC of the patients has a PD-L1 tumor cell expression 1-49%. In some embodiments, the LS- SCLC of the patients has a PD-L1 tumor cell expression >25%. In some embodiments, the LS-SCLC of the patients has a PD-L1 tumor cell expression >50%. In certain embodiments, a patient's tumor PD-L1 status is determined using Ventana PD-L1 (SP263) immunohistochemistry (IHC) assay applied to formalin fixed paraffin embedded tissue sample.

[0101] As used herein, the terms "tumor mutational burden" or "TMB" refers to the quantity of mutations found in a tumor or target lesion. TMB varies among different tumor types. Some tumor types have a higher rate of mutation than others. TMB can be measured by a variety of tools known in the field. In certain embodiments, these tools are the Foundation Medicine and Guardant Health measurement tools. Determining whether a tumor has high or low levels of tumor mutational burden can be determined by comparison to a reference population having similar tumors and determining median or mean level of expression. In some embodiments, a high TMB is defined as > 10 mutations / megabase (mut / Mb), > 11 mutations / megabase (mut / Mb), > 12 mutations / megabase (mut / Mb), > 13 mutations / megabase (mut / Mb), > 14 mutations / megabase (mut / Mb), > 15 mutations / megabase (mut / Mb), > 16 mutations / megabase (mut / Mb), > 17 mutations / megabase (mut / Mb), > 18 mutations / megabase (mut / Mb), > 19 mutations / megabase (mut / Mb), or > 20 mutations / megabase (mut / Mb). In some embodiments, a high TMB is defined as > 12 to > 20 mutations / megabase (mut / Mb). In other embodiments, a high TMB is defined as > 16 mutations / megabase (mut / Mb). In other embodiments, a high TMB is defined as > 20 mutations / megabase (mut / Mb) or more.

[0102] It is to be understood that the particular aspects of the specification are described herein are not limited to specific embodiments presented, and can vary. It also will be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. Moreover, particular embodiments disclosed herein can be combined with other embodiments disclosed herein, as would be recognized by a skilled person, without limitation.

[0103] Without limiting the disclosure, a number of embodiments of the disclosure are described below for purpose of illustration.

[0104] Embodiments:

[0105] Embodiment 1 : A method of treating a patient having limited-stage small-cell lung cancer (LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein the patient having LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy.

[0106] Embodiment 2. A method for improving progression free survival (PFS) and / or overall survival (OS) in a patient having limited-stage small-cell lung cancer (LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein prior to administering to the patient, the LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy.

[0107] Embodiment 3 : The method of either embodiment 1 or embodiment 2, wherein the PD-

[0108] L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559.

[0109] Embodiment 4: The method of any one of embodiments 1 to 3, wherein the PD-L1 inhibitor is durvalumab.

[0110] Embodiment 5: The method of any one of embodiments 1 to 4, wherein the treatment is administered to the patient about every 28 days (Q4W) for at least about 4 cycles. Embodiment 6: The method of any one of embodiments 1 to 4, wherein the treatment is administered to the patient about every 28 days (Q4W) for 4 cycles.

[0111] Embodiment 7: The method of any one of embodiments 1 to 6, wherein the treatment further comprises administering a CTLA-4 inhibitor selected from tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab; optionally tremelimumab.

[0112] Embodiment 8: The method of embodiment 7, wherein the CTLA-4 inhibitor is tremelimumab and tremelimumab is administered in combination with the PD-L1 inhibitor to the patient about every 28 days (Q4W) for at least about 4 cycles.

[0113] Embodiment 9: The method of either embodiment 7 or embodiment 8, wherein the

[0114] CTLA-4 inhibitor is tremelimumab and tremelimumab is administered to the patient about every 28 days (Q4W) for 4 cycles. Embodiment 10: The method of any one of embodiments 1 to 9, wherein the treatment is administered to the patient about every 28 days (Q4W) for up to about an additional 10, 20, 30, 40, or 50 cycles after the 4 cycles or at least 4 cycles of the PD-L1 inhibitor or the PD-L1 inhibitor and tremelimumab, or up to about an additional 10, 20, 30, 40, or 50 cycles.

[0115] Embodiment 11 : The method of any one of embodiments 1 to 10, wherein the PD-L1 inhibitor is durvalumab and about 1000 mg to 2000 mg of durvalumab is administered to the patient.

[0116] Embodiment 12: The method of embodiment 11, wherein about 1500 mg of durvalumab is administered to the patient.

[0117] Embodiment 13: The method of any one of embodiments 7 to 12, wherein about 50 mg to 100 mg of tremelimumab is administered to the patient.

[0118] Embodiment 14: The method of embodiment 13, wherein about 75 mg of tremelimumab is administered to the patient.

[0119] Embodiment 15: The method of any one of embodiments 1 to 14, wherein the chemotherapy comprises a platinum-based chemotherapy.

[0120] Embodiment 16: The method of embodiment 15, wherein the platinum-based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin. Embodiment 17: The method of any one of embodiments 1 to 16, wherein the patient having LS-SCLC has responded to or has been stabilized by chemotherapy concurrent with radiation therapy.

[0121] Embodiment 18: The method of any one of embodiments 1 to 17 further comprising one or more of:

[0122] (a) determining tumor mutational burden (TMB); and

[0123] (b) determining PD-L1 expression on tumor cells.

[0124] Embodiment 19: The method of any one of embodiments 1 to 18, wherein the patient has one or more of:

[0125] (a) a high tumor mutational burden (TMB); and

[0126] (b) a PD-L1 expression on tumor cells (TC) of >25%.

[0127] Embodiment 20: The method of any one of embodiments 1 to 19, wherein the method results in one or more of:

[0128] (a) improvement in progression-free survival (PFS) of at least about 7 months; and

[0129] (b) improvement in overall survival (OS) of at least about 22 months. Embodiment 21 : The method of any one of embodiments 1 to 20, wherein the method results in improvement in one or more of PFS and OS compared to a standard of care.

[0130] Embodiment 22: The method of any one of embodiments 1 to 20, wherein the method results in improvement in one or more of PFS and OS compared to a chemoradiation therapy alone.

[0131] Embodiment 23 : The method of embodiment 22, wherein the chemoradiation therapy comprises:

[0132] (a) a radiation therapy and cisplatin;

[0133] (b) a radiation therapy and carboplatin;

[0134] (c) a radiation therapy, cisplatin, and etoposide; or

[0135] (d) a radiation therapy, carboplatin, and etoposide.

[0136] Embodiment 24: The method of embodiment 23, wherein the radiation therapy comprises:

[0137] (a) a total dose of about 60 Gy to about 66 Gy administered once daily; or

[0138] (b) a total dose of about 45 Gy administered twice daily.

[0139] Embodiment 25: A treatment comprising a PD-L1 inhibitor for use in treating limitedstage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy in a patient in need thereof.

[0140] Embodiment 26: The treatment for use of embodiment 25, wherein the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (C SI 001), or BMS-936559.

[0141] Embodiment 27: The treatment for use of either embodiment 25 or embodiment 26, wherein the PD-L1 inhibitor is durvalumab.

[0142] Embodiment 28: The treatment for use of any one of embodiments 25 to 27, wherein the treatment is administered to the patient about every 28 days (Q4W) for at least about 4 cycles.

