Abundance of immunotherapy combinations leaves treatment selection uncertain in advanced NSCLC

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) with or without 2 cycles of chemotherapy are both appropriate first-line treatment options for patients with advanced non-small cell lung cancer (NSCLC) without actionable alterations, explained Marina Chiara Garassino, MBBS, who added that although PD-L1 expression and histology served as useful stratifying factors in pivotal trials, the paradigm will need to develop more selective strategies. customized as additional checkpoint inhibitors progress through development.

“We have several options for NSCLC, and we don’t have a best option, so we have to talk very carefully with the patient. [about what is best for them]”, Garassino, professor of medicine at the University of Chicago, said in a presentation during the 19th Annual Lung Cancer Winter Conference®a program hosted by Physicians’ Education Resource®LLC.

“We have a lot of scientific layers, but we only talk about genomics or transcriptomics, and we don’t fit all of those layers,” Garassino said. “We need to integrate as much science as possible, perhaps with artificial intelligence, to understand how to go further in this situation.”

In his presentation, Garassino reviewed key results from several trials, including those of CheckMate 227 (NCT02477826), CheckMate 9LA (NCT03215706), POSEIDON (NCT03164616), and CITYSCAPE (NCT03563716).

Check Mate 227

In Part 1 of the Phase 3 CheckMate 227 trial, patients with stage IV or recurrent NSCLC who had not received prior systemic therapy and had no sensitizing effect EGFR known mutations ALK Untreated central nervous system alterations or metastases were randomized 1:1:1 to 1 of 3 arms: nivolumab plus ipilimumab, chemotherapy, or nivolumab. Patients enrolled in Part 1a (n=1189) had PD-L1 expression of at least 1%, and patients in Part 1b (n=550) had PD-L1 expression less than 1%.

Progression-free survival (PFS) in patients with high tumor mutation load (≥ 10 mut/Mb) and overall survival (OS) in patients with at least 1% PD-L1 expression with the combination versus the chemotherapy as co-primary endpoints.

The primary results showed a median PFS of 7.2 months with the combination (n=139) versus 5.5 months with chemotherapy (n=160). The 1-year PFS rates were 42.6% versus 13.2%, respectively (HR, 0.58; 97.5% CI, 0.41-0.81; P 1 The benefit of OS in this population was “less clear than PFS [benefit]said Garassino, with a median OS of 23 months with the combination versus 16.4 months with chemotherapy and 1-year OS rates of 67% versus 58%, respectively (HR, 0.79; 95%, 0.56-1.10).2

At 4 years of follow-up, the combination demonstrated “clear superiority” over chemotherapy in patients with at least 1% PD-L1 expression, Garassino said, with a median OS of 17.1 months. versus 14.9 months, respectively, and OS at 4 years. rate of 29% versus 18%, respectively (HR, 0.76; 95% CI, 0.65-0.90).3 Among patients with at least 50% PD-L1 expression, the OS rate at 4 years was 37% with the combination versus 20% with chemotherapy (HR, 0.66; 95% CI, 0 ,52-0.84).

Although patients with squamous and non-squamous histologies had similar RRs in favor of the association, 32% of patients with non-squamous histology were alive at 4 years versus 20% of patients with squamous histology. Notably, in patients with less than 1% PD-L1 expression, 25% of patients with nonsquamous histology and 22% of patients with squamous histology were alive at 4 years.

CheckMate 9LA

The Phase 3 CheckMate 9LA trial enrolled patients with stage IV or recurrent NSCLC who had not received prior systemic therapy and had no sensitization EGFR mutations or known ALK alterations. Patients were randomized 1:1 to receive nivolumab and ipilimumab plus 2 cycles of chemotherapy (n=361) or 4 cycles of chemotherapy with optional pemetrexed (Alimta) maintenance treatment (n=358).

The operating system served as the primary endpoint.

Primary outcomes showed a median OS of 15.6 months with triplet versus 10.9 months with chemotherapy and 1-year OS rates of 63% versus 47%, respectively (HR, 0.66; 95% CI %, 0.55-0.80).4

With an additional year of follow-up, the 2-year OS rate was 38% with triplet versus 26% with chemotherapy (HR, 0.72; 95% CI, 0.61-0.86).5

“If you look at the results divided by PD-L1 expression of less than 1% and more than 1%, the HRs are superimposable, at 0.67 and 0.70, respectively,” Garassino said, indicating that PD-L1 expression should not be used. as a decisive factor for this scheme.

Conversely, when examining histology, patients with PD-L1 expression less than 1% and scaly histology had an HR of 0.48 and those with PD-L1 expression of at least 1% had an HR 0.70 versus 0.75 and 0.71 in non-scaly patients. , respectively.6


The Phase 3 POSEIDON trial enrolled patients with stage IV NSCLC who had never been treated for metastatic disease and who had no EGFR transfer or ALK alterations. Patients were randomized 1:1:1 to receive durvalumab (Imfinzi) plus chemotherapy, durvalumab plus tremelimumab and chemotherapy, or chemotherapy alone.

