Keeping Pace with Immunotherapy Advances in NSCLC:
Management of non-small cell lung cancer (NSCLC) has traditionally been done with systemic cytotoxic chemotherapy, and in the 40% of patients who present with metastatic disease, the goals are to prolong survival and maintain quality of life while minimizing side effects.1 In recent years, many phase 3 clinical trials have provided evidence that supports the use of molecularly targeted therapies for first- and subsequent-line treatment in this population.2 In patients newly diagnosed with metastatic NSCLC, routine testing for expression of programmed cell death ligand 1 (PD-L1) is recommended as a way to guide selection of first-line therapy, especially in combination with testing for the presence of driver mutations such as EGFR, ALK, and BRAF that might impact therapy choice.3-8
Tumor mutation burden (TMB) is a promising new biomarker that is being investigated.9 Some tumors that have a high rate of mutations, such as NSCLC, appear to respond better to immunotherapy.9,10 One exogenous factor associated with high TMB in lung cancer is smoking.11 TMB can be assessed through whole exome sequencing or targeted next-generation sequencing (NGS).12 While outcomes in NSCLC in relationship to TMB have been studied in several clinical trials of immunotherapies, it has not yet been validated as a biomarker for clinical use.9 As our understanding of the biology of lung tumors grows and more key mutations are identified, the importance of molecular testing for directing therapy for metastatic NSCLC will be increasingly supported.1
Factors for Selection of First-Line Therapies
Immunotherapy plus chemotherapy is now the first-line treatment of choice for metastatic NSCLC, with the specific combination typically dependent on the level of PD-L1 expression in a patient’s tumor and in keeping with guidelines from the American Society of Clinical Oncology (ASCO) and Ontario Health.13 For patients with <50% expression of PD-L1, chemotherapy plus platinum-doublet chemotherapy is standard, whereas pembrolizumab alone is standard for those whose tumors have ≥50% expression of PD-L1. 13 If EGFR mutations or ALK or ROLS1 translocations are present, a specific tyrosine kinase inhibitor (TKI) should be used.14 TKIs may also be appropriate for patients whose tumors carry BRAF mutations.
When selecting treatment, the potential for immunotherapy side effects, such as the high risk of the development of pneumonitis, and the impact of prior treatments in other settings, such as adjuvant therapies or treatment for locally advanced disease, should be taken into consideration. Determination of whether to start treatment immediately or wait for results of next-generation sequencing should be based on an assessment of the tumor’s aggressiveness as reflected on imaging studies and in histologic analysis combined with consideration of the severity of the patient’s symptoms.
Current and Emerging Immunotherapy Options
Based on outcomes demonstrated in several phase 3 trials in recent years, pembrolizumab has replaced cytotoxic chemotherapy as the treatment of choice in first-line therapy for patients with NSCLC whose tumors have a high expression of PD-L1. Results of the KEYNOTE-189 trial, published in 2018, showed that in patients with previously untreated metastatic NSCLC, regardless of PD-L1 expression, adding pembrolizumab to standard chemotherapy with pemetrexed and a platinum-based drug produced significantly longer overall survival (OS) and progression-free survival (PFS) than chemotherapy alone (Table 1).15-17
Updated results from KEYNOTE-189 were presented at the ASCO conference in 2019.18 A further update was published by Gadgeel and colleagues in 2020 with a median follow-up of 24 months; these latter data are also presented in Table 1 for comparison to the 12-month OS data published in 2018.17 The ongoing OS benefit (Table 1) was reported in all PD-L1 subsets, including patients whose tumors expressed <1% PD-L1. These benefits accrued regardless of liver or brain metastases and with manageable safety and tolerability.17 For comparison to the data segmented by percent PD-L1 expression, data for OS at 24 months for the total population is also provided in Table 1.
In patients with previously untreated advanced NSCLC and PD-L1 expression of at least 50% of tumor cells in the KEYNOTE-024 trial, pembrolizumab was associated with significantly longer PFS and OS (hazard ratio [HR]=0.60; 95% CI, 0.41-0.89; P=0.005) and with fewer adverse events than was platinum-based chemotherapy. In KEYNOTE-042, OS was significantly longer in the pembrolizumab group than in the chemotherapy group in all three PD-L1 status populations (≥50%; ≥20%; and ≥1%; HR=0.69; 0.77; and 0.81, respectively; P=0.0003; 0.0020; and 0.0018, respectively).19
Other options available for anti-PD-L1 therapy in metastatic NSCLC include combinations with atezolizumab, nivolumab, and ipilimumab.