[0143] Embodiment 29: The treatment for use of any one of embodiments 25 to 28, wherein the treatment is administered to the patient about every 28 days (Q4W) for 4 cycles.

[0144] Embodiment 30: The treatment for use of any one of embodiments 25 to 29, wherein the treatment further comprises a CTLA-4 inhibitor selected from tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab; optionally tremelimumab. Embodiment 31 : The treatment for use of embodiment 30, wherein the CTLA-4 inhibitor is tremelimumab and tremelimumab is administered in combination with the PD-L1 inhibitor to the patient about every 28 days (Q4W) for at least about 4 cycles.

[0145] Embodiment 32: The treatment for use of either embodiment 30 or embodiment 31, wherein the CTLA-4 inhibitor is tremelimumab and tremelimumab is administered to the patient about every 28 days (Q4W) for 4 cycles.

[0146] Embodiment 33 : The treatment for use of any one of embodiments 25 to 32, wherein the treatment is administered to the patient about every 28 days (Q4W) for up to about an additional 10, 20, 30, 40, or 50 cycles after the at least 4 cycles or at least 4 cycles of the PD- L1 inhibitor or the PD-L1 inhibitor and the CTLA-4 inhibitor, or up to about an additional 10, 20, 30, 40, or 50 cycles.

[0147] Embodiment 34: The treatment for use of any one of embodiments 25 to 33, wherein the

[0148] PD-L1 inhibitor is durvalumab and about 1000 mg to 2000 mg of durvalumab is administered to the patient.

[0149] Embodiment 35: The treatment for use of embodiment 34, wherein about 1500 mg of durvalumab is administered to the patient.

[0150] Embodiment 36: The treatment for use of any one of embodiments 30 to 35, wherein about 50 mg to 100 mg of tremelimumab is administered to the patient.

[0151] Embodiment 37: The treatment for use of embodiment 36, wherein about 75 mg of tremelimumab is administered to the patient.

[0152] Embodiment 38: The treatment for use of any one of embodiments 25 to 37, wherein the chemotherapy comprises a platinum-based chemotherapy.

[0153] Embodiment 39: The treatment for use of embodiment 38, wherein the platinum -based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin.

[0154] Embodiment 40: The treatment for use of any one of embodiments 25 to 39, wherein the patient having LS-SCLC has responded to or has been stabilized by chemotherapy concurrent with radiation therapy.

[0155] Embodiment 41 : The treatment for use of any one of embodiments 25 to 40 further comprising one or more of:

[0156] (a) determining tumor mutational burden (TMB); and

[0157] (b) determining PD-L1 expression on tumor cells.

[0158] Embodiment 42: The treatment for use of any one of embodiments 25 to 41, wherein the patient has one or more of:

[0159] (a) a high tumor mutational burden (TMB); and (b) a PD-L1 expression on tumor cells (TC) of >25%.

[0160] Embodiment 43 : The treatment for use of any one of embodiments 25 to 42, wherein the use of the treatment results in one or more of:

[0161] (a) improvement in progression-free survival (PFS) of at least about 7 months; and

[0162] (b) improvement in overall survival (OS) of at least about 22 months.

[0163] Embodiment 44: The treatment for use of any one of embodiments 25 to 43, wherein the use of the treatment results in improvement in one or more of PFS and OS compared to a standard of care.

[0164] Embodiment 45: The treatment for use of any one of embodiments 25 to 43, wherein the use of the treatment results in improvement in one or more of PFS and OS compared to a chemoradiation therapy.

[0165] Embodiment 46: The treatment for use of embodiment 45, wherein the chemoradiation therapy comprises:

[0166] (a) a radiation therapy and cisplatin;

[0167] (b) a radiation therapy and carboplatin;

[0168] (c) a radiation therapy, cisplatin, and etoposide; or

[0169] (d) a radiation therapy, carboplatin, and etoposide.

[0170] Embodiment 47: The treatment for use of embodiment 46, wherein the radiation therapy comprises:

[0171] (a) a total dose of about 60 Gy to about 66 Gy administered once daily; or

[0172] (b) a total dose of about 45 Gy administered twice daily.

[0173] Embodiment 48: Use of a treatment comprising a PD-L1 inhibitor for the manufacture of a medicament for treating limited-stage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy in a patient in need thereof.

[0174] Embodiment 49: The use of embodiment 48, wherein the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (C SI 001), or BMS-936559.

[0175] Embodiment 50: The use of either embodiment 48 or embodiment 49, wherein the PD-

[0176] L1 inhibitor is durvalumab.

[0177] Embodiment 51 : The use of any one of embodiments 48 to 50, wherein the medicament is administered to the patient about every 28 days (Q4W) for at least about 4 cycles. Embodiment 52: The use of any one of embodiments 48 to 51, wherein the medicament is administered to the patient about every 28 days (Q4W) for 4 cycles.

[0178] Embodiment 53: The use of any one of embodiments 48 to 52, wherein the medicament further comprises a CTLA-4 inhibitor selected from tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab; optionally tremelimumab.

[0179] Embodiment 54: The use of embodiment 53, wherein the medicament is administered to the patient about every 28 days (Q4W) for at least about 4 cycles.

[0180] Embodiment 55: The use of either embodiment 53 or embodiment 54, wherein the medicament is administered to the patient about every 28 days (Q4W) for 4 cycles. Embodiment 56: The use of any one of embodiments 48 to 55, wherein the medicament is administered to the patient about every 28 days (Q4W) for up to about an additional 10, 20, 30, 40, or 50 cycles after the at least 4 cycles or at least 4 cycles of the PD-L1 inhibitor or the PD-L1 inhibitor and the CTLA-4 inhibitor, or up to about an additional 10, 20, 30, 40, or 50 cycles.

[0181] Embodiment 57: The use of any one of embodiments 48 to 56, wherein the medicament comprises about 1000 mg to 2000 mg of durvalumab.

[0182] Embodiment 58: The use of embodiment 57, wherein the medicament comprises about

[0183] 1500 mg of durvalumab.

[0184] Embodiment 59: The use of any one of embodiments 53 to 58, wherein the medicament comprises about 50 mg to 100 mg of tremelimumab.

[0185] Embodiment 60: The use of embodiment 59, wherein the medicament comprises about

[0186] 75 mg of tremelimumab.

[0187] Embodiment 61 : The use of any one of embodiments 48 to 52, wherein the chemotherapy comprises a platinum-based chemotherapy.

[0188] Embodiment 62: The use of embodiment 61, wherein the platinum-based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin.

[0189] Embodiment 63 : The use of any one of embodiments 48 to 62, wherein the patient having LS-SCLC has responded to or has been stabilized by chemotherapy concurrent with radiation therapy.

[0190] Embodiment 64: The use of any one of embodiments 48 to 63 further comprising one or more of:

[0191] (a) determining tumor mutational burden (TMB); and

[0192] (b) determining PD-L1 expression on tumor cells. Embodiment 65: The use of any one of embodiments 48 to 64, wherein the patient has one or more of:

[0193] (a) a high tumor mutational burden (TMB); and

[0194] (b) a PD-L1 expression on tumor cells (TC) of >25%.

[0195] Embodiment 66: The use of any one of embodiments 48 to 65, wherein the use of the medicament results in one or more of:

[0196] (a) improvement in progression-free survival (PFS) of at least about 7 months; and

[0197] (b) improvement in overall survival (OS) of at least about 22 months.

