Abundance of Immunotherapy Combinations Leaves Treatment Selection Unclear in Advanced NSCLC

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) with or without 2 cycles of chemotherapy are both appropriate frontline 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 helpful stratification factors in the pivotal trials, the paradigm will need to build out more tailored selection strategies as additional checkpoint inhibitors move through development.

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

“We have a lot of layers of science, but we are speaking just about the genomics or transcriptomics, and we are not matching all these layers,” Garassino said. “We have to integrate as much science as possible, perhaps with artificial intelligence, to understand how to move further in this situation.”

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

CheckMate 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 did not have sensitizing EGFR mutations, known ALK alterations, or untreated central nervous system 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 of less than 1%.

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

Primary findings showed a median PFS of 7.2 months with the combination (n = 139) vs 5.5 months with chemotherapy (n = 160). The 1-year PFS rates were 42.6% vs 13.2%, respectively (HR, 0.58; 97.5% CI, 0.41-0.81; P < .001).¹ The OS benefit in this population was “less clear than the PFS [benefit],” said Garassino, with a median OS of 23 months with the combination vs 16.4 months with chemotherapy and 1-year OS rates of 67% vs 58%, respectively (HR, 0.79; 95% CI, 0.56-1.10).²

At 4 years of follow-up, the combination demonstrated “clear superiority” vs chemotherapy in patients with at least 1% PD-L1 expression, said Garassino, with a median OS of 17.1 months vs 14.9 months, respectively, and 4-year OS rates of 29% vs 18%, respectively (HR, 0.76; 95% CI, 0.65-0.90).³ Among patients with at least 50% PD-L1 expression, the 4-year OS rate was 37% with the combination vs 20% with chemotherapy (HR, 0.66; 95% CI, 0.52-0.84).

Although patients with squamous and nonsquamous histologies had similar HRs favoring the combination, 32% of patients with nonsquamous histology were alive at 4 years vs 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 did not have sensitizing EGFR mutations or known ALK alterations. Patients were randomized 1:1 to nivolumab and ipilimumab plus 2 cycles of chemotherapy (n = 361) or 4 cycles of chemotherapy with optional pemetrexed (Alimta) maintenance (n = 358).

OS served as the primary end point.

Primary results showed a median OS of 15.6 months with the triplet vs 10.9 months with chemotherapy and 1-year OS rates of 63% vs 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 the triplet vs 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,” said Garassino, indicating that PD-L1 expression should not be used as a deciding factor for this regimen.

Conversely, when looking at histology, patients with PD-L1 expression of less than 1% and squamous histology had an HR of 0.48 and those with PD-L1 expression of at least 1% had an HR of 0.70 vs 0.75 and 0.71 in nonsquamous patients, respectively.⁶

POSEIDON

The phase 3 POSEIDON trial enrolled patients with stage IV NSCLC who were treatment naïve for metastatic disease and did not have EGFR mutations or ALK alterations. Patients were randomized 1:1:1 to 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 end point of the study, with secondary end points of PFS and OS with the triplet vs chemotherapy.

Although the co-primary end points were statistically negative for the comparison between durvalumab plus chemotherapy and chemotherapy alone, the trial was positive for the comparison between the triplet and chemotherapy, reflecting 1-year PFS rates of 26.6% vs 13.1% (HR, 0.72; 95% CI, 0.60-0.86; P = .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

CITYSCAPE

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

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

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

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

“In this trial, atezolizumab didn’t perform very well, so it will be really important to see the 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, added Garassino.

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

References

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5. Reck M, Ciuleanu TE, Cobo M, et al. First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA. J Clin Oncol. 2021;39(suppl 15):9000. doi:10.1200/JCO.2021.39.15_suppl.9000
6. Redman MW. Optimizing effective and safe deployment of immune checkpoint inhibitors for patients with NSCLC. Presented at: 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. Abstract PL02.01.
8. Cho BC, Rodriguez-Abreu D, Hussein M, et al. LBA2 - Updated analysis and patient-reported outcomes (PROs) from CITYSCAPE: a randomised, double-blind, phase II study of the anti-TIGIT antibody tiragolumab + atezolizumab (TA) versus placebo + atezolizumab (PA) as first-line treatment for PD-L1+ NSCLC. Presented at: 2021 ESMO Immuno-Oncology Congress; December 9, 2021; virtual. Presentation LBA2.