In the phase 3 IMpower150 trial, adding atezolizumab to bevacizumab plus carboplatin plus paclitaxel (ABCP) significantly improved survival in patients with metastatic NSCLC, regardless of PD-L1 expression and EGFR or ALK status.20 Median PFS was 8.3 months in the ABCP group versus 6.8 months in the group that only received BCP (HR=0.62; 95% CI, 0.52-0.74; P<0.001). Median OS was 19.2 months in the ABCP group versus 14.7 months in the BCP group (HR=0.78; 95% CI, 0.64-0.96; P=0.02).20 Atezolizumab was also studied in the phase 3 IMpower130 trial, which showed a significant and clinically meaningful improvement in OS and a significant improvement in PFS with the drug in combination with carboplatin plus paclitaxel versus chemotherapy alone.21 In the group that received atezolizumab, median OS was 18.6 months versus 13.9 months with chemotherapy alone. Median PFS was 7.0 months with the addition of atezolizumab versus 5.5 months in the chemotherapy group (P<0.0001).21 No new safety signals were identified.
The combination of nivolumab plus ipilimumab was studied in the phase 3 CheckMate 227 trial in patients with stage IV or recurrent NSCLC and PD-L1 expression ≥1%.22 First-line treatment with the combination resulted in longer OS than chemotherapy alone (17.1 months versus 14.9 months; P=0.007), independent of PD-L1 expression level. At 2 years, the response rate was 49% with nivolumab plus ipilimumab versus 11% with chemotherapy.22 An analysis of patient-reported outcomes from CheckMate 227 showed improvements in symptom burden with nivolumab plus ipilimumab.23 Symptom deterioration by week 12 was lower with the combination versus chemotherapy (22.3% versus 35.0%; absolute risk reduction: 12.7% [95% CI, 2.4-22.5]) regardless of discontinuation.23 On May 15, 2020, the US Food and Drug Administration (FDA) approved the combination of nivolumab plus ipilimumab as first-line treatment for patients with metastatic NSCLC whose tumors express PD-L1 ≥1%, as determined by an FDA-approved test, with no EGFR or ALK or genomic tumor aberrations.24
Research is ongoing on other immunotherapy combinations for first-line treatment of metastatic NSCLC. For example, the PD-L1 inhibitor durvalumab was studied in the phase 3 MYSTIC trial, which was conducted in 203 cancer treatment centers in 17 countries.25 Patients with previously untreated metastatic NSCLC with no EGFR or ALK mutations received durvalumab, durvalumab plus tremelimumab, or platinum-based doublet chemotherapy. The trial did not meet its primary endpoints. Exploratory analyses identified a blood tumor mutational burden of ≥20 mutations per megabase for optimal OS benefit with durvalumab plus tremelimumab.25 A similar negative outcome was seen for nivolumab in the first-line treatment of stage IV or recurrent NSCLC in the phase 3 CheckMate 026 trial.26 OS was similar in patients who received nivolumab and those treated with platinum-based chemotherapy, and no benefit in PFS was seen with the PD-L1 inhibitor.26
Tumor Mutation Burden and Immunotherapy Efficacy
One of the most important emerging biomarkers in the armamentarium for metastatic NSCLC is TMB, or the total number of nonsynonymous mutations in a tumor.9,27 A study of whole-genome sequencing of NSCLC treated with pembrolizumab showed that higher TMB was associated with improved objective response, durable clinical benefit, and PFS.3 Drawbacks to clinical use of TMB as a biomarker are the need for additional tissue for testing, lengthy turnaround time for results, and the lack of standardization and validation of assays and an accepted definition of TMB.9,27 TMB is also not currently included in algorithms from the National Comprehensive Cancer Network.
The relationship between TMB and outcomes with immunotherapy agents for metastatic NSCLC has been investigated in several clinical trials. In CheckMate 026, nivolumab improved PFS in patients with high tumor load compared to chemotherapy.26 In CheckMate 227, combining PD-L1 expression and level did not identify a subgroup with increased benefit for nivolumab plus ipilimumab versus chemotherapy alone.22 In the MYSTIC study of durvalumab plus tremelimumab, TMB ≥10 but not <10 was associated with numerically longer OS in both immunotherapy groups compared to chemotherapy.25
KEYNOTE-158, in which pembrolizumab was studied, demonstrated an anti-PD-L1 benefit in patients with high microsatellite instability/mismatch repair deficiency.28 The FDA recently approved and expanded pembrolizumab’s tumor-agnostic indication using TMB-high (TMB-H) as a biomarker to identify eligible patients with refractory solid tumors.29
For first-line therapy in metastatic NSCLC, anti-PD-L1 therapies are the standard of care. Given the expanding evidence from clinical trials about existing agents and the ongoing development of new agents in this category, clinicians face challenges in determining how to optimize treatment for individual patients. Histology, presence or absence of driver mutations, and factors such as an individual’s age and comorbidities should all be considered when determining choice of therapy for an individual. Testing for PD-L1 expression should be performed in newly diagnosed patients. Current evidence indicates that pembrolizumab is the treatment of choice for tumors with high PD-L1 expression, whereas a platinum-based chemotherapy doublet plus immunotherapy is appropriate for tumors with low or intermediate PD-L1 expression. The promise of TMB as a biomarker for response to immunotherapy has recently been validated by the FDA’s approval and expansion of pembrolizumab’s tumor-agnostic indication using TMB-high (TMB-H) as a biomarker to identify eligible patients with refractory solid tumors.
