Methods of treating lung cancer with a pd-1 axis binding antagonist, an antimetabolite, and a platinum agent

Abstract

This invention provides a method for treating an individual with lung cancer (such as non-small cell lung cancer, e.g., stage IV non-squamous non-small cell lung cancer). The method includes administering to the individual a PD-1 axis binding antagonist (such as an anti-PD-L1 antibody, e.g., atezolizumab), an antimetabolite (e.g., pemetrexed), and a platinum-based agent (e.g., cisplatin or carboplatin).

Description

[Technical Field] This invention relates to a method for treating cancer by administering a combination of a PD-1 axis binding antagonist (e.g., atezolizumab) and an antimetabolite (e.g., pemetrexed) and a platinum agent (e.g., carboplatin or cisplatin). [Previous Technology] Lung cancer remains the leading cause of cancer death worldwide; it is the most common cancer in men and accounted for approximately 13% of all new cancer cases in 2008 (Jemal et al., (2011) CA Cancer J. Clin 61: 69-90). An estimated 313,000 new cases of lung cancer and 268,000 deaths were reported in Europe in 2012 (GLOBOCAN (2012). Estimated cancer incidence: mortality and prevalence Worldwide in 2012. Available from globocan(dot)iarc(dot)fr / Pages / fact_sheets_cancer.aspx.). Similar estimates from the United States suggest 221,200 new cases of lung cancer and 158,040 deaths in 2015 (Siegel et al., (2015) CA Cancer J Clin. 65:5-29). Non-small cell lung cancer (NSCLC) is the dominant subtype of lung cancer, accounting for approximately 85% of all cases (Molina et al., (2008) Mayo Clin Proc 83: 584 (94); Howlader et al., (2011) SEER cancer statistics review, 1975-2011, National Cancer Institute). NSCLC can be divided into two main histological types: adenocarcinoma and squamous cell carcinoma (Travis et al., (2011) J Thorac Oncol 6:244-85). Adenocarcinoma accounts for more than half of all NSCLC cases, while squamous cell carcinoma accounts for approximately 25% (Langer et al., (2010) J Clin Oncol 28:5311-20). The remaining NSCLC cases are represented by large cell carcinoma, neuroendocrine tumors, sarcomatoid carcinoma, and poorly differentiated histology. The overall 5-year survival rate for advanced-stage disease is 2% to 4%, depending on geographic location (Cetin et al., (2011) Clin Epidemiol 3:139-48). Poor prognostic factors for NSCLC patient survival include advanced-stage disease at initial diagnosis, poor physical condition, and a history of unintentional weight loss. More than half of NSCLC patients are diagnosed with distant disease, which directly contributes to a poor survival prospect. Platinum-based regimens remain the standard first-line choice for patients with locally advanced or metastatic NSCLC who do not carry EGFR mutations or ALK gene rearrangements. Specifically, for newly diagnosed advanced non-squamous NSCLC, the standard of care is a platinum-based doublet regimen using cisplatin or carboplatin and taxane or pemetrexed, with or without bevacizumab. However, current treatment regimens are associated with substantial toxicities (such as febrile neutropenia, myelosuppression, nausea, alopecia, nephropathy, and neuropathy) and are generally poorly tolerated in elderly and impaired patients. Furthermore, the survival benefit of cytotoxic chemotherapy has plateaued, with an overall response rate of approximately 20% and a 1-year survival rate ranging from 31% to 36% (Schiller et al., (2002) N Engl J Med. 346: 92-98). There are recognized differences in disease characteristics between adenocarcinoma and squamous NSCLC. First, squamous cell tumors are typically located in the central airways and are typically localized within the bronchial epithelium (Hirsch et al., (2008) J Thorac Oncol. 3: 1468-1481), while non-squamous tumors are more commonly located in the soft tissues of the lungs distal to the central airways. Evaluation of NSCLC tumor tissue typically reveals cytological differences between squamous cell types (keratinization, intracellular bridging, and central necrosis) and adenocarcinoma (glandular structures). Immunohistochemical markers can support a histological diagnosis in cases of poorly differentiated tumor samples or limited available tissue. Thyroid transcription factor-1 is rarely expressed in squamous cells but strongly expressed in adenocarcinoma. Conversely, p63, CK5 / 6, and 34βE12 are strongly expressed in squamous cell carcinoma and less common in adenocarcinoma (Travis et al., (2011) J Thorac Oncol. 6:244-85). Genetic alterations of prognostic and / or predictive significance in NSCLC include epidermal growth factor receptor (EGFR) mutations, ALK gene rearrangements, and GTPase Kras (KRAS) gene mutations. The rates of these mutations differ between squamous cell carcinoma and adenocarcinoma. For example, EGFR kinase domain mutations have been reported in 10% to 40% of adenocarcinoma NSCLC patients, but are rarely observed in squamous NSCLC patients (Herbst et al., (2008) N Engl J Med. 359:1367-80). Similarly, the ALK fusion oncogene, recognized as a driver of lung tumorigenesis, has been observed in approximately 7% of adenocarcinoma patients, but is very rare in squamous cell histology (Herbst et al., (2008) N Engl J Med. 359:1367-80; Langer et al., (2010) J Clin Oncol 28: 5311-20). In addition, KRAS mutations are very rare in squamous NSCLC, but can be found in up to 30% of adenocarcinoma NSCLC cases (Travis et al., (2011) J Thorac Oncol. 