[0198] Embodiment 67: The use of any one of embodiments 48 to 66 wherein the use of the medicament results in improvement in one or more of PFS and OS compared to a standard of care.

[0199] Embodiment 68: The use of any one of embodiments 48 to 66, wherein the use of the medicament results in improvement in one or more of PFS and OS compared to a chemoradiation therapy.

[0200] Embodiment 69: The use of embodiment 68, wherein the chemoradiation therapy comprises:

[0201] (a) a radiation therapy and cisplatin;

[0202] (b) a radiation therapy and carboplatin;

[0203] (c) a radiation therapy, cisplatin, and etoposide; or

[0204] (d) a radiation therapy, carboplatin, and etoposide.

[0205] Embodiment 70: The use of embodiment 69, wherein the radiation therapy comprises:

[0206] (a) a total dose of about 60 Gy to about 66 Gy administered once daily; or

[0207] (b) a total dose of about 45 Gy administered twice daily.

[0208] EXAMPLES

[0209] The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only and should not be construed as limiting the scope of the invention in any way.

[0210] Example 1: A Phase III, Randomized, Double-blind, Placebo-controlled, Multi-center, International Study of Durvalumab or Durvalumab and Tremelimumab as Consolidation Treatment for Patients with Limited Stage Small-Cell Lung Cancer Who Have Not Progressed Following Concurrent Chemoradiation Therapy (ADRIATIC)

[0211] Lung cancer has been among the most common cancers in the world for several decades, with an estimated 2.1 million new cases in 2018 (11.6% of all new cancers), and was also the most common cause of death from cancer in 2018, with 1.76 million deaths (18.4% of the total cancer deaths; GLOBOCAN 2018). Small-cell lung cancer (SCLC) represents approximately 14% of all newly diagnosed lung cancers (Howlander et al 2016). In the United States (US), over 56,000 new cases of SCLC were diagnosed between 1983 and 2012 (Wang et al 2017). There has been little improvement in the median overall survival (OS) over the last 3 decades - essentially remaining at 7 months (Wang et al 2017).

[0212] Limited Stage (LS) was defined as tumor tissue that could be encompassed in a single radiation port, and Extensive Stage (ES) was defined as any tumor that extended beyond the boundaries of a single radiation port. At present, LS is diagnosed in -30% of patients presenting with SCLC, and ES is diagnosed in -70% of patients.

[0213] The standard-of-care treatment for LS-SCLC is thoracic radiotherapy (once daily with a total dose of 60 to 66 Gy or twice daily with a total dose of 45 Gy) combined with 4 cycles of either cisplatin or carboplatin and etoposide chemotherapy (Friih et al 2013, NCCN 2017). Response rates for concurrent chemoradiation therapy (CRT) in LS-SCLC are approximately 90%, but the majority of patients eventually progress, with median PF S of 10 to 15 months and median OS of 15 to 30 months (Faivre-Finn et al 2017, Granberg et al 2016, Seckl et al 2017). Therefore, there is still a significant unmet medical need for additional treatment options for this patient population to improve PFS and OS.

[0214] There remains a significant unmet medical need for additional treatment options for patients with LS-SCLC. Despite favorable initial responses with the current standard of care in this aggressive disease, the majority of LS-SCLC patients relapse with a median OS of 15 to 30 months (Faivre-Finn et al 2017, Granberg et al 2016, Seckl et al 2017). The poor prognosis reflects the limited treatment options available, highlighting the need for the development of newer therapeutic options.

[0215] The efficacy of treatment with checkpoint inhibitor immunotherapies in patients with SCLC has been observed in multiple recent studies, including studies with durvalumab alone or in combination with tremelimumab (e.g., Study 1108 [NCT01693562] and Study 10 [NCT02261220]). These data suggested that durvalumab is active in SCLC. The safety profile of durvalumab with or without tremelimumab is consistent with the pharmacology of the target and other agents in the immune checkpoint inhibitor class.

[0216] Results from the PACIFIC study (D4191C00001 [NCT02125461]) further support the efficacy and safety of durvalumab as consolidation treatment post CRT. The results from the CASPIAN (D419QC00001 [NCT03043872]) study demonstrated statistical significant and sustained improvement in OS in patients with ES-SCLC when durvalumab was added to platinum based chemotherapy.

[0217] In order to be eligible for this study, patients have achieved complete response (CR), partial response (PR), or stable disease (SD) and have not progressed following definitive, platinum-based chemotherapy, concurrent with radiotherapy (cCRT). This cCRT treatment, and prophylactic cranial irradiation (PCI) treatment if received per local standard of care, is completed within 1 to 42 days prior to randomization and the first dose of investigational product (IP; i.e., durvalumab, tremelimumab, or placebo) in this study. In addition, the baseline efficacy assessment is performed post-CRT as part of the screening procedures within 42 days before randomization and the first dose of IP.

[0218] Initially, patients are randomized in a 1 : 1 : 1 ratio to 1 of 3 treatment groups: durvalumab monotherapy, durvalumab and tremelimumab combination therapy, or placebo. Once 600 patients have been randomized, subsequent patients are randomized 1 : 1 to durvalumab monotherapy or placebo. Randomization is stratified by stage (I / II versus III) based on tumor, node, and metastatic classification (TNM) and receipt of PCI (yes versus no).

[0219] For an overview of the study design, see Figure 1 and Figure 4.

[0220] Treatments and treatment duration'.

[0221] Durvalumab monotherapy. Durvalumab (1500 mg intravenous [IV]) every 4 weeks (Q4W) in combination with placebo (IV) Q4Wfor 4 doses / cycles each, followed by durvalumab 1500 mg Q4W. The first durvalumab monotherapy 1500 mg dose Q4W is 4 weeks after the final dose of durvalumab in combination with placebo. Following completion of enrollment in the durvalumab and tremelimumab combination therapy group, all patients newly randomized to durvalumab monotherapy receive 1 infusion only (durvalumab) from Cycle 1. Patients randomized prior to completion of enrollment to the durvalumab and tremelimumab treatment group receive 2 infusions (durvalumab and placebo) for the first 4 cycles, followed by 1 durvalumab infusion from Cycle 5 onwards.

[0222] Durvalumab in combination with tremelimumab'. Durvalumab (1500 mg IV) Q4W in combination with tremelimumab (75 mg IV) Q4W for 4 doses / cycles each, followed by durvalumab 1500 mg q4w. The first durvalumab monotherapy 1500 mg dose Q4W is 4 weeks after the final dose of durvalumab in combination with tremelimumab. Once 600 patients have been randomized, subsequent patients are randomized 1 : 1 to the durvalumab monotherapy and placebo groups only.

[0223] Placebo'. Placebo (IV) Q4W in combination with a second placebo (IV) Q4Wfor 4 doses / cycles each, followed by placebo monotherapy (IV) Q4W from Cycle 5. The first placebo monotherapy dose Q4W is 4 weeks after the final dose of the 2 placebo combination. Following completion of enrollment in the durvalumab and tremelimumab combination therapy group, all patients newly randomized to placebo receive 1 infusion only (placebo) from Cycle 1. Patients randomized prior to completion of enrollment to the durvalumab and tremelimumab treatment group receive 2 infusions (placebo + placebo) for the first 4 cycles, followed by 1 placebo infusion from Cycle 5 onwards.

