Immunotherapy as first-line treatment in locally advanced/metastatic and previously untreated squamous cell lung cancer: which advances?

Lung cancer is the main cause of death for cancer in the world (1). Non-small cell lung cancer (NSCLC) accounts for 80–85% of lung cancer and the percentage of patients with an advanced diagnosis of NSCLC is approximately one-third (2). Surgical resection is currently the only treatment with curative intent for the early stage of NSCLC. Unfortunately, most NSCLC patients present advanced-stage disease at diagnosis (3). For these patients, platinum-based chemotherapy is the first-line treatment of choice (4,5). However, the prognosis remains poor, with a 5-year survival rate of less than 5% after combined approaches including surgery, radiotherapy, and chemotherapy (6).

In the last years, immunotherapy emerged as a new option for the management of advanced-stage NSCLC. The phase II/III KEYNOTE-010 study showed that pembrolizumab, an immune checkpoint inhibitor (ICI) of the programmed cell death 1 (PD-1) receptor, administered as second line treatment improved overall survival (OS) of patients with programmed death ligand 1 (PD-L1)-positive tumors, who were previously treated with platinum-based chemotherapy (7). Similar results were observed with other ICIs of the PD-1 axis, such as, in CheckMate 227 study, nivolumab and, in the phase III Blood-First Assay Screening Trial (BFAST), atezolizumab (8) when used as second-line treatment in combination with chemotherapy (9). In the IMPOWER110 trial, the Food and Drug Administration approved the use of atezolizumab as a first-line treatment in patients with metastatic NSCLC and PD-L1 expression ≥50% (10).

Then, the results of the phase III KEYNOTE trials confirmed the superiority of Pembrolizumab vs. other ICIs (11). Additionally, further studies investigated if immunotherapy could be extended as first-line therapy in patients with advanced or metastatic squamous NSCLC, without oncogenic driver mutations, naive to previous chemotherapy treatment and with PD-L1 ≥50% (12,13). In this open-label, phase 3 KEYNOTE-024 trial (14), pembrolizumab significantly improved OS compared with platinum-based doublet chemotherapy (30 vs. 14.2 months) in patients with previously untreated advanced NSCLC, with a PD-L1 ≥50% and without EGFR/ALK aberrations. Moreover, pembrolizumab compared to standard chemotherapy was associated with less treatment-related grade 3 to 5 adverse events (31.2% vs. 53.3%, respectively).

Additionally, the phase 3 KEYNOTE-042 study (15) confirmed the superiority of pembrolizumab vs. standard chemotherapy in terms of OS also in patients with low PDL-1 expression and without EGFR/ALK aberrations (15).

Furthermore, the phase III KEYNOTE-407 study evaluated the benefits of a combined first-line treatment option including pembrolizumab plus chemotherapy in previously untreated, advanced squamous NSCLC regardless of PD-L1 expression (16). Five hundred and fifty-nine untreated patients with metastatic squamous NSCLC were randomized into two groups. One received chemotherapy plus pembrolizumab (n=278) and another placebo plus carboplatin chemotherapy plus paclitaxel or nab-paclitaxel (n=281). The analysis’ median follow-up time was 56.9 months (range, 49.9–66.2 months).

Progression-free survival (PFS) and OS were the primary endpoints of this trial. Median PFS improved in the pembrolizumab plus chemotherapy group at independent blinded central review {8 vs. 5.1 months, respectively; hazard ratio (HR), 0.62 [95% confidence interval (CI): 0.52–0.74]; P<0.001}. In detail, median PFS improved in all PD-L1 subgroups: 6.3 vs. 5.9 months; HR, 0.70 (95% CI: 0.52–0.95) in the PD-L1 negative group; 8.2 vs. 6 months; HR, 0.60 (95% CI: 0.45–0.81) in the group with PD-L1 expression in 1–49% on tumor cells; finally, 8.3 vs. 4.2 months; HR, 0.48 (95% CI: 0.33–0.69) in the group of patients with PD-L1 ≥50% showing therefore a remarkable difference (16).