6:244-85). Genotype-targeted therapy has the potential to significantly improve the balance of benefit and toxicity in selected patients with NSCLC (primarily non-squamous histology) characterized by oncogene alterations, including EGFR mutations and ALK rearrangement sensitization. However, these mutations are more prevalent in adenocarcinoma NSCLC and very rare in squamous NSCLC. Randomized phase III studies of gefitinib (IPASS), erlotinib (EURTAC), and afatinib (LUX-Lung 3) have shown significant improvements in PFS and ORR compared to platinum-based doublet chemotherapy (Fukuoka et al., (2011) J Clin Oncol. 29: 2866-2874; Rosell et al., (2012) Lancet Oncol. 13: 239-246; Yang et al., (2012) Lancet Oncol. 13: 539-548). Similarly, ALK inhibitors crizotinib and ceritinib have shown efficacy in patients with NSCLC who are positive for ALK rearrangement as defined by fluorescence in situ hybridization (Crino et al., (2011) J Clin Oncol. 29: Abstract 7514; Camidge et al., (2012) Lancet Oncol. 13: 1011-1019; Shaw et al., (2012) European Society of Medical Oncology Meeting. Abstract LBA1 PR; Shaw et al., (2014) N Engl J Med. 370: 2537-2539; XALKORI® USPI; ZYKADIA™ USPI). Despite some progress made in the combination of new targeted therapies and new chemotherapy, survival rates for advanced NSCLC remain low, and acquired resistance to targeted agents is a major clinical problem. Therefore, alternative treatment options are needed to improve the prognosis of patients with this disease, such as treatments that prolong survival. All references cited in this document, including patent applications, patent publications and UniProtKB / Swiss-Prot registry numbers, are incorporated herein by reference in their entirety, as if each individual reference were expressly and individually indicated to be incorporated by reference. [Summary of the Invention] This article provides methods and uses for the treatment of lung cancer patients with anti-PD-L1 antibodies. Specifically, these methods and uses are based on data from a randomized phase III clinical trial of atezolizumab (TECETRIQ®) in combination with pemetrexed and a platinum-based agent (e.g., carboplatin or cisplatin) for the treatment of treatment-naïve individuals (e.g., chemotherapy-naïve individuals) with stage IV non-squamous non-small cell lung cancer (NSCLC). The study showed that initial (first-line) treatment with TECENTRIQ® (atezolizumab) plus chemotherapy (pemetrexed + carboplatin or pemetrexed + cisplatin) reduced the risk of disease progression or death (PFS) compared to chemotherapy alone. Furthermore, patients receiving TECENTRIQ® (atezolizumab) plus chemotherapy (pemetrexed + carboplatin or pemetrexed + cisplatin) showed improved overall survival compared to chemotherapy alone. The safety profile of the TECENTRIQ® combination with chemotherapy appeared consistent with the known safety profile of the individual drugs, and no new safety signals were identified in the combination. In one embodiment, this document provides methods for treating an individual with lung cancer, methods comprising administering to the individual an effective amount of an anti-PD-L1 antibody, an antimetabolite, and platinum, wherein the treatment prolongs the individual's progression-free survival (PFS). In some embodiments, the treatment prolongs the individual's overall survival (OS). In some embodiments, the treatment increases the individual's PFS by at least about 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 months (inclusive of any range between these values). In some embodiments, the treatment increases the individual's PFS by at least about 7.6 months. In some embodiments, the treatment increases the individual's PFS by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4 months (including any range between these values) compared to an individual receiving an antimetabolite (e.g., pemetrexed) and platinum (e.g., carboplatin or cisplatin). In another embodiment, methods for treating an individual with lung cancer are provided herein, including administering to the individual an effective amount of an anti-PD-L1 antibody, an antimetabolite, and platinum, wherein the treatment prolongs the individual's overall survival (OS). In some embodiments, overall survival (OS) is measured as the period from the start of treatment to death. In some embodiments, the treatment increases the individual's OS by at least about 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 months (inclusive of any range between these values). In