[0224] Standard of Care (SoC): The standard-of-care treatment for LS-SCLC is thoracic radiotherapy (once daily with a total dose of 60 to 66 Gy or twice daily with a total dose of 45 Gy) combined with 4 cycles of either cisplatin or carboplatin and etoposide chemotherapy (Friih et al 2013, NCCN 2017). In addition, data suggest that prophylactic cranial irradiation (PCI; for patients that respond to initial therapy) may increase the OS and PFS in LS-SCLC patients (Auperin et al 1999).

[0225] Duration of treatment: All treatment is administered beginning on Day 1 until clinical / RECIST 1.1 -defined radiological progression, until intolerable toxicity, or for a maximum of 24 months, whichever occurs first.

[0226] This study evaluates dual primary endpoints of PFS and OS for durvalumab monotherapy versus placebo. Efficacy assessments of PFS, objective response rate (ORR), PFS at 18 months and at 24 months from randomization (PFS 18 and PFS24), and time to death or distant metastasis (TTDM) are derived using BICR RECIST 1.1 assessments. In addition, OS, OS at 24 months and at 36 months from randomization (OS24 and OS36), and time from randomization to second progression (PFS2) are evaluated. Tumor assessments utilize images from CT or MRI, each preferably with IV contrast, of the chest and abdomen (including the entire liver and both adrenal glands), collected during screening / baseline and at regular (follow-up) intervals during the study. Pelvic imaging is recommended only when primary or metastatic disease in the pelvic region is likely. Any other areas of disease involvement (e.g., pelvis, brain) should be additionally imaged based on the signs and symptoms of individual patients. It is important to follow the tumor assessment schedule as closely as possible (refer to the SoAs). If an unscheduled assessment is performed (e.g., to investigate clinical signs / symptoms of progression) and the patient has not progressed, every attempt should be made to perform the subsequent assessments at the next scheduled visit. Scanning / tumor assessments continue throughout the study until RECIST 1.1 -defined radiological progression plus one follow-up scan (if clinically feasible). Scanning / tumor assessments up to progression may continue after the PFS analysis and up to the end of the study.

[0227] The RECIST 1.1 guidelines provide a method of assessment of change in tumor burden in response to treatment. Screening / Baseline imaging should be performed post-CRT within 42 days before randomization and start of study treatment. The RECIST 1.1 assessments of baseline images identify TLs (defined as measurable) and Non-Target Lesions (NTLs). On study images are evaluated for TLs and NTLs chosen at baseline and for New Lesions (NLs) when they appear. This allows determination of follow-up TL response, NTL lesion response, the presence of unequivocal NLs, and overall time point responses (CR, PR, SD, PD, or Not Evaluable [NE]).

[0228] A follow-up scan is collected after the initial RECIST 1.1-defined PD, no earlier than 4 weeks later and no later than the next scheduled imaging visit. The follow-up scan is evaluated using RECIST 1.1 criteria.

[0229] Example 2: Durvalumab versus placebo - interim analysis (15 Jan 2024).

[0230] Eligible limited-stage small-cell lung cancer patients had stage I-III LS-SCLC (stage I / II inoperable), WHO PS 0 / 1, and had not progressed after cCRT (PCI was permitted before randomization). Patients were randomized 1-42 days after cCRT to: (1) durvalumab 1500 mg + placebo, (2) durvalumab 1500 mg + tremelimumab 75 mg, or (3) placebo + placebo every 4 weeks (Q4W) for 4 cycles, followed by durvalumab or placebo Q4W until investigator- determined progression, intolerable toxicity, or for a maximum of 24 months. The first 600 patients were randomized in a 1 : 1 : 1 ratio; subsequent patients were randomized 1 : 1 to (1) durvalumab or (3) placebo arms (see FIG. 4 and FIG. 5). Randomization was stratified by stage (VII vs III) and receipt of PCI (yes vs no). The dual primary endpoints were OS and PFS (blinded independent central review per RECIST vl.l) for (1) durvalumab vs (3) placebo arms. OS and PFS for (2) durvalumab + tremelimumab vs (3) placebo arms were alpha-controlled secondary endpoints (data not shown for comparison of (2) durvalumab + tremelimumab vs (3) placebo arms).

[0231] 730 patients were randomized, including 264 to (1) durvalumab and 266 to (3) placebo arms. Baseline characteristics and prior treatment were well balanced between arms. Radiation schedule in the (1) durvalumab vs (3) placebo arms was once daily in 73.9% vs 70.3% of patients and twice daily in 26.1% vs 29.7%; 53.8% of patients in each arm received PCI. At this interim analysis, median (range) duration of follow-up for OS (FIG. 2) and PFS (FIG. 3) in censored patients was 37.2 (0.1-60.9) and 27.6 (0.0-55.8) months, respectively. OS was significantly improved with durvalumab (55.9 months) vs placebo (33.4 months) (HR 0.73 [95% CI 0.57-0.93]; p=0.0104; median OS 55.9 months [95% CI 37.3 - not estimable] vs 33.4 months [95% CI 25.5-39.9]; 24-month OS rate 68.0% vs 58.5%; 36-mo OS rate 56.5% vs 47.6%) (see FIG. 2). PFS was also significantly improved with durvalumab (16.6 months) vs placebo (9.2 months) (HR 0.76 [95% CI 0.61-0.95]; p=0.0161; median PFS 16.6 months [95% CI 10.2-28.2] vs 9.2 months [95% CI 7.4-12.9]; 18-month PFS rate 48.8% vs 36.1%; 24-month PFS rate 46.2% vs 34.2%) (see FIG. 3). Treatment benefit was generally consistent across predefined patient subgroups for both OS and PFS. In the durvalumab vs placebo arms, maximum grade 3 / 4 all-cause adverse events (AEs) occurred in 24.3% vs 24.2% of patients and AEs led to treatment discontinuation in 16.3% vs 10.6% of patients and to death in 2.7% vs 1.9%. Any grade pneumonitis / radiation pneumonitis was reported in 38.0% of patients with durvalumab vs 30.2% with placebo (maximum grade 3 / 4 in 3.0% vs 2.6%). The durvalumab + tremelimumab arm remains blinded until the next planned analysis.

[0232] Durvalumab as consolidation treatment after cCRT demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with placebo in patients with LS-SCLC. Durvalumab was well tolerated and consistent with the known safety profile, with no new signals observed. These data support consolidation durvalumab as a new standard of care for patients with LS-SCLC who have not progressed after cCRT.

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[0315] Background The phase 3, randomized, double-blind, placebo-controlled, ADRIATIC study is evaluating durvalumab (±tremelimumab) as consolidation therapy for patients with limitedstage small-cell lung cancer (SCLC) and without disease progression after standard-of-care concurrent platinum-based chemoradiotherapy.

[0316] Methods Patients (N=730) were randomly assigned to durvalumab 1500 mg (n=264), durvalumab+tremelimumab 75 mg (first 4 cycles only) (n=200), or placebo (n=266) every 4 weeks for up to 24 months. Randomization was stratified by stage (I / II vs. Ill) and receipt of prophylactic cranial irradiation (yes vs. no). The first planned interim analysis of the dual primary end points of overall survival and progression-free survival (blinded independent central review per RECIST vl. l) with durvalumab versus placebo (data cut-off: lanuary 15, 2024) is reported; the durvalumab+tremelimumab group remains blinded.