As concern OS, this endpoint showed statistically significant improvement in patients treated with pembrolizumab and chemotherapy, with clinical benefit evident as a median OS of 17.2 vs. 11.6 months, and a 5-year OS of 18.4% vs. 9.7%, HR 0.71 (95% CI: 0.59–0.85), P<0.001. A consistent prolongation of OS of consistent entity was observed in every category of the PD-L1 tumor proportion score (TPS), regardless of the intensity of expression (16). In patients with 1–49% PD-L1, the median OS was 18 in the combination with pembrolizumab arm vs. 13.1 months in the chemotherapy arm with a statistically significant difference at 5 years, reporting OS of 20% vs. 7.6%, HR 0.61 (95% CI: 0.45–0.83), respectively. Similarly, for patients with PD-L1 ≥50%, median OS was 19.9 vs. 11.5 and 5-year OS was 23.3% vs. 8.3%, HR 0.68 (95% CI: 0.47–0.97) (16). Conversely, in PD-L1 negative patients (PD-L1 ≤1) no significant differences were found regarding OS in the two study groups.

The patients in the combination group with pembrolizumab received four cycles of pembrolizumab 200 mg every 3 weeks. Chemotherapy consisted of a maximum of four cycles of administration every 3 weeks. Pembrolizumab or placebo treatment cycles were continued for up to 35 cycles in total until progressive disease (PD) developed. In this trial, crossover from the chemotherapy group to pembrolizumab was allowed. In the pembrolizumab plus chemotherapy group, patients completed 35 cycles of pembrolizumab, subsequently 12 patients received administration of a second cycle of pembrolizumab (16). In fact, it is interesting to note the clear separation of the results showing that the OS curves were in favor of the pembrolizumab arm at the time of data analysis for patients with PD-L1 TPS 1–49% on tumor cells and for the entire study population.

At 5-year follow-up, monotherapy and first-line treatment with pembrolizumab achieved substantially longer OS and prolonged PFS2 (time from random assignment to next PD after next line of treatment or death from any cause) compared to platinum-based chemotherapy treatment (HR, 0.60; 95% CI: 0.50 to 0.72). Five-year PFS2 rates were 18.1% (95% CI: 13.6 to 23.1%) vs. 7.1% (95% CI: 4.4% to 10.7%) in patients with locally advanced/metastatic NSCLC regardless of PD-L1 expression and without EGFR/ALK alterations (16).

Objective response rate (ORR) and duration of response (DOR) were the secondary endpoints. Respectively, the ORR in pembrolizumab plus chemotherapy was 62.2% (56.2% to 68.0%) vs. placebo plus chemotherapy 38.8% (33.1% to 44.8%). The median DOR was in pembrolizumab plus chemotherapy 9.0 (1.31 to 61.51) vs. 4.9 (1.31 to 58.61) months in placebo plus chemotherapy, respectively. Among patients in the chemotherapy group with PD, 117 patients received subsequent therapy with pembrolizumab and another 26 patients switched to subsequent anti PD-(L)1 therapy outside the study for an effective crossover rate of 50.9% (16).

Pembrolizumab had a lower incidence of treatment-related adverse events of any grade than platinum-based chemotherapy either at first treatment or in that subgroup of patients who completed 35 cycles with most patients (69.0%) alive at data cut-off (i.e., about 5 years after random assignment). Grade 3 to 5 adverse events occurred with a slightly greater difference in the pembrolizumab plus chemotherapy group of 74.8% compared to 70% of the placebo plus chemotherapy patients (16).

The key results of the study (16) are summarized in Table 1.

However, the lack of personalized medicine was the main limitation of this study. In fact, the therapeutic decision should be made on an individual basis after a discussion of the relative risks and benefits of the characteristics for individual patients (17). For example, the real clinical benefit of immunotherapy agents in patients with brain metastases undergoing radiotherapy may be questionable due to the poor prognosis and radio-related adverse events (18). If a subject is unstable as a result of a new or progressing brain metastasis(es), the subject will not be eligible for crossover. Only male/female subjects with squamous NSCLC who did not receive prior systemic chemotherapy/anti-cancer treatment for their metastatic NSCLC could be enrolled in the study. Even if the 5-year OS rates were about doubled with pembrolizumab plus chemotherapy compared to placebo plus chemotherapy, approximately a limited number of 560 subjects were enrolled at risk at 5 years.

Additional issues should be addressed in the future. Immunotherapy with pembrolizumab in synergy with another immunotherapy and/or surgery and/or chemotherapy treatment could reshape the treatment of advanced lung cancer from a malignant and intractable disease to a chronic and controllable disease. Yet, in the KEYNOTE-671 study, pembrolizumab could have a role as neoadjuvant treatment for patients with early-stage resectable NSCLC (19). We believe that the selection of patients is crucial and the identification of new strategies to improve PD-L1 predictive value is urgently needed. The evaluation of PD-L1 expression in circulating tumor cells could possibly help in the selection of patients potentially susceptible to this treatment (20).

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.

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