some embodiments, the treatment increases the individual's OS by at least about 18.1 months. In some embodiments, the treatment increases the individual's overall survival (OS) by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 months (including any range between these values) compared to an individual receiving an antimetabolite (e.g., pemetrexed) and a platinum-based agent (e.g., carboplatin or cisplatin). In some embodiments, the anti-PD-L1 antibody comprises: (a) a heavy chain variable region (VH) comprising HVR-H1 containing the amino acid sequence GFTFSDSWIH (SEQ ID NO:1), HVR-2 containing the amino acid sequence AWISPYGGSTYYADSVKG (SEQ ID NO:2), and HVR-3 containing the amino acid RHWPGGFDY (SEQ ID NO:3); and (b) a light chain variable region (VL) comprising HVR-L1 containing the amino acid sequence RASQDVSTAVA (SEQ ID NO:4), HVR-L2 containing the amino acid sequence SASFLYS (SEQ ID NO:5), and HVR-L3 containing the amino acid QQYLYHPAT (SEQ ID NO:6). In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region (VH) containing the amino acid sequence SEQ ID NO:7 and a light chain variable region (VL) containing the amino acid sequence SEQ ID NO:8. In some embodiments, the anti-PD-L1 antibody is atezolizumab. In some embodiments, the antimetabolite is pemetrexed, 5-fluorouracil, 6-mercaptopurine, capecitabine, cytarabine, fluxuridine, fludarabine, hydroxycarbamide, or methotrexate. In some embodiments, the antimetabolite is pemetrexed. In some embodiments, the platinum agent is carboplatin. In some embodiments, the platinum agent is cisplatin. In some embodiments, the anti-PD-L1 system is administered at a dose of 1200 mg, wherein the platinum agent is carboplatin and administered at a dose sufficient to achieve an AUC of 6 mg / ml / min, and wherein the antimetabolite is pemetrexed and administered at a dose of 500 mg / m². In some embodiments, the anti-PD-L1 system is administered at a dose of 1200 mg, wherein the platinum agent is cisplatin and administered at a dose of 75 mg / m², and wherein the antimetabolite is pemetrexed and administered at a dose of 500 mg / m². In some embodiments, the anti-PD-L1 antibody, the antimetabolite, and the platinum preparation are administered over four 21-day cycles, wherein the anti-PD-L1 antibody is atezolizumab and is administered at a dose of 1200 mg on day 1 of each 21-day cycle from cycle 1 to cycle 4, wherein the antimetabolite is pemetrexed and is administered at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 4, and wherein the platinum preparation is carboplatin and is administered at a dose sufficient to achieve an AUC of 6 mg / ml / min on day 1 of each 21-day cycle from cycle 1 to cycle 4. In some embodiments, the anti-PD-L1 antibody, the antimetabolite, and the platinum preparation are administered over four 21-day cycles, wherein the anti-PD-L1 antibody is atezolizumab and is administered at a dose of 1200 mg on day 1 of each 21-day cycle from cycle 1 to cycle 4, wherein the antimetabolite is pemetrexed and is administered at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 4, and wherein the platinum preparation is cisplatin and is administered at a dose of 75 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 4. In some embodiments, the anti-PD-L1 antibody, the antimetabolite, and the platinum preparation are administered sequentially on day 1 of each cycle from cycle 1 to cycle 4. In some embodiments, the anti-PD-L1 antibody is administered before the antimetabolite on day 1 of each cycle from cycle 1 to cycle 4, wherein the antimetabolite is administered before the platinum preparation. In some embodiments, the anti-PD-L1 antibody and the antimetabolite are further administered after cycle 4, wherein the anti-PD-L1 antibody is atezolizumab and is administered at a dose of 1200 mg on day 1 of each 21-day cycle after cycle 4, and wherein the antimetabolite is pemetrexed and is administered at a dose of 500 mg / m² on day 1 of each 21-day cycle after cycle 4. In some embodiments, the anti-PD-L1 antibody and the antimetabolite are administered sequentially on day 1 of each 21-day cycle after cycle 4. In some embodiments, the anti-PD-L1 antibody is administered on day 1 after cycle 4, prior to the antimetabolite. In some embodiments, the anti-PD-L1 antibody, the antimetabolite, and the platinum preparation are administered over four 21-day cycles, wherein the anti-PD-L1 antibody is atezolizumab and is administered at a dose of 1200 mg on day 1 of each 21-day cycle for cycles 1 through 6, wherein the antimetabolite is pemetrexed and is administered at a dose of 500 mg / m² on day 1 of each 21-day cycle for cycles 1 through 6, and wherein the platinum preparation is carboplatin and is administered at a dose sufficient to achieve an AUC of 6 mg / ml / min on day 1 of each 21-day cycle for cycles 1 through 6. In some embodiments, the anti-PD-L1 antibody, the antimetabolite, and the platinum preparation are administered over four 21-day cycles, wherein the