[0317] Results Durvalumab significantly improved overall survival (hazard ratio 0.73; 95% CI, 0.57 to 0.93; P=0.0104; median 55.9 [95% CI, 37.3 to not estimable] vs. 33.4 [25.5 to 39.9] months) and progression-free survival (hazard ratio 0.76; 95% CI, 0.61 to 0.95; P=0.0161; median 16.6 [95% CI, 10.2 to 28.2] vs. 9.2 [7.4 to 12.9] months) versus placebo. In patients receiving durvalumab and placebo, respectively, maximum grade 3 / 4 adverse events occurred in 24.4% and 24.2%, adverse events led to discontinuation in 16.4% and 10.6% and to death in 2.7% and 1.9%, and grade 3-4 pneumonitis / radiation pneumonitis occurred in 3.1% and 2.6%.

[0318] Conclusions Consolidation durvalumab significantly improved overall survival and progression-free survival in patients with limited-stage SCLC.

[0319] Detailed Summary of the Results

[0320] Patients and Treatment

[0321] Between September 28, 2018 and August 18, 2021, 939 patients were enrolled at 179 sites in 19 countries in Asia, Europe, and North and South America; 730 were randomly assigned to receive (1) durvalumab (n=264), (2) durvalumab plus tremelimumab (n=200), or (3) placebo (n=266) (intention-to-treat population, Fig. 5). The baseline characteristics of patients in the (1) durvalumab and (3) placebo groups were balanced between groups (Table 3); these patients were generally representative of the overall population of patients with limited-stage SCLC in the study regions (Table 4). The median age of the patients was 62 years, and most were former (68.5%) or current (22.3%) smokers. Most patients had stage III disease at diagnosis (87.4%). Prior concurrent chemoradiotherapy used etoposide plus cisplatin in 66.2% and carboplatin in 33.8% of patients, respectively, with 88.3% receiving 4 cycles of chemotherapy. Radiotherapy schedules used were once-daily or hyperfractionated twice-daily radiotherapy in 72.1% and 27.9% of patients, respectively, with 93.6% receiving the recommended radiotherapy doses of 60 to 66 Gy once-daily or 45 Gy twice-daily. Overall, 53.8% of patients received PCI.

[0322] Table 3. Baseline Patient Demographics and Disease Characteristics in the

[0323] Intention-to-Treat Population

[0324] Table 4. Representativeness of Study Participants

[0325] Of the 263 and 265 patients who received at least one dose of study treatment in the

[0326] (1) durvalumab and (3) placebo groups, respectively, 88 (33.5%) and 70 (26.4%) completed the maximum permitted 24 months of treatment, and 175 (66.5%) and 195 (73.6%) discontinued treatment, primarily due to disease progression in 121 (46.0%) and 154 (58.1%) patients or adverse events in 43 (16.3%) and 29 (10.9%) patients, respectively (Fig. 5). In the 262 and 265 patients in the safety populations in the durvalumab and placebo groups, respectively, the median number of infusions was 9 (range, 1 to 26) in each group, with means of 12.9 and 11.8 in the durvalumab and placebo groups, respectively (Fig. 6). As of data cutoff (January 15, 2024), 95 (36.0%) and 127 (47.7%) patients in the intention-to-treat populations in the durvalumab and placebo groups had received subsequent anticancer therapy, with 82 (31.1%) and 114 (42.9%) having received cytotoxic chemotherapy and 17 (6.4%) and 31 (11.7%) having received immunotherapy as their first subsequent therapy, respectively (Fig. 5).

[0327] Efficacy At data cut-off, 261 patients had died (49.2% data maturity). The median duration of follow-up in censored patients in the durvalumab and placebo groups was 37.2 (range, 0.1 to 60.2) and 37.2 (0.6 to 60.9) months for overall survival. Overall survival was significantly longer in the (1) durvalumab group versus the (3) placebo group, with a stratified hazard ratio for death of 0.73 (98.321% CI, 0.54 to 0.98; P=0.010, 2-sided significance level 0.01679) (Fig. 2A). Estimated median overall survival was 55.9 months (95% CI, 37.3 to not estimable) in the (1) durvalumab group versus 33.4 months (95% CI, 25.5 to 39.9) in the (3) placebo group; respective 24-month overall survival rates were 68.0% and 58.5%, and 36- month rates were 56.5% and 47.6% (Fig. 2A).

[0328] For progression-free survival, 308 patients had progressed or died (58.1% data maturity). The median duration of follow-up in censored patients in the (1) durvalumab and (3) placebo groups was 27.4 (0.0 to 55.4) and 27.7 (0.0 to 55.8) months for progression-free survival. Progression-free survival was significantly longer in the (1) durvalumab group versus the (3) placebo group, with a stratified hazard ratio for progression or death of 0.76 (97.195% CI, 0.59 to 0.98; P=0.016, 2-sided significance level 0.02805 after alpha recycling from overall survival and testing at the overall 5% level) (Fig. 3 A). Median progression-free survival was 16.6 months (95% CI, 10.2 to 28.2) in the (1) durvalumab group versus 9.2 months (95% CI, 7.4 to 12.9) in the (3) placebo group; respective 18-month progression-free survival rates were 48.8%, and 36.1% and 24-month rates were 46.2% and 34.2% (Fig. 3 A).

[0329] The overall survival (Fig. 2B) and progression-free survival benefits (Fig. 3B) with durvalumab versus placebo were generally consistent in most prespecified subgroups defined by baseline demographics and clinical characteristics, including age, race, prior radiotherapy schedule, and receipt of PCI.

[0330] At baseline, 175 and 169 patients in the durvalumab and placebo groups, respectively, had measurable disease and were evaluable for additional on-study response, of whom 53 and 54, respectively, had an objective response. The objective response rate was 30.3% (95% CI, 23.6 to 37.7) in the (1) durvalumab group and 32.0% (25.0 to 39.6) in the (3) placebo group (Table 5); the respective median durations of response were 33.0 (95% CI, 22.4 to not estimable) and 27.7 (9.6 to not estimable) months (Table 5, Fig. 7).

[0331] Table 5. Objective Responses in the Intention-to-Treat Population.*

[0332] Safety

[0333] Adverse events of any cause were reported in 94.3% and 88.3% of patients in the (1) durvalumab and (3) placebo groups, respectively (Table 6); adverse events of maximum grade 3 or 4 occurred in 24.4% and 24.2%, respectively. The overall incidence of pneumonitis or radiation pneumonitis (grouped preferred terms) was 38.2% and 30.2% in the (1) durvalumab and (3) placebo groups, respectively, including 3.1% and 2.6% with maximum grade 3 or 4 events and one grade 5 event (0.4%) in the durvalumab group.

[0334] Adverse events led to treatment discontinuation in 16.4% and 10.6% of patients in the durvalumab and placebo groups, respectively (Table 7), with 8.8% and 3.0% discontinuing due to pneumonitis or radiation pneumonitis (Table 6); serious adverse events occurred in 29.8% and 24.2% of patients, respectively (Table 8). Immune-mediated adverse events were reported in 32.1% and 10.2% of patients in the (1) durvalumab and (3) placebo groups, respectively (Table 6), with hypothyroid events in 13.7% and 3.4% and pneumonitis events in 11.8% and 3.0%, respectively (Table 9). Overall, 2.7% and 1.9% of patients in the (1) durvalumab and (3) placebo groups, respectively, had adverse events leading to death (Table 6); two patients (0.8%) in the durvalumab group had events considered possibly related to treatment by the investigator - encephalopathy (1 patient, 0.4%) and pneumonitis (1 patient, 0.4%) (Table 10).

