KEYNOTE-189 5-years update: setting a backbone for the next generation clinical research in advanced non-squamous non-small cell lung cancer without oncogenic addiction

Lung cancer represents the first cause of cancer-related death worldwide, with cigarette smoking being still the major risk factor (1). The last 20 years have witnessed a continuous and rapid evolution of systemic treatment paradigms. As a result of seminal research works, the historical dichotomy between small cell lung cancer and non-small cell lung cancer (NSCLC) became outdated, following the discovery that non-squamous (nsqNSCLC) tumors can be treated with pemetrexed-based chemotherapy (2), derive benefit from maintenance chemotherapy (3), and that they are enriched (especially in never-smokers) of genomic alterations leading to dramatic and long-lasting responses upon tyrosine kinase inhibitors therapy (4-7). As the last but not the least, immunotherapy with immune checkpoint inhibitors (ICIs) has unfolded the possibility of long-term benefits even in pre-treated patients with advanced NSCLC without driver mutations (8-10).

Following these encouraging results, ICIs rapidly moved to the front-line setting, initially as single-agent therapy in patients selected according to programmed death ligand 1 (PD-L1) levels of expression. Indeed, the monoclonal antibody (mAb) directed against the programmed death protein 1 (PD-1) pembrolizumab demonstrated to be superior to platinum-based chemotherapy in PD-L1 high [50% tumor proportion score (TPS)] and PD-L1 positive (1% TPS) in treatment-naïve patients with advanced NSCLC, although in the latter trial the benefit was mainly pulled by high expressors (11,12). Subsequent studies showed similar results with other ICIs like cemiplimab and atezolizumab (13,14). Notably, single-agent ICIs therapy is characterized by a small, although clinically significant, excess of patients who develop early disease progression (12). This observation, along with the debatable benefit of single-agent ICIs in treatment-naïve patients with advanced NSCLC with low PD-L1 levels, paved the way to define the role of the association of chemotherapy and anti-PD(L)1. In this scenario, KEYNOTE-189 was a phase 3, randomized (2:1), multicenter, global trial that explored the addition of pembrolizumab/placebo to platinum-pemetrexed chemotherapy in treatment-naïve patients with metastatic, nsqNSCLC without epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) rearrangements (15). Doublet chemotherapy was administered for 4 cycles, while maintenance pemetrexed was allowed until progression/unacceptable toxicity. Pembrolizumab/placebo was administered for up to 35 cycles, with the option to receive a second course pembrolizumab (17 cycles) in the experimental arm at the time of progression. The study primary end-points were progression-free survival (PFS) and overall survival (OS) by blinded, independent central review (BICR). The study showed a meaningful and statistically significant improvement of both PFS [median 8.8 vs. 4.9 months, hazard ratio (HR) 0.52, 95% confidence interval (CI): 0.43–0.64, P<0.001] and OS (median 22 vs. 10.7 months, HR 0.56, 95% CI: 0.45–0.70) favoring the experimental arm (15,16). The percentages of patients with brain metastases are comparable in both treatment arms, with approximately 10% of patients completing 35 cycles of pembrolizumab, indicating encephalic activity of the immunotherapy regimen. Since the first publication of KEYNOTE-189, the triplet regimen has become one of the standards of care for patients with advanced nsqNSCLC without oncogenic addiction. The 5-years update strengthen the role of such regimen as the HR for OS and PFS were 0.60 (95% CI: 0.50–0.72) and 0.50 (95% CI: 0.42–0.60), respectively, favoring the experimental treatment, with 19.4% of patients alive at 5 years in the chemo-immunotherapy arm as compared to 11.3% in the chemotherapy-placebo arm. Notably, the experimental treatment led to higher objective response rate (48.3% vs. 19.9%). Sub-group analyses by PD-L1 expression levels suggest that the survival benefit was present even in patients with PD-L1 low (1–49%) and negative tumors. Of note, adverse events (AEs) were similar between arms and, despite the long follow-up, the rate of immune-mediated AEs did not change significantly. By analyzing patients who completed 35 cycles of pembrolizumab, 54.4% had PD-L1-high tumors (>50%) and all patients experienced at least one AE, 66.7% of grade 3 or 4 (17).

Patients treated with the experimental regimen showed also a PFS2 (defined as time from random assignment to second/subsequent progression on next-line therapy or death from any cause) of 17.0 months (95% CI: 15.0–19.2), compared to 9.1 months (95% CI: 7.6–10.8) of the control arm (HR 0.54, 95% CI: 0.45–0.65), thus confirming that upfront ICI-based regimens have an impact on disease history.