anti-PD-L1 antibody is atezolizumab and is administered at a dose of 1200 mg on day 1 of each 21-day cycle from cycle 1 to cycle 6, wherein the antimetabolite is pemetrexed and is administered at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 6, and wherein the platinum preparation is cisplatin and is administered at a dose of 75 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 6. In some embodiments, the anti-PD-L1 antibody, the antimetabolite, and the platinum preparation are administered sequentially on day 1 of each cycle from cycle 1 to cycle 6. In some embodiments, the anti-PD-L1 antibody is administered before the antimetabolite on day 1 of each cycle from cycle 1 to cycle 6, wherein the antimetabolite is administered before the platinum preparation. In some embodiments, the anti-PD-L1 antibody and the antimetabolite are further administered after cycle 6, wherein the anti-PD-L1 antibody is atezolizumab and is administered at a dose of 1200 mg on day 1 of each 21-day cycle after cycle 6, and wherein the antimetabolite is pemetrexed and is administered at a dose of 500 mg / m² on day 1 of each 21-day cycle after cycle 6. In some embodiments, the anti-PD-L1 antibody and the antimetabolite are administered sequentially on day 1 of each 21-day cycle after cycle 6. In some embodiments, the anti-PD-L1 antibody is administered before the antimetabolite on day 1 of each 21-day cycle after cycle 6. In some embodiments, the anti-PD-L1 antibody, the platinum agent, and the antimetabolite inhibitor are each administered intravenously. In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is stage IV non-squamous NSCLC. In some embodiments, the individual is a treatment-naïve individual with respect to stage IV non-squamous NSCLC. In some embodiments, the individual is a chemotherapy-naïve individual with respect to stage IV non-squamous NSCLC. In some embodiments, the individual is Asian or of Asian descent. In some embodiments, the individual is at least 65 years old. In some embodiments, the individual is a non-smoker. In some embodiments, the individual is a high PD-L1 individual. In some embodiments, the individual is a PD-L1 negative individual. In some embodiments, the individual is a human. In another embodiment, this document provides methods for treating an individual with stage IV non-squamous non-small cell lung cancer (NSCLC), methods comprising administering to the individual an effective amount of atezolizumab, pemetrexed, and carboplatin, wherein atezolizumab is administered at a dose of 1200 mg, pemetrexed at a dose of 500 mg / m², and carboplatin at a dose sufficient to achieve an AUC of 6 mg / ml / min, wherein the treatment prolongs progression-free survival (PFS). In some embodiments, the treatment prolongs the individual's overall survival (OS). In some embodiments, the treatment increases the individual's PFS by at least about 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 months (inclusive of any range between these values). In some embodiments, the treatment increases the individual's PFS by at least about 7.6 months. In some embodiments, the treatment increases the individual's progression-free survival (PFS) by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4 months (inclusive) compared to an individual receiving pemetrexed and carboplatin treatment. In some embodiments, the treatment prolongs the individual's overall survival (OS). In some embodiments, overall survival (OS) is measured from the start of treatment to death. In some embodiments, the treatment increases the individual's OS by at least about 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 months (inclusive). In some embodiments, the treatment increases the individual's OS by at least about 18.1 months. In some embodiments, the treatment increases the individual's overall survival (OS) by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 months (including any range between these values) compared to an individual receiving pemetrexed and carboplatin.In some embodiments, atezolizumab, pemetrexed, and carboplatin are administered in four 21-day cycles, with further administration of atezolizumab and pemetrexed in 21-day cycles after the fourth cycle; wherein atezolizumab is administered at a dose of 1200 mg on day 1 of each 21-day cycle from the first to the fourth cycle, pemetrexed is administered at a dose of 500 mg / m² on day 1 of each 21-day cycle from the first to the fourth cycle, and carboplatin is administered at a dose sufficient to achieve an AUC of 6 mg / ml / min on day 1 of each 21-day cycle from the first to the fourth cycle, and wherein for each cycle after the fourth cycle, atezolizumab is further administered at a dose of 1200 mg on day 1 of each 21-day cycle, and for each cycle after the fourth cycle, pemetrexed is further administered at a dose of 500 mg / m² on day 1 of each 21-day cycle. In some embodiments, atezolizumab, pemetrexed, and carboplatin are administered sequentially on day 1 of