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Immunotherapy in lung cancer: Update from the year 2020

Dr. Bivas Biswas1, Dr. Sandip Ganguly1

1MD, DM, Department of Medical Oncology, Tata Medical Center, Kolkata- 700160

Phone: +91-9830922005 | +91-033 66057628
Email: bivasbiswas@gmail.com

It’s not new to mention that management of lung cancer, especially non-small cell lung cancer (NSCLC) has changed drastically over the last decade thanks to identification of driver mutations/rearrangements and successful development as well as application of novel targeted therapies. To add that armamentarium immunotherapy, mostly checkpoint inhibitors (ICI), has flooded the field (mostly to those with molecular driver mutation negative tumor) and we have multiple options of ICI either as single agent of combination (chemotherapy or another immunotherapy) in management of lung cancer.

In this update, we will briefly mention those studies, their results & clinical implication that has been presented and/or published in the year 2020.

Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM) [1]

In this open-label, multi-center, single-arm phase two trial patients with resectable stage IIIA NSCLC received neoadjuvant treatment with paclitaxel (200 mg/m2) and carboplatin (6 x AUC) plus nivolumab (360 mg) every three-weekly for three cycles before surgical resection, followed by adjuvant intravenous nivolumab monotherapy for one year. The primary endpoint was progression free survival (PFS) at 24 months. A total of 46 patients were enrolled and received treatment. The 24 months PFS was 77·1% (95% CI 59·9-87·7) and 14 (30%) had treatment-related adverse events of grade - 3 or worse but no death (after median follow-up of 24 months). This study opened a new era of neoadjuvant immunotherapy in resectable NSCLC.

Neoadjuvant durvalumab in resectable non-small cell lung cancer (IFCT-1601 IONESCO) [2]

This was a single arm, multi-center study where 46 eligible patients (stage IB to IIIA, non-N2 NSCLC) received three courses of durvalumab 750 mg (days 1, 15, 29) followed by resection of lung tumor (between day two and 14 after last infusion). Primary endpoint was % of R0 resection. Nine had pneumonectomy, 31 lobectomy, three bilobectomy, and three an exploratory thoracotomy (2 pleural carcinosis; 1 esophageal invasion). The study was stopped because of an excess in 90-day postoperative mortality (four deaths, 9%, one unknown (died at home); two acute respiratory failures; 1 tracheal fistula). 41 patients were R0 (90%) and there was no Grade 3-5 durvalumab related AEs.

Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer [3]

In this open-label, multi-center, single-arm, phase 2 trial, IB-IIIA NSCLC patients received neoadjuvant atezolizumab (1200 mg-d1), nab-paclitaxel (100 mg/m2 on d1,8,15) and carboplatin (5 X AUC-d1) every three-weekly for four cycles followed by surgical resection. The primary endpoint was major pathological response (MPR), defined as the presence of 10% or less residual viable tumor at the time of surgery. 30 patients enrolled; 23 patients had stage IIIA disease and 26 (out of 29) underwent successful R0 resection after a median follow-up period of 12·9 months (IQR 6·2-22·9). Seventeen (57%) of 30 patients had an MPR. There were no treatment-related deaths.

Consolidation pembrolizumab following concurrent chemoradiotherapy (cCTRT) for patients with unresectable stage III NSCLC [4]

This was a single arm phase two study of maintenance pembrolizumab for one-year duration in patients who had non-progressive disease after concurrent chemoradiation in unresectable stage three NSCLC patients. The primary endpoint was the time to metastatic disease or death (TMDD). 93 patients were enrolled and after median follow-up of 32.2 months (range, 1.2-46.6 months), the median TMDD was 30.7 months (95% CI: 18.7 months to not reached). The median PFS was 18.7 months (95% CI, 12.4-33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). Grade-2 or higher pneumonitis was noted in 16 patients (17.2%). Consolidation pembrolizumab after cCTRT improves TMDD, PFS, and overall survival (OS) in comparison with historical controls.

Consolidation ipilimumab and nivolumab after chemo-radiotherapy (CTRT) in limited stage small cell lung cancer (SCLC): Results from the ETOP/IFCT 4-12 STIMULI trial [5]

In this abstract by Solange Peters presented in ESMO 2020, the investigators conducted a phase two study to evaluate efficacy of nivolumab and ipilimumab as consolidation therapy (C) after completion of chemo-radiotherapy in limited stage SCLC patients, if they had non-progressive disease. It was a 1:1 randomized study with observation (O) as control arm and two co-primary endpoints - PFS and OS with superiority design (HR of 0.57). 222 patients enrolled and 153 patients randomized. Two-year PFS rate was 43% and 40% in C and O, respectively. Median OS was not reached in C, while it was 31.6 months in O, HR=1.06 (95% CI: 0.61-1.86), P=0.83. The authors concluded that consolidation with immunotherapy (nivolumab plus ipilimumab) didn’t result in superior outcome compared to observation after CTRT in limited stage SCLC.

Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC [ORIENT] [6]

In this randomized, double-blind, phase three study in China to compare the efficacy and safety of sintilimab (an anti PD-1 antibody) with placebo, both in combination with such chemotherapy (similar to KEYNOTE 189 study design), 397 advanced non-squamous NSCLC patients (negative for EGFR and ALK) were treated with PFS as primary end-point. After a median follow-up of 8.9 months, median PFS was longer in sintilimab combination group over placebo and chemotherapy group ((8.9 versus 5.0 months; HR, 0.482, [95%CI: 0.362-0.643]; p < 0.00001) and better objective response rate (51.9% vs 29.8%). Adverse effects were comparable (grade - 3 or higher AE of 61.7% vs 58.8%, respectively).

Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: CheckMate 153 [7]

Debate exists about the optimum duration of immunotherapy (ICI) during second line setting in advanced NSCLC. This was a largely community-based phase IIIb/IV study to evaluate the impact of one-year fixed-duration versus continuous therapy with nivolumab. Patients who remain non-progressive after one year use of nivolumab were randomized to either continuation of nivolumab or stoppage of the drug (with provision of restarting on progression). After post-random assignment follow-up of 13.5 months in 252 patients, median PFS was longer with continuous versus one year fixed-duration treatment (24.7 months v 9.4 months; HR], 0.56 [95% CI, 0.37 to 0.84]). Median overall survival from random assignment was longer with continuous versus one-year fixed-duration treatment in the PFS (not reached v 32.5 months; HR, 0.61 [95% CI, 0.37 to 0.99]). This was the first prospective study to suggest that continuation of nivolumab beyond one year improves the outcome.

Five year OS update of KEYNOTE 024 study [8]

This was a five-year OS update of the landmark KEYNOTE-024 study of first line pembrolizumab versus platinum based doublet chemotherapy in advanced NSCLC with PDL1 TPS of ≥50%. After 305 patients were randomized and with a median follow-up of 59.9 (55.1e68.4) months, the five-year OS was 31.9% in pembrolizumab group versus 16.3% in chemotherapy group (HR, 0.62 (95% CI: 0.48-0.81). Pembrolizumab continues to show improvements in OS versus chemo as first line treatment for metastatic NSCLC with PD-L1 TPS ≥50%, despite the high crossover rate.

IMpower150: Updated efficacy analysis in patients with EGFR mutations [9]

This was a phase III trial of first line treatment with Atezolizumab (A=1200 mg) with Bevacizumab (B=15 mg/kg) and Carboplatin (C=6 x AUC) and Paclitaxel (P=200 mg/m2) versus BCP and ACP in advanced non-squamous NSCLC patients and ABCP has shown superior PFS and OS over BCP including patients with EGFR mutation (exon 19 deletions or L858R mutations, after first line TKI failure). Out of 1202 patients, 123 patients had EGFR mutations, including 91 (7.5%) with a sensitizing mutation and after median follow-up of 39.3 months, OS was improved with ABCP (median - 29.4 months) vs BCP (median- 18.1 months) in patients with sensitizing EGFR mutations (HR, 0.60 [95% CI: 0.31, 1.14]) and ACP didn’t have any OS advantage over BCP (median of 19.0 vs 18.1 months; HR, 1.0 [95% CI: 0.57, 1.74]). Thus, ABCP regimen may represent a new option for patients with sensitizing EGFR mutations after 1st line EGFR TKI failure.

Pembrolizumab in recurrent or metastatic SCLC: Results from the KEYNOTE-028 and KEYNOTE-158 Studies [10]

It was a pooled analysis of patients from KEYNOTE-028 and KEYNOTE-158 who received pembrolizumab in recurrent or metastatic SCLC in the third line and beyond regardless of PDL1 expression. Data of 83 patients were analyzed with median follow-up of 7.7 (range, 0.5-48.7) months. Overall response rate (ORR) was 19.3% (95% CI: 11.4-29.4). The median duration of response was not reached and 61% of responders had responses lasting 18 months or longer.

