Hope in the fight against lung cancer: new developments in PD-1 and PD-L1 therapies
Lung cancer is the second most common malignancy in the world, and is the leading cause of cancer deaths worldwide. In 2012 there were diagnosed more than 1,8 million new lung cancer cases and lung cancer caused more than 1.6 million deaths. In 2017, 1 688 780 new cancer cases and 600 920 cancer deaths were projected to occur in the United States, and among them the estimated new lung cancer number in 2017 in US was 222 500 and estimated deaths due to lung cancer number was 155 870. [1, 2]
Inhibitors of programed death 1 (PD-1) and its ligand PD-L1 are effective therapies for metastatic non-small-cell lung cancer (NSCLC) without Epidermal Growth Factor Receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations. Pembrolizumab, nivolumab and atezolizumab are currently approved as single agent second-line therapy for NSCLC treatment. Pembrolizumab has replaced cytotoxic chemotherapy in the first-line treatment among patients in whom the percentage of tumor cells with membranous PD-L1 staining is 50 percent or greater. In the first-line setting platinum-doublet chemotherapy has been established as the standard of care in metastatic NSCLC. Response rates after chemotherapy are in the range 25-35 percent, and improvements in survival are small and durable responses are uncommon. Addition of a PD-1 or PD-L1 inhibitor to the first-line chemotherapy (CHTH) regimens may maximize the chance of response and lead to prolonged survival. [3-6]
Promise of combined treatments
Addition of pembrolizumab to first line chemotherapy (carboplatin plus pemetrexed) in the cohort of the open-label phase 2 study KEYNOTE-021 increased significantly the response rate and prolonged progression-free survival (PFS).  Also results of the phase 3 study KEYNOTE-189 published in 2018 confirmed the efficacy of combined treatment (chemotherapy plus pembrolizumab) in first line setting in advanced non-squamous NSCLC without EGFR or ALK alterations.  This study demonstrated an improvement in overall response rate (ORR), PFS, and overall survival (OS) across all groups of patients, irrespective of PD-L1 expression. Median PFS was 8.8 months in the CHTH+pembrolizumab group in comparison with 4.9 months in the CHTH+placebo group (P < 0.001). Pembrolizumab reduced the risk of death by 51 percent when combined with CHTH, versus CHTH alone. Adverse events of grade ≥ 3 occurred in similar group of patients in both arms (67.2 percent in the CHTH+pembrolizumab group and in 65.8 percent in the CHTH+placebo group). Immune-related adverse events (irAE) occurred in 22.7 percent of patients in the CHTH+pembrolizumab group, versus 11.9 percent of patients in the control arm. 
Phase 1b data of atezolizumab+platinum-doublet chemotherapy in first line treatment of NSCLC also demonstrated promising efficacy and tolerability.  Primary PFS and safety analyses of randomized phase 3 study of carboplatin+paclitaxel+/-bevacizumab, with or without atezolizumab, in first line non-squamous metastatic NSCLC (IMpower130) were published in 2017. The OS data are immature but are promising, the median OS after 9.5 months follow-up was 19.2 months in arm B (4-6 cycles of atezolizumab+carboplatin+paclitaxel+bevacizumab with atezolizumab+bevacizumab as maintenance) in comparison to 14.4 months in arm C (4-6 cycles of carboplatin+paclitaxel+bevacizumab with bevacizumab as maintenance) (P = 0.0262). PFS in the subpopulation of patients without EGFR or ALK genetic alterations (87 percent) was 8.3 months in arm B in comparison to 6.8 months in arm C (P < 0.0001). Atezolizumab in combination with chemotherapy ± bevacizumab appears to be well tolerated and its safety profile is consistent with known safety risks. Treatment related grade 3-4 adverse event were reported in 56 percent in arm B and 48 percent in arm C. [8,9]
Also phase 1 CheckMate 012 study confirmed the efficacy and good tolerability of chemotherapy combination with anti-PD1 drug, nivolumab. After 45.5 months follow-up period patients had a median duration of response of 10.4 months, PFS of 6.0 months, median OS 19.2 months and the 3-year OS rate 25 percent.  The phase 3 Checkmate 026 trial comparing nivolumab, against doublet chemotherapy in first line treatment of patients with >1percent PD-L1 expression, failed to meet its endpoint, nivolumab did not improve PFS (4.2 vs 5.9, P= 0.25) or OS (14.4 vs 13.2 months). The combination of nivolumab and another check-point inhibitor ipilimumab improved PFS compared with chemotherapy in treatment-naïve patients NSCLC in phase 3 study CheckMate-227. PFS among patients with a high tumor mutational burden (TMB) was significantly longer with nivolumab plus ipilimumab than with chemotherapy, the median PFS was 7.2 months versus 5.5 months (P < 0.001), the objective response rate was 45.3 percent with nivolumab plus ipilimumab and 26.9 percent with chemotherapy. 
What the future holds
In summary, recent FDA decisions based on the clinical trials results seem to bring significant changes to the landscape of NSCLC and it will be interesting to see the moves of remaining key jurisdictions of the world. PD-1/PD-L1 immunotherapies have recently emerged as an important new treatment option for NSCLC patients. The results of recent phase 3 trials with immune checkpoint inhibitors in the first-line are inconsistent. Despite of that, these are practice-changing data giving new hope to NSCLC patients. There are additionally rapidly emerging data suggesting the importance of TMB as a predictive biomarker for benefit with immunotherapy. This is very important information and new target for future development, taking into consideration that only a minority of all patients with NSCLC respond to this treatment.
Author: Monika Dudzisz-Sledz, MD, PhD, Medical Monitor, KCR
- Siegel RL, Miller KD, Jemal A. Cancer Statistics, Cancer J CLin 2017;67:7-30
- Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5): E359-86.
- Gandhi L, Rodríguez-Abreu D, Gadgeel S et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018; doi: 10.1056/NEJMoa1801005.
- Langer CJ, Gadgeel SM, Borghaei H et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508.
- Opdivo (nivolumab), summary of product characteristics.
- Keytruda (pembrolizumab), summary of product characteristics.
- Tecentriq (atezolizumab), summary of product characteristics.
- Camidge R, Liu SV, Powderly J, et al. Atezolizumab (MPDL3280A) combined with platinum-based chemotherapy in non-small-cell lung cancer (NSCLC): a phase Ib safety and efficacy update. Presented at: 16th World Conference on Lung Cancer; September 6-9; Denver, CO. Abstract 02.07.
- Reck M. Primary PFS and safety analyses of a randomized Phase III study of carboplatin + paclitaxel +/- bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150). Annals of Oncology, 2017;28(11). Abstract LBA1_PR.
- Juergens R, Hellmann M, Brahmer J et al. OA 17.03 First-Line Nivolumab plus Platinum-Based Doublet Chemotherapy for Advanced NSCLC: CheckMate 012 3-Year Update.
- 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; 376:2415-2426.
- Hellmann MD, Ciuleanu TE, Pluzanski A et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018. doi: 10.1056/NEJMoa1801946.
Associate Director, PR & Marketing
mobile: (+48) 605 053 164