cycles 1 through 4. In some embodiments, atezolizumab is administered before pemetrexed on day 1 of cycles 1 through 4, wherein pemetrexed is administered before carboplatin. In some embodiments, for each cycle after cycle 4, atezolizumab and pemetrexed are administered sequentially on day 1 of each 21-day cycle. In some embodiments, for each cycle after cycle 4, atezolizumab is administered before pemetrexed on day 1 of each 21-day cycle. In some embodiments, atezolizumab, pemetrexed, and carboplatin are administered in six 21-day cycles, with further administration of atezolizumab and pemetrexed in 21-day cycles after cycle 6; wherein atezolizumab is administered at a dose of 1200 mg on day 1 of each 21-day cycle from cycle 1 to cycle 6, pemetrexed is administered at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 6, and carboplatin is administered at a dose sufficient to achieve an AUC of 6 mg / ml / min on day 1 of each 21-day cycle from cycle 1 to cycle 6, and wherein for each cycle after cycle 6, atezolizumab is further administered at a dose of 1200 mg on day 1 of each 21-day cycle, and for each cycle after cycle 6, pemetrexed is further administered at a dose of 500 mg / m² on day 1 of each 21-day cycle. In some embodiments, atezolizumab, pemetrexed, and carboplatin are administered sequentially on day 1 of cycles 1 through 6. In some embodiments, atezolizumab is administered before pemetrexed on day 1 of cycles 1 through 6, wherein pemetrexed is administered before carboplatin. In some embodiments, for each cycle after cycle 6, atezolizumab and pemetrexed are administered sequentially on day 1 of each 21-day cycle. In some embodiments, for each cycle after cycle 6, atezolizumab is administered before pemetrexed on day 1 of each 21-day cycle. In some embodiments, atezolizumab, pemetrexed, and carboplatin are each administered intravenously. In another embodiment, this document provides methods for treating an individual with stage IV non-squamous non-small cell lung cancer (NSCLC), methods comprising administering to the individual an effective dose of atezolizumab, pemetrexed, and cisplatin, wherein atezolizumab is administered at a dose of 1200 mg, pemetrexed at a dose of 500 mg / m², and cisplatin at a dose of 75 mg / m², wherein the treatment prolongs the individual's progression-free survival (PFS). In some embodiments, the treatment prolongs the individual's overall survival (OS). In some embodiments, the treatment increases the individual's PFS by at least about 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 months (inclusive of any range between these values). In some embodiments, the treatment increases the individual's PFS by at least about 7.6 months. In some embodiments, the treatment increases the individual's progression-free survival (PFS) by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, or 4 months (inclusive) compared to individuals with lung cancer (such as non-small cell lung cancer, e.g., stage IV non-squamous non-small cell lung cancer) treated with pemetrexed and cisplatin. In some embodiments, the treatment prolongs the individual's overall survival (OS). In some embodiments, overall survival (OS) is measured from the start of treatment to death. In some embodiments, the treatment increases the individual's OS by at least about 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, or 20 months (inclusive). In some embodiments, the treatment increases the individual's OS by at least about 18.1 months. In some embodiments, the treatment increases the individual's overall survival (OS) by at least about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, or 7 months (including any range between these values) compared to an individual receiving pemetrexed and cisplatin.In some embodiments, atezolizumab, pemetrexed, and cisplatin are administered in four 21-day cycles, with further administration of atezolizumab and pemetrexed in 21-day cycles after the fourth cycle; wherein atezolizumab is administered at a dose of 1200 mg on day 1 of each 21-day cycle from the first to the fourth cycle, pemetrexed at a dose of 500 mg / m² on day 1 of each 21-day cycle from the first to the fourth cycle, and cisplatin is administered at a dose of 75 mg / m² on day 1 of each 21-day cycle from the first to the fourth cycle, and wherein for each cycle after the fourth cycle, atezolizumab is further administered at a dose of 1200 mg on day 1 of each 21-day cycle, and for each cycle after the fourth cycle, pemetrexed is further administered at a dose of 500 mg / m² on day 1 of each 21-day cycle. In some embodiments, atezolizumab, pemetrexed, and cisplatin are administered sequentially on day 1 of cycles 1 through 4. In some embodiments, atezolizumab is administered before pemetrexed on day 1 of cycles 1 through 4, wherein pemetrexed is administered before cisplatin. In some embodiments, for each cycle after cycle 4, atezolizumab and pemetrexed are administered sequentially on day 1 of each 21-day cycle. In