[0335] Table 6. Summary of Adverse Events in the Safety Population

[0336] |~Advcrsc event - no, of patients (%) | Durvalumab Group | Placebo Group

[0337] Table 7 Adverse Events of Any Cause Leading to Treatment Discontinuation (Safety

[0338] Population). able 8. Serious Adverse Events of Any Cause Occurring in >2 Patients in Either

[0339] Treatment Group (Safety Population).

[0340] Table 9. Immune-Mediated Adverse Events* (Safety Population).

[0341] Table 10. Treatment-related Adverse Events (Safety Population).

[0342] Discussion: Systemic treatment for limited-stage SCLC has not advanced in recent decades.2Early survival improvements in limited-stage SCLC occurred following adoption of concurrent platinum-based chemoradiotherapy and early-onset thoracic radiotherapy in patients fit enough to undergo this treatment.21However, poor long-term outcomes led to exploration of alternative radiotherapy schedules and systemic therapy. There was early enthusiasm for twice-daily thoracic radiotherapy22but a meta-analysis revealed similar overall survival and toxicity as with once-daily radiotherapy in limited-stage SCLC.23Previous trials of consolidation and maintenance systemic therapy also failed to demonstrate significant improvements in outcomes in limited-stage SCLC.24'27In the current double-blind ADRIATIC trial, the first planned interim analysis revealed that, in patients with limitedstage SCLC who had not progressed following definitive concurrent chemoradiotherapy, use of consolidation durvalumab resulted in clinically meaningful and statistically significant improvements in the dual primary end points of overall survival and progression-free survival. ADRIATIC is thus the first positive trial of consolidation therapy after standard-of- care concurrent chemoradiotherapy in limited-stage SCLC.

[0343] With standard-of-care concurrent chemoradiotherapy, median overall survival is 25 to 30 months and 5-year overall survival rates are 29% to 34%.6-10This interim analysis of ADRIATIC has shown a 3-year overall survival rate of 56.5% with consolidation durvalumab. The significant benefit compared with placebo was demonstrated in the context of a 3-year overall survival rate in the placebo group of 47.6% and a median of 33.4 months, which exceeded that reported in recent phase 3 studies.6'8For example, the CONVERT trial established a median overall survival benchmark of 25.4 to 30.0 months.7,8This finding could be accounted for by: the inclusion in ADRIATIC of only patients who had not progressed following chemoradiotherapy and the exclusion of those with any grade 2 or higher toxicity; improvements in radiotherapy techniques;6,23and possibly access to chemoimmunotherapy regimens for patients who developed distant recurrences.4Nevertheless, ADRIATIC demonstrated a substantially greater magnitude of improvement in overall survival with consolidation durvalumab compared with previous studies in limited-stage SCLC. Additionally, most patients with limited-stage SCLC experience disease relapse or progression within 2 years.5'10’28The 24-month progression-free survival rate in the placebo group of ADRIATIC was 34.2%, as compared with 46.2% in the durvalumab group.

[0344] Reflecting these findings, the rate of ongoing response after 18 months in the placebo group was 55.2% and in the durvalumab group was 71.5%. Together, these data support the use of consolidation durvalumab for 24 months, the period during which patients are at highest risk of relapse.

[0345] The safety profile in ADRIATIC was consistent with that established for durvalumab,14 16and the rates of treatment discontinuation and treatment-related mortality were low. Consistent with previous studies,7’8 12 13’25’31pneumonitis or radiation pneumonitis were among the most commonly reported adverse events in both groups, with a higher rate of events leading to discontinuation (8.8% vs. 3.0%) with durvalumab versus placebo, but similar rates of maximum grade 3 or higher events (3.4% vs. 2.6%, including 1 [0.4%] vs. 0 grade 5 events). These data are also consistent with those from the PACIFIC trial in NSCLC.12,13

[0346] In conclusion, incorporation of consolidation durvalumab significantly improved overall survival and progression-free survival in patients with limited-stage SCLC following definitive concurrent chemoradiotherapy, with a low rate of toxicity and a favorable benefitrisk profile. These findings support a new treatment paradigm for limited-stage SCLC.

[0347] References

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[0402] 59. Li D, Xu X, Liu J, et al. Small cell lung cancer (SCLC) incidence and trends vary by gender, geography, age, and subcategory based on population and hospital cancer registries in Hebei, China (2008-2017). Thorac Cancer 2020;11:2087-93. Example 4. Durvalumab (D) as consolidation therapy in limited-stage SCLC (LS- SCLC): Outcomes by prior concurrent chemoradiotherapy (cCRT) regimen and prophylactic cranial irradiation (PCI) use in the ADRIATIC trial.

[0403] Background: At the first interim analysis of the phase 3 ADRIATIC trial (NCT03703297), consolidation (1) durvalumab vs (3) placebo significantly improved the dual primary endpoints overall survival (OS) and progression free survival (PFS) in patients with LS- SCLC who had not progressed after cCRT. Reported here is data in prespecified subgroups defined by prior cCRT and PCI use.

[0404] Methods: cCRT comprised of QD or BID RT and 3 / 4 cycles of platinum-etoposide chemotherapy (CT), ± PCI (investigator’s choice). Patients were randomised (1-42 days post cCRT) to: (1) durvalumab (D; n=264), (2) durvalumab + tremelimumab (D+T; n=200; arm remains blinded), or (3) placebo (P; n=266).

[0405] Results: Overall, 91.7% (1) durvalumab and 95.5% (3) placebo patients received full recommended dose of 60-66Gy QD or 45Gy BID RT. In both arms -88% received 4 cycles CT and -54% PCI. The (1) durvalumab consistently improved OS and PFS versus (3) placebo across subgroups; magnitude of benefit with (1) durvalumab versus (3) placebo varied between CT subgroups. Multivariable analyses of OS and PFS showed no significant interactions between durvalumab treatment effect and PCI or cCRT subgroups. Rates of maximum grade 3-4 TEAEs with (1) durvalumab versus (3) placebo were 18.8% vs 22.8% in the BID and 26.4% vs 24.7% in the QD RT subgroups, 31.5% vs 31.8% in the carboplatin and 20.8% vs 20.3% in the cisplatin CT subgroups, and 28.4% vs 29.6% in PCI-yes and 19.8% vs 17.9% in PCI-no. Rates of TEAEs leading to (1) durvalumab or (3) placebo discontinuation were 17.4% vs 6.3% in the BID and 16.1% vs 12.4% in the QD RT subgroups, 16.9% vs 10.2% in the carboplatin and 16.2% vs 10.7% in the cisplatin CT subgroups, and 17.0% vs 15.5% in PCI-yes and 15.7% vs 4.9% in PCI-no.

[0406] Table 11.

[0407] Conclusions: The (1) durvalumab arm demonstrated benefit versus (3) placebo irrespective of prior cCRT components and PCI use, supporting consolidation durvalumab as a new standard of care in LS-SCLC.