While these updated results confirm the efficacy of chemo-immunotherapy combination in treatment-naïve, advanced, nsqNSCLC patients, a few questions still need to be answered. As KEYNOTE-189 included patients regardless of PD-L1 expression levels, some thoughts should be made on different subgroups. Indeed, to what extent adding chemotherapy (and thus toxicity) is necessary in patients with PD-L1 TPS <50% is debatable. As already mentioned, the addition of chemotherapy seems to avoid the excess of early progressors observed with single-agent ICIs. However, real-world data suggest that a clear survival benefit is unlikely (18,19) and therefore, until ongoing clinical trials such as INSIGNA (NCT03793179) and PERSEE (NCT04547504) would answer this question, the decision on which treatment should be administered in this patient population is made on a case-by-case discussion. Indeed, meta-analyses suggest that factors such as smoking status and possibly sex may be useful in selecting patients for chemo-immunotherapy (never smokers, female sex) despite high PD-L1 expression levels, while also disease burden in association of other mutations like KEAP1, STKII/LKB1 + KRAS, PBRM1, STKII/LKB1 + KEAP1 + SMARCA4 + PBRM1 (20) may be considered (21). In patients with low PD-L1 expression (1–49%), it is still unclear how to accurately identify subgroups that would benefit from either immunotherapy alone or from the combination of chemotherapy and immunotherapy. An FDA pooled analysis of 8 randomized controlled trials showed improved OS for patients with PD-L1 expression between 1–49% treated with immunotherapy plus chemotherapy, compared to those receiving immunotherapy alone (22). Conversely, a retrospective observational study found no significant difference in OS, attributing the discrepancies to small sample sizes, short follow-up periods, shorter treatment durations, and potential differences between the real-world population enrolled and those in clinical trials (23). Still when dealing with toxicity, patients treated in KEYNOTE-189 trial received maintenance pemetrexed in both arms, according to the results of the PARAMOUNT study (3). The median number of pemetrexed cycles in the experimental arm was 9, and 20.7% and 23.8% of those treated with cisplatin or carboplatin-based regimens discontinued pemetrexed due to toxicity in the experimental arm, respectively (15). Notably, 2% of patients in chemo-immunotherapy arm experienced nephritis, most of grade 3 or 4, while this AE was not observed in the control arm (16). Considering these data, it would be of great importance to assess the need of maintenance pemetrexed in patients treated with chemo-immunotherapy combinations. As of today, the only trial that allowed early discontinuation of all cytotoxic drugs in the experimental arm is the CheckMate-9LA that compared platinum-based chemotherapy to 2 cycles of the same doublet plus the anti-PD-1 nivolumab and the anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) ipilimumab for up to 2 years (24). However, only 33% of patients with nsqNSCLC did not receive maintenance pemetrexed in the experimental arm, demonstrating how confident researchers are with this approach. In this trial, nephritis occurred in 1% of patients, mostly of grade 1–2.

Patients with PD-L1 negative tumors derive less benefit from the combination of chemotherapy and anti-PD-(L)1 mAbs (17,25-27). Another possible front-line option in newly diagnosed advanced NSCLC patients without oncogenic drivers is using an association of anti PD-(L)1 and anti-CTLA-4 mAbs alone or in combination with chemotherapy. Indeed, the blockade of CTLA-4 is expected to increase the T-cell repertoire thus improving the likelihood of tumor recognition by the immune system (28). Based on such preclinical evidence, the addition of anti-CTLA-4 mAbs may be a rational choice especially in “cold tumors” such as PD-L1 negative ones. However, even if subgroup analyses of trials investigating anti-CTLA-4-containing regimens are promising, as of today no clear evidence about the preferential use of such combinations in patients with PD-L1 negative NSCLC is available. In conclusion, the 5 years update of the KEYNOTE-189 trial confirms the role of chemo-immunotherapy as the backbone therapy for patients with advanced nsqNSCLC without oncogenic drivers. As this is the standard, next generation clinical trials should be designed to overtake these solid results.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-23-68/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-68/coif). P.B. received honoraria from AstraZeneca, BMS, MSD, Roche, Sanofi, Janssen, Novartis; institutional research grant from Roche, Pfizer; and also served as advisory boards of Janssen, Roche, Pierre Fabre, Regeneron, Seagen. The above are outside of the present work. The other authors have no conflicts of interest to declare.

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