some embodiments, for each cycle after cycle 4, atezolizumab is administered before pemetrexed on day 1 of each 21-day cycle. In some embodiments, atezolizumab, pemetrexed, and cisplatin are administered in six 21-day cycles, with further administration of atezolizumab and pemetrexed in 21-day cycles after cycle 6; wherein atezolizumab is administered at a dose of 1200 mg on day 1 of each 21-day cycle from cycle 1 to cycle 6, pemetrexed at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 6, and cisplatin at a dose of 75 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 6, and wherein for each cycle after cycle 6, atezolizumab is further administered at a dose of 1200 mg on day 1 of each 21-day cycle, and for each cycle after cycle 6, pemetrexed is further administered at a dose of 500 mg / m² on day 1 of each 21-day cycle. In some embodiments, atezolizumab, pemetrexed, and cisplatin are administered sequentially on day 1 of cycles 1 through 6. In some embodiments, atezolizumab is administered before pemetrexed on day 1 of cycles 1 through 6, wherein pemetrexed is administered before cisplatin. In some embodiments, atezolizumab and pemetrexed are administered sequentially on day 1 of each 21-day cycle after cycle 6. In some embodiments, atezolizumab is administered before pemetrexed on day 1 of each 21-day cycle after cycle 6. In some embodiments, atezolizumab, pemetrexed, and cisplatin are each administered intravenously. In some embodiments, the individual is a treatment-naïve individual with respect to stage IV non-squamous NSCLC. In some embodiments, the individual is a chemotherapy-naïve individual with respect to stage IV non-squamous NSCLC. In some embodiments, the individual is Asian or of Asian descent. In some embodiments, the individual is at least 65 years old. In some embodiments, the individual is a non-smoker. In some embodiments, the individual is a high PD-L1 individual. In some embodiments, the individual is a PD-L1 negative individual. In some embodiments, the individual is human. In another embodiment, kits are provided comprising an anti-PD-L1 antibody in combination with an antimetabolite and platinum for use in treating an individual with lung cancer according to the methods disclosed herein. In some embodiments, kits are provided comprising atezolizumab in combination with pemetrexed and carboplatin for use in treating an individual with lung cancer according to the methods disclosed herein. In some embodiments, kits are provided comprising atezolizumab in combination with pemetrexed and cisplatin for use in treating an individual with lung cancer according to the methods disclosed herein. In another embodiment, this document provides a composition comprising an anti-PD-L1 antibody for a method of treating an individual with lung cancer, the method comprising administering to the individual an effective amount of the anti-PD-L1 antibody, an antimetabolite, and platinum, wherein the treatment prolongs the individual's progression-free survival (PFS). In some embodiments, the treatment prolongs the individual's overall survival (OS). In some embodiments, the composition comprising the anti-PD-L1 antibody is used according to the method disclosed herein. In another embodiment, this document provides a composition comprising atezolizumab for the treatment of stage IV non-squamous non-small cell lung cancer (NSCLC), the method comprising administering to the individual an effective amount of atezolizumab, pemetrexed, and carboplatin, wherein the atezolizumab is administered at a dose of 1200 mg, the pemetrexed at a dose of 500 mg / m², and the carboplatin at a dose sufficient to achieve an AUC of 6 mg / ml / min, and wherein the treatment prolongs the individual's progression-free survival (PFS). In some embodiments, the treatment prolongs the individual's overall survival (OS). In some embodiments, the composition is used according to the method disclosed herein. In another embodiment, this document provides a composition comprising atezolizumab for the treatment of stage IV non-squamous non-small cell lung cancer (NSCLC), the method comprising administering to the individual an effective amount of atezolizumab, pemetrexed, and cisplatin, wherein the atezolizumab is administered at a dose of 1200 mg, the pemetrexed at a dose of 500 mg / m², and the cisplatin at a dose of 75 mg / m², and wherein the treatment prolongs the individual's progression-free survival (PFS). In some embodiments, the treatment prolongs the individual's overall survival (OS). In some embodiments, the composition is used according to the method disclosed herein. It should be understood that one, some, or all of the features of the various embodiments described herein can be combined to form other embodiments of the invention. These and other features of the invention will be readily apparent to those skilled in the art. These and other embodiments of the invention are further described in the following detailed description.