[0408] Example 5. Patterns of disease progression with durvalumab (D) after concurrent chemoradiotherapy (cCRT) in limited-stage small-cell lung cancer (LS-SCLC): Results from ADRIATIC (exploratory analyses to characterise patterns of disease progression) Background: At the first planned interim analysis of the phase 3 ADRIATIC study, Durvalumab as consolidation treatment significantly improved overall and progression-free survival (PFS) vs placebo (P), in patients (pts) with LS-SCLC and no progression after cCRT. Reported here is the exploratory analyses to characterise patterns of disease progression. Methods: Patients with stage I— III LS-SCLC and no progression after cCRT were randomised to: (1) Durvalumab, (2) Durvalumab plus tremelimumab (arm still blinded), or (3) Placebo, and stratified by disease stage and prophylactic cranial irradiation (PCI) use. First site of progression (RECIST vl.l by BICR) was classified as intra-thoracic (IT; any lesion within lungs) and / or extra-thoracic (ET; lesions outside the lung, including chest wall / diaphragm). Patients with only IT progression were censored in time to ET progression or death analyses and vice versa. In time to progression to brain / CNS or death analyses, patients with ET progression in other locations only or IT progression only were censored. Results: At data cut off (15 Jan 2024), 139 / 264 (52.7%) and 169 / 266 (63.5%) patients in the (1) durvalumab and (3) placebo arms, respectively, had progression or death. Time to IT progression or death and ET progression or death were prolonged with (1) durvalumab versus (3) placebo (see Table 12). The rate of IT progression was similar with durvalumab and placebo, but ET progression was lower in the (1) durvalumab arm. ET lesions at first progression occurred in 19.7% vs 29.7% of patients in the (1) durvalumab and (3) placebo arms, respectively, and mostly in a single organ (18.9% vs 28.6%); the most common site was the brain / CNS (6.8% vs 12.4%). Rates of first progression with brain / CNS metastases were reduced with durvalumab versus placebo for patients who received PCI (2.8% [4 / 142] vs 6.3% [9 / 143]) and with no PCI (11.5% [14 / 122] vs 19.5% [24 / 123]). Time to brain / CNS metastases is shown in Table 12.

[0409] Conclusions: Findings suggest durvalumab consolidation reduced the rate of ET metastases and prolonged time to progression for IT and ET metastases, including brain / CNS metastases. Durvalumab reduced brain / CNS metastases regardless of PCI use.

[0410] Table 12. Summary of interim analysis of the phase 3 ADRIATIC study.

[0411] All patents and publications mentioned in this specification are herein incorporated by reference to the same extent as if each independent patent and publication was specifically and individually indicated to be incorporated by reference. Citation or identification of any reference in any section of this application shall not be construed as an admission that such reference is available as prior art to the present disclosure.