- International Association for the Study of Lung Cancer. Increased survival in patients with metastatic NSCLC receiving treatment in academic centers. Published October 10, 2018. Accessed July 1, 2020. https://medicalxpress.com/news/2018-10-survival-patients-metastatic-nsclc-treatment.html
- Ternyila D. Molecular testing benefits patients as targeted therapies continue to evolve for metastatic NSCLC. Targeted Oncology. Published September 6, 2019. Accessed July 1, 2020. http://www.targetedonc.com/news/molecular-testing-benefits-patients-as-targeted-therapies-continue-to-evolve-for-metastatic-nsclc
- Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124-128.
- Francisco LM, Salinas VH, Brown KE, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med. 2009;206(13):3015-3029.
- Amarnath S, Mangus CW, Wang JC, et al. The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med. 2011;3(111):111ra120.
- Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science. 2011;331(6024):1565-1570.
- Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline for selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guideline from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Arch Pathol Lab Med. 2013;137(6):828-860.
- Leighl NB, Rekhtman N, Biermann WA, et al. Molecular testing for selection of patients with lung cancer for epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the study of lung cancer/association for molecular pathology guideline. J Clin Oncol. 2014;32(32):3673-3679.
- Hendriks LE, Rouleau E, Besse B. Clinical utility of tumor mutational burden in patients with non-small cell lung cancer treated with immunotherapy. Transl Lung Cancer Res. 2018;7(6):647-660.
- Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415-421.
- Pfeifer GP. Environmental exposures and mutational patterns of cancer genomes. Genome Med. 2010;2(8):54.
- Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9(1):34.
- Hanna NH, Schneider BJ, Temin S, et al. Therapy for stage IV non-small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol. 2020;38(14):1608-1632.
- NCCN Clinical Practice Guidelines in Oncology in partnership with the American Society of Clinical Oncology (ASCO). Version 2.2019. Management of Immunotherapy-Related Toxicities website. Accessed July 1, 2020. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf
- Gandhi L, Garassino MC. Pembrolizumab plus chemotherapy in lung cancer. N Engl J Med. 2018;379(11):e18.
- Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018;378(22):2078-2092.
- Gadgeel S, Rodriguez-Abreu D, Speranza G, et al. Updated Analysis from KEYNOTE-189: pembrolizumab or placebo plus pemetrexed and platinum for previously untreated metastatic nonsquamous non-small-cell lung cancer. J Clin Oncol. 2020;38(14):1505-1517.
- Gadgeel SM, Garassino MC, Esteban E, et al. KEYNOTE-189: Updated OS and progression after the next line of therapy (PFS2) with pembrolizumab (pembro) plus chemo with pemetrexed and platinum vs placebo plus chemo for metastatic nonsquamous NSCLC. J Clin Oncol. 2019;37(15_suppl):9013.
- Mok TSK, Wu YL, Kudaba I, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet. 2019;393(10183):1819-1830.
- Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378(24):2288-2301.
- West H, McCleod M, Hussein M, et al. Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy compared with chemotherapy alone as first-line treatment for metastatic non-squamous non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(7):924-937.
- Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031.
- Reck M, Schenker M, Lee KH, et al. Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. Eur J Cancer. 2019;116:137-147.
- U.S. Food and Drug Administration. FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥1%). Accessed July 1, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1
- Rizvi NA, Cho BC, Reinmuth N, et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: the MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020;6(5):661-674.
- Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med. 2017;376(25):2415-2426.
- Alexander M, Galeas J, Cheng H. Tumor mutation burden in lung cancer: a new predictive biomarker for immunotherapy or too soon to tell? J Thorac Dis. 2018;10(Suppl 33):S3994-S3998.
- Strosberg J, Mizuno N, Doi T, et al. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study. Clin Cancer Res. 2020;26(9):2124-2130.
- US Food and Drug Administration. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. Accessed July 1, 2020. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-pembrolizumab-adults-and-children-tmb-h-solid-tumors