Implementation Method

Claims

1. An use of atezolizumab for the treatment of an individual with stage IV non-squamous non-small cell lung cancer (NSCLC), wherein the use comprises administering an effective amount of atezolizumab, pemetrexed, and carboplatin to the individual, wherein the atezolizumab is administered at a dose of 1200 mg, the pemetrexed at a dose of 500 mg / m², and the carboplatin at a dose sufficient to achieve an AUC of 6 mg / ml / min, wherein (a) the atezolizumab, pemetrexed, and carboplatin are administered over four 21-day cycles, and further atezolizumab and pemetrexed are administered over a 21-day cycle after the fourth cycle; wherein on day 1 of each of the 21-day cycles from the first to the fourth cycle, the atezolizumab, pemetrexed, and carboplatin are administered at a dose of 1200 mg / m². Atezolizumab was administered at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 4, and carboplatin was administered at a dose sufficient to achieve an AUC of 6 mg / ml / min on day 1 of each 21-day cycle from cycle 1 to cycle 4, wherein for each cycle after cycle 4, atezolizumab was further administered at a dose of 1200 mg / m² on day 1 of each 21-day cycle, and for each cycle after cycle 4, pemetrexed was further administered at a dose of 500 mg / m² on day 1 of each 21-day cycle, or (b) atezolizumab, pemetrexed, and carboplatin were administered over six 21-day cycles, and atezolizumab and pemetrexed were further administered over 21-day cycles after cycle 6; wherein for each cycle after cycle 1 to cycle 6, atezolizumab was further administered at a dose of 1200 mg / m² on day 1 of each 21-day cycle, and atezolizumab and pemetrexed were further administered at a dose of 5 ... Atezolizumab was administered at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 6, and carboplatin was administered at a dose sufficient to achieve an AUC of 6 mg / ml / min on day 1 of each 21-day cycle from cycle 1 to cycle 6. For each cycle after cycle 6, atezolizumab was further administered at a dose of 1200 mg on day 1 of each 21-day cycle, and pemetrexed was further administered at a dose of 500 mg / m² on day 1 of each 21-day cycle after cycle 6. This treatment prolonged the median progression-free survival (PFS) of the individual compared to treatment with an effective dose of pemetrexed and an effective dose of carboplatin.