PFS and OS with durvalumab plus chemotherapy vs. chemotherapy served as the primary endpoint of the study, with secondary endpoints of PFS and OS with triplet vs. chemotherapy.

Although the co-primary endpoints were statistically negative for the comparison between durvalumab plus chemotherapy and chemotherapy alone, the trial was positive for the comparison between triplet and chemotherapy, reflecting PFS rates at 1 year 26.6% vs 13.1% (HR, 0.72 95% CI, 0.60-0.86; P = 0.00031) and 2-year OS rates of 32.9% and 22.1%, respectively (HR, 0.77; 95% CI, 0.65-0.92; P = .00304).7


The CITYSCAPE Phase 2 trial enrolled patients with stage IV, EGFR and wild-type ALK NSCLC with a PD-L1 tumor proportion score of at least 1%. Patients were randomized 1:1 to receive tiragolumab plus atezolizumab (Tecentriq) or placebo plus atezolizumab.

Objective response rate (ORR) and PFS served as co-primary endpoints.

The trial was positive, reflecting a median PFS of 5.6 months with the combination versus 3.9 months with placebo and 1-year PFS rates of 36.2% versus 21.1%, respectively (HR, 0.62; 95% CI, 0.42-0.91).8 The ORR was 38.8% with the combination versus 20.6% with the placebo.

Notably, patients with at least 50% PD-L1 expression (n=58) benefited the most from the combination, with a 1-year PFS rate of 51% (HR, 0.29; CI 95%, 0.15-0.53) versus 24.9% (HR, 1.07; 95% CI, 0.67-1.71) in patients with PD-L1 expression of 1% at 49% (n=77).

“In this trial, atezolizumab did not perform very well, so it will be very important to see phase 3 trials to assess the true role of tiragolumab. Hopefully, [tiragolumab can] become a new and important agent in the treatment of patients with NSCLC,” said Garassino.

In addition to CITYSCAPE, other data with TIGIT antibodies, including monalizumab, are beginning to emerge, Garassino added.

“In the future, we will see a lot of checkpoint inhibitors in the pipeline, but we [will] we must integrate science because we must move towards more personalized medicine [approach] in the field of immunotherapy,” concluded Garassino.

The references

  1. Hellmann MD, Ciuleanu TE, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational load. N English J med. 2018;378(22):2093-2104. doi:10.1056/NEJMoa1801946
  2. Martinez P, Peters S, Stammers T, et al. Immunotherapy for the first-line treatment of patients with metastatic non-small cell lung cancer. Clin Cancer Res. 2019;25(9):2691-2698. doi:10.1158/1078-0432.CCR-18-3904
  3. Paz-Ares LG, Ramalingam SS, Ciuleanu TE, et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year results from the randomized, open-label, phase 3 CheckMate 227 trial, part 1. J Thorac Oncol. 2022;17(2):289-308. doi:10.1016/j.jtho.2021.09.010
  4. Reck M, Ciuleanu TE, Dols MC, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of doublet platinum-based chemotherapy (chemo) vs. 4 cycles of chemotherapy as first-line therapy (1L) (tx) for non-small cell lung cancer (NSCLC) stage IV/recurrent: CheckMate 9LA. J Clin Oncol. 2020;38(supplement 15):9501. doi:10.1200/JCO.2020.38.15_suppl.9501
  5. Reck M, Ciuleanu TE, Cobo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemotherapy alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): a two-year update from CheckMate 9LA. J Clin Oncol. 2021;39(supplement 15):9000. doi:10.1200/JCO.2021.39.15_suppl.9000
  6. Redman MW. To optimize the efficient and safe deployment of immune checkpoint inhibitors for patients with NSCLC. Presented at the 2021 ASCO Annual Meeting. June 4-8, 2021; virtual.
  7. Johnson ML, Cho BC, Luft A, et al. Durvalumab + tremelimumab + chemotherapy as first-line treatment for mNSCLC: results from the phase 3 POSEIDON study. Presented at: International Association for the Study of Lung Cancer 2021 World Conference on Lung Cancer; September 8-14, 2021; virtual. Summary PL02.01.
  8. Cho BC, Rodriguez-Abreu D, Hussein M, et al. LBA2 – Updated Analysis and Patient-Reported Outcomes (PRO) from CITYSCAPE: A Randomized, Double-Blind, Phase II Study of the Anti-TIGIT Antibody Tiragolumab + Atezolizumab (TA) Versus Placebo + Atezolizumab (PA) as a Treatment for first line for NSCLC PD-L1+. Presented at: ESMO Immuno-Oncology Congress 2021; December 9, 2021; virtual. Presentation LBA2.

Martin E. Berry