Claims

What is claimed is:Claim 1 : A method of treating a patient having limited-stage small-cell lung cancer(LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein the patient having LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy. Claim 2. A method for improving progression free survival (PFS) and / or overall survival (OS) in a patient having limited-stage small-cell lung cancer (LS-SCLC), the method comprising administering to the patient a treatment comprising a PD-L1 inhibitor, wherein prior to administering to the patient, the LS-SCLC has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy.Claim 3: The method of either claim 1 or claim 2, wherein the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (C SI 001), or BMS-936559.Claim 4: The method of any one of claims 1 to 3, wherein the PD-L1 inhibitor is durvalumab.Claim 5: The method of any one of claims 1 to 4, wherein the treatment is administered to the patient about every 28 days (Q4W) for at least about 4 cycles.Claim 6: The method of any one of claims 1 to 4, wherein the treatment is administered to the patient about every 28 days (Q4W) for 4 cycles.Claim 7: The method of any one of claims 1 to 6, wherein the treatment further comprises administering a CTLA-4 inhibitor selected from tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab; optionally tremelimumab.Claim 8: The method of claim 7, wherein the CTLA-4 inhibitor is tremelimumab and tremelimumab is administered in combination with the PD-L1 inhibitor to the patient about every 28 days (Q4W) for at least about 4 cycles.Claim 9: The method of either claim 7 or claim 8, wherein the CTLA-4 inhibitor is tremelimumab and tremelimumab is administered to the patient about every 28 days (Q4W) for 4 cycles.Claim 10: The method of any one of claims 1 to 9, wherein the treatment is administered to the patient about every 28 days (Q4W) for up to about an additional 10, 20, 30, 40, or 50 cycles after the 4 cycles or at least 4 cycles of the PD-L1 inhibitor or the PD-L1 inhibitor and the CTLA-4 inhibitor, or up to about an additional 10, 20, 30, 40, or 50 cycles.Claim 11 : The method of any one of claims 1 to 10, wherein the PD-L1 inhibitor is durvalumab and about 1000 mg to 2000 mg of durvalumab is administered to the patient. Claim 12: The method of claim 11, wherein about 1500 mg of durvalumab is administered to the patient.Claim 13: The method of any one of claims 7 to 12, wherein about 50 mg to 100 mg of tremelimumab is administered to the patient.Claim 14: The method of claim 13, wherein about 75 mg of tremelimumab is administered to the patient.Claim 15: The method of any one of claims 1 to 14, wherein the chemotherapy comprises a platinum-based chemotherapy.Claim 16: The method of claim 15, wherein the platinum-based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin.Claim 17: The method of any one of claims 1 to 16, wherein the patient having LS- SCLC has responded to or has been stabilized by chemotherapy concurrent with radiation therapy.Claim 18: The method of any one of claims 1 to 17 further comprising one or more of:(a) determining tumor mutational burden (TMB); and(b) determining PD-L1 expression on tumor cells.Claim 19: The method of any one of claims 1 to 18, wherein the patient has one or more of:(a) a high tumor mutational burden (TMB); and(b) a PD-L1 expression on tumor cells (TC) of >25%.Claim 20: The method of any one of claims 1 to 19, wherein the method results in one or more of:(a) improvement in progression-free survival (PFS) of at least about 7 months; and(b) improvement in overall survival (OS) of at least about 22 months.Claim 21 : The method of any one of claims 1 to 20, wherein the method results in improvement in one or more of PFS and OS compared to a standard of care.Claim 22: The method of any one of claims 1 to 20, wherein the method results in improvement in one or more of PFS and OS compared to a chemoradiation therapy alone. Claim 23 : The method of claim 22, wherein the chemoradiation therapy comprises:(a) a radiation therapy and cisplatin;(b) a radiation therapy and carboplatin;(c) a radiation therapy, cisplatin, and etoposide; or(d) a radiation therapy, carboplatin, and etoposide.Claim 24: The method of claim 23, wherein the radiation therapy comprises:(a) a total dose of about 60 Gy to about 66 Gy administered once daily; or(b) a total dose of about 45 Gy administered twice daily.Claim 25: A treatment comprising a PD-L1 inhibitor for use in treating limited-stage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy in a patient in need thereof.Claim 26: The treatment for use of claim 25, wherein the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559. Claim 27: The treatment for use of either claim 25 or claim 26, wherein the PD-L1 inhibitor is durvalumab.Claim 28: The treatment for use of any one of claims 25 to 27, wherein the treatment is administered to the patient about every 28 days (Q4W) for at least about 4 cycles.Claim 29: The treatment for use of any one of claims 25 to 28, wherein the treatment is administered to the patient about every 28 days (Q4W) for 4 cycles.Claim 30: The treatment for use of any one of claims 25 to 29, wherein the treatment further comprises a CTLA-4 inhibitor selected from tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab; optionally tremelimumab.Claim 31 : The treatment for use of claim 30, wherein the CTLA-4 inhibitor is tremelimumab and tremelimumab is administered in combination with the PD-L1 inhibitor to the patient about every 28 days (Q4W) for at least about 4 cycles.Claim 32: The treatment for use of either claim 30 or claim 31, wherein the CTLA-4 inhibitor is tremelimumab and tremelimumab is administered to the patient about every 28 days (Q4W) for 4 cycles.Claim 33 : The treatment for use of any one of claims 25 to 32, wherein the treatment is administered to the patient about every 28 days (Q4W) for up to about an additional 10, 20, 30, 40, or 50 cycles after the at least 4 cycles or at least 4 cycles of the PD-L1 inhibitor or the PD-L1 inhibitor and the CTLA-4 inhibitor, or up to about an additional 10, 20, 30, 40, or 50 cycles.Claim 34: The treatment for use of any one of claims 25 to 33, wherein the PD-L1 inhibitor is durvalumab and about 1000 mg to 2000 mg of durvalumab is administered to the patient.Claim 35: The treatment for use of claim 34, wherein about 1500 mg of durvalumab is administered to the patient.Claim 36: The treatment for use of any one of claims 30 to 35, wherein about 50 mg to 100 mg of tremelimumab is administered to the patient.Claim 37: The treatment for use of claim 36, wherein about 75 mg of tremelimumab is administered to the patient.Claim 38: The treatment for use of any one of claims 25 to 37, wherein the chemotherapy comprises a platinum-based chemotherapy.Claim 39: The treatment for use of claim 38, wherein the platinum -based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin.Claim 40: The treatment for use of any one of claims 25 to 39, wherein the patient having LS-SCLC has responded to or has been stabilized by chemotherapy concurrent with radiation therapy.Claim 41 : The treatment for use of any one of claims 25 to 40 further comprising one or more of:(a) determining tumor mutational burden (TMB); and(b) determining PD-L1 expression on tumor cells.Claim 42: The treatment for use of any one of claims 25 to 41, wherein the patient has one or more of:(a) a high tumor mutational burden (TMB); and(b) a PD-L1 expression on tumor cells (TC) of >25%.Claim 43 : The treatment for use of any one of claims 25 to 42, wherein the use of the treatment results in one or more of:(a) improvement in progression-free survival (PFS) of at least about 7 months; and(b) improvement in overall survival (OS) of at least about 22 months.Claim 44: The treatment for use of any one of claims 25 to 43, wherein the use of the treatment results in improvement in one or more of PFS and OS compared to a standard of care.Claim 45: The treatment for use of any one of claims 25 to 43, wherein the use of the treatment results in improvement in one or more of PFS and OS compared to a chemoradiation therapy.Claim 46: The treatment for use of claim 45, wherein the chemoradiation therapy comprises:(a) a radiation therapy and cisplatin;(b) a radiation therapy and carboplatin;(c) a radiation therapy, cisplatin, and etoposide; or(d) a radiation therapy, carboplatin, and etoposide.Claim 47: The treatment for use of claim 46, wherein the radiation therapy comprises:(a) a total dose of about 60 Gy to about 66 Gy administered once daily; or(b) a total dose of about 45 Gy administered twice daily.Claim 48: Use of a treatment comprising a PD-L1 inhibitor for the manufacture of a medicament for treating limited-stage small-cell lung cancer (LS-SCLC) that has responded to or has been stabilized by one or more of chemotherapy, radiation therapy, and chemoradiation therapy in a patient in need thereof.Claim 49: The use of claim 48, wherein the PD-L1 inhibitor is durvalumab, acasunlimab (BNT311), adebrelimab (SHR-1316), atezolizumab, avelumab, cosibelimab (CK-301), envafolimab, erfonrilimab (KN046), sugemalimab (CS1001), or BMS-936559.Claim 50: The use of either claim 48 or claim 49, wherein the PD-L1 inhibitor is durvalumab.Claim 51 : The use of any one of claims 48 to 50, wherein the medicament is administered to the patient about every 28 days (Q4W) for at least about 4 cycles. Claim 52: The use of any one of claims 48 to 51, wherein the medicament is administered to the patient about every 28 days (Q4W) for 4 cycles.Claim 53: The use of any one of claims 48 to 52, wherein the medicament further comprises a CTLA-4 inhibitor selected from tremelimumab, ipilimumab, ONC-392, AGEN1884, or Botensilimab; optionally tremelimumab.Claim 54: The use of claim 53, wherein the medicament is administered to the patient about every 28 days (Q4W) for at least about 4 cycles.Claim 55: The use of either claim 53 or claim 54, wherein the medicament is administered to the patient about every 28 days (Q4W) for 4 cycles.Claim 56: The use of any one of claims 48 to 55, wherein the medicament is administered to the patient about every 28 days (Q4W) for up to about an additional 10, 20,30, 40, or 50 cycles after the at least 4 cycles or at least 4 cycles of the PD-L1 inhibitor or the PD-L1 inhibitor and the CTLA-4 inhibitor, or up to about an additional 10, 20, 30, 40, or 50 cycles.Claim 57: The use of any one of claims 48 to 56, wherein the medicament comprises about 1000 mg to 2000 mg of durvalumab.Claim 58: The use of claim 57, wherein the medicament comprises about 1500 mg of durvalumab.Claim 59: The use of any one of claims 53 to 58, wherein the medicament comprises about 50 mg to 100 mg of tremelimumab.Claim 60: The use of claim 59, wherein the medicament comprises about 75 mg of tremelimumab.Claim 61 : The use of any one of claims 48 to 52, wherein the chemotherapy comprises a platinum-based chemotherapy.Claim 62: The use of claim 61, wherein the platinum-based chemotherapy is one or more of carboplatin, cisplatin, nedaplatin, and oxaliplatin.Claim 63 : The use of any one of claims 48 to 62, wherein the patient having LS-SCLC has responded to or has been stabilized by chemotherapy concurrent with radiation therapy. Claim 64: The use of any one of claims 48 to 63 further comprising one or more of:(a) determining tumor mutational burden (TMB); and(b) determining PD-L1 expression on tumor cells.Claim 65: The use of any one of claims 48 to 64, wherein the patient has one or more of:(a) a high tumor mutational burden (TMB); and(b) a PD-L1 expression on tumor cells (TC) of >25%.Claim 66: The use of any one of claims 48 to 65, wherein the use of the medicament results in one or more of:(a) improvement in progression-free survival (PFS) of at least about 7 months; and(b) improvement in overall survival (OS) of at least about 22 months.Claim 67: The use of any one of claims 48 to 66 wherein the use of the medicament results in improvement in one or more of PFS and OS compared to a standard of care. Claim 68: The use of any one of claims 48 to 66, wherein the use of the medicament results in improvement in one or more of PFS and OS compared to a chemoradiation therapy.Claim 69: The use of claim 68, wherein the chemoradiation therapy comprises:(a) a radiation therapy and cisplatin;(b) a radiation therapy and carboplatin;(c) a radiation therapy, cisplatin, and etoposide; or(d) a radiation therapy, carboplatin, and etoposide.Claim 70: The use of claim 69, wherein the radiation therapy comprises: (a) a total dose of about 60 Gy to about 66 Gy administered once daily; or(b) a total dose of about 45 Gy administered twice daily.