2. As requested in claim 1, wherein treatment with atezolizumab, pemetrexed, and carboplatin resulted in a longer median overall survival (OS) compared to treatment with pemetrexed and carboplatin.

3. As requested in claim 1, wherein the treatment with atezolizumab, pemetrexed, and carboplatin prolonged the median PFS by at least about 2 months compared to treatment with pemetrexed and carboplatin.

4. As claimed in claim 1, wherein the treatment with atezolizumab, pemetrexed, and carboplatin prolonged the median overall survival by at least about 4.5 months compared to treatment with pemetrexed and carboplatin.

5. An use of atezolizumab for the treatment of an individual with stage IV non-squamous non-small cell lung cancer (NSCLC), wherein the use comprises administering an effective amount of atezolizumab, pemetrexed, and cisplatin to the individual, wherein the atezolizumab is administered at a dose of 1200 mg, the pemetrexed at a dose of 500 mg / m², and the cisplatin at a dose of 75 mg / m², wherein: (a) Administering atezolizumab, pemetrexed, and cisplatin in four 21-day cycles, with further administration of atezolizumab and pemetrexed in 21-day cycles after cycle 4; wherein atezolizumab is administered at a dose of 1200 mg on day 1 of each 21-day cycle from cycle 1 to cycle 4, pemetrexed at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 4, and cisplatin at a dose of 75 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 4, and wherein for each cycle after cycle 4, atezolizumab is further administered at a dose of 1200 mg on day 1 of each 21-day cycle, and pemetrexed is further administered at a dose of 500 mg / m² on day 1 of each 21-day cycle after cycle 4, or (b) The patient was administered atezolizumab, pemetrexed, and cisplatin in six 21-day cycles, with further administration of atezolizumab and pemetrexed in 21-day cycles after cycle 6. Specifically, atezolizumab was administered at a dose of 1200 mg on day 1 of each 21-day cycle from cycle 1 to cycle 6; pemetrexed at a dose of 500 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 6; and cisplatin at a dose of 75 mg / m² on day 1 of each 21-day cycle from cycle 1 to cycle 6. Furthermore, for each cycle after cycle 6, atezolizumab was further administered at a dose of 1200 mg on day 1 of each 21-day cycle, and pemetrexed was further administered at a dose of 500 mg / m² on day 1 of each 21-day cycle after cycle 6. Compared with treatment with effective doses of pemetrexed and cisplatin, treatment with atezolizumab, pemetrexed, and cisplatin prolonged median progression-free survival (PFS).

6. As claimed in claim 5, wherein treatment with atezolizumab, pemetrexed, and cisplatin resulted in a longer median overall survival (OS) compared to treatment with pemetrexed and cisplatin.

7. As claimed in claim 5, wherein the treatment with atezolizumab, pemetrexed, and cisplatin prolonged the median PFS by at least about 2 months compared to treatment with pemetrexed and cisplatin.

8. As claimed in claim 5, wherein the treatment with atezolizumab, pemetrexed, and cisplatin prolonged the median overall survival by at least approximately 4.5 months compared to treatment with pemetrexed and cisplatin.

9. For the purposes of any of the claims 1-8, the individual is a treatment-naïve individual with respect to stage IV non-squamous NSCLC, and, where applicable, a chemotherapy-naïve individual with respect to stage IV non-squamous NSCLC.

10. For any of the uses described in items 1-8, wherein the individual is Asian, at least 65 years of age and / or a non-smoker.

11. For any of the uses of items 1-8, wherein the individual is a high PD-L1 individual or a PD-L1 negative individual.

12. A kit comprising atezolizumab, which is used in combination with pemetrexed and carboplatin for the treatment of an individual with stage IV non-small cell lung cancer according to any one of claims 1-4 and 9-11.

13. A kit comprising atezolizumab, which is used in combination with pemetrexed and cisplatin for the treatment of an individual with stage IV non-small cell lung cancer according to any one of claims 5-11.

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