REACTION: A phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer [11]

In this phase two study by Benjamin Besse et al. (presented in ESMO 2020), investigators evaluated the benefit of first-line pembrolizumab (P) combined with platinum-etoposide (PE) from cycle three in the subgroup of chemo-sensitive extensive stage-SCLC (ES-SCLC). Patients with ES-SCLC and stable brain metastasis who achieved an objective response to 2 x PE were randomized 1:1 with pembrolizumab vs placebo for two years with next four cycles of PE (total 6 cycles) with primary endpoint of PFS from randomization. Crossover was allowed to P-PE from PE only group. 119 patients were randomized and after median follow-up of 14 months, median PFS (80% CI) was 4.7 months (4.5, 5.3) vs 5.4 (4.9, 5.5), HR = 0.84 (0.65, 1.09) and one-sided P=0.194. Pembrolizumab combined with platinum based chemotherapy was well tolerated but did not improve PFS over only chemotherapy in chemo-sensitive patients with ES-SCLC.

References
  • 1. Provencio M, Nadal E, Insa A, García-Campelo MR, Casal-Rubio J, Dómine M, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicenter, single-arm, phase 2 trial. Lancet Oncol. 2020 Nov;21(11):1413–22.
  • 2. Wislez M, Mazieres J, Lavole A, Zalcman G, Carre O, Egenod T, et al. 1214O Neoadjuvant durvalumab in resectable non-small cell lung cancer (NSCLC): Preliminary results from a multicenter study (IFCT-1601 IONESCO). Ann Oncol [Internet]. 2020 Sep 1 [cited 2021 Jan 23]; 31:S794. Available from: https://www.annalsofoncology.org/article/S0923-7534(20)41412-7/abstract
  • 3.Shu CA, Gainor JF, Awad MM, Chiuzan C, Grigg CM, Pabani A, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicenter, single-arm, phase 2 trial. Lancet Oncol. 2020 Jun;21(6):786–95.
  • 4. Durm GA, Jabbour SK, Althouse SK, Liu Z, Sadiq AA, Zon RT, et al. A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179. Cancer. 2020 Oct 1;126(19):4353–61.
  • 5.Peters S, Pujol J-L, Dafni U, Dómine M, Becker A, Andrade J, et al. LBA84 Consolidation ipilimumab and nivolumab vs observation in limited stage SCLC after chemo-radiotherapy: Results from the ETOP/IFCT 4-12 STIMULI trial. Ann Oncol [Internet]. 2020 Sep 1 [cited 2021 Jan 26]; 31:S1211. Available from: https://www.annalsofoncology.org/article/S0923-7534(20)42408-1/abstract
  • 6.Yang Y, Wang Z, Fang J, Yu Q, Han B, Cang S, et al. Efficacy and Safety of Sintilimab Plus Pemetrexed and Platinum as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC: a Randomized, Double-Blind, Phase 3 Study (Oncology pRogram by InnovENT anti-PD-1-11). J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2020 Oct;15(10):1636–46.
  • 7. Waterhouse DM, Garon EB, Chandler J, McCleod M, Hussein M, Jotte R, et al. Continuous Versus 1-Year Fixed-Duration Nivolumab in Previously Treated Advanced Non-Small-Cell Lung Cancer: CheckMate 153. J Clin Oncol Off J Am Soc Clin Oncol. 2020 Nov 20;38(33):3863–73.
  • 8. Brahmer JR, Rodriguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. LBA51 KEYNOTE-024 5-year OS update: First-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥50%. Ann Oncol [Internet]. 2020 Sep 1 [cited 2021 Jan 24];31:S1181–2. Available from: https://www.annalsofoncology.org/article/S0923-7534(20)42366-X/abstract
  • 9. Reck M, Mok T, Socinski MA, Jotte RM, Lim DW-T, Cappuzzo F, et al. 1293P IMpower150: Updated efficacy analysis in patients with EGFR mutations. Ann Oncol [Internet]. 2020 Sep 1 [cited 2021 Jan 23];31:S837–8. Available from: https://www.annalsofoncology.org/article/S0923-7534(20)41603-5/abstract
  • 10. Chung HC, Piha-Paul SA, Lopez-Martin J, Schellens JHM, Kao S, Miller WH, et al. Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic SCLC: Results From the KEYNOTE-028 and KEYNOTE-158 Studies. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer. 2020 Apr;15(4):618–27.
  • 11. Besse B, Menis J, Bironzo P, Gervais R, Greillier L, Monnet I, et al. LBA85 REACTION: A phase II study of etoposide and cis/carboplatin with or without pembrolizumab in untreated extensive small cell lung cancer. Ann Oncol [Internet]. 2020 Sep 1 [cited 2021 Jan 26];31:S1211–2. Available from: https://www.annalsofoncology.org/article/S0923-7534(20)42418-4/abstract

Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
Editor-in-Chief - Dr. Padmaj Kulkarni