EMPOWER Lung-3 Part 2: empowering options for anti-PD-1 and chemotherapy in non-small cell lung cancer with current landscape and remaining challenges
Introduction
Immune checkpoint inhibitors (ICIs) have significantly improved overall survival (OS) for individuals with non-small cell lung cancer (NSCLC) without a targetable mutation and with high tumor programmed death-ligand 1 (PD-L1) expression (1,2). In recent years, several landmark studies have demonstrated the utility of combining ICIs with chemotherapy in patients with advanced and metastatic NSCLC (3-8).
In the EMPOWER-Lung 3 study, the initial primary analysis showed enhanced OS, progression-free survival (PFS), and overall response rate (ORR) through the combination of cemiplimab with platinum-based doublet chemotherapy. This editorial commentary will focus on the 2-year follow-up results reported in EMPOWER-Lung 3 Part 2 (9).
EMPOWER-Lung Part 2
EMPOWER-Lung 3 was a multi-regional, randomized, double-blind, placebo-controlled phase III trial to compare first-line cemiplimab in combination with platinum-based doublet chemotherapy against chemotherapy with placebo. This trial was designed for patients with metastatic NSCLC or advanced NSCLC ineligible for definitive treatment. A total of 466 patients were randomized 2:1 to receive four cycles investigator’s choice of histology-specific platinum-based chemotherapy and appropriate maintenance with either cemiplimab (n=312) or placebo (n=154) every 3 weeks for up to 108 weeks. This trial excluded patients with ROS1 fusions in addition to alterations in EGFR and ALK, whereas most other first-line ICI trials excluded only the latter two mutations. The EMPOWER-Lung 3 Part 2 study focused on updated outcomes, encompassing a median follow-up period of 28.4 months, extending beyond the primary analysis of 16.4 months (9).
The primary endpoint of EMPOWER-Lung 3 was OS. Continuing the trend, EMPOWER-Lung 3 Part 2 demonstrated sustained improvement in median OS for the cemiplimab arm at 21.1 months [95% confidence interval (CI): 15.9–23.5], compared to 12.9 months (95% CI: 10.6–15.7) in the placebo arm [hazard ratio (HR) =0.65; 95% CI: 0.51–0.82] (9).
The benefits observed across all secondary endpoints (PFS, ORR, and 12-month survival rate) remained statistically significant in the updated analysis for patients receiving cemiplimab. PFS was 8.2 months (95% CI: 6.4–9.0) compared to 5.5 months (95% CI: 4.3–6.2) for placebo. The ORR per independent central review showed a substantial difference at 43.6% (95% CI: 38.0–49.3%) for cemiplimab, in contrast to 22.1% (95% CI: 15.8–29.5%) for placebo. Furthermore, the estimated 12-month proportion of patients alive without disease progression was 38.7% (95% CI: 33.1–44.3%) for cemiplimab and 16.1% (95% CI: 10.5–22.8%) for placebo recipients. Additionally, patients treated with cemiplimab enjoyed a significantly longer median duration of response, reaching 16.4 months (95% CI: 13.1–18.9), while the placebo group had a median of 7.3 months (95% CI: 4.2–11.3) (9).
EMPOWER-Lung 3 Part 2 was stratified based on histology. This trial comprised of 200 (42.9%) squamous and 266 (57.1%) non-squamous patients. For those with squamous NSCLC, the median OS was 22.3 months (95% CI: 15.7–27.2) with cemiplimab, compared to 13.8 months (95% CI: 9.3–18.0) with placebo (HR =0.61; 95% CI: 0.42–0.87). Within the non-squamous NSCLC cohort, the median OS was 19.4 months (95% CI: 14.0–23.5) with cemiplimab, contrasting with 12.4 months (95% CI: 10.1–16.1) with placebo (HR =0.64; 95% CI: 0.47–0.88). Interestingly, in this trial, patients with squamous histology exhibited numerically longer median OS (9).
Aside from histology, this trial specifically examined outcomes based on tumor PD-L1 expression by utilizing the SP263 assay. Among all patients, 152 (32.6%) demonstrated PD-L1 expression of ≥50%, 175 (37.6%) had PD-L1 levels ranging from 1–49%, and 139 (29.8%) had PD-L1 expression below 1%. In patients with PD-L1 expression of ≥1%, treatment with cemiplimab led to significantly improved OS compared to placebo. The HR for death were 0.56 (95% CI: 0.36–0.86) for PD-L1 ≥50% and 0.50 (95% CI: 0.34–0.74) for PD-L1 1–49%. However, for patients with PD-L1 <1%, there was no statistically significant improvement in OS with HR 0.94 (95% CI: 0.62–1.42). Similar to the improvement in OS with cemiplimab, PFS was improved in both ≥50% and 1–49% PD-L1 groups, but only a trend toward improvement in PD-L1 negative patients. Across all three PD-L1 subgroups, the objective response rate (ORR) was numerically higher among patients treated with cemiplimab compared to placebo. Notably, within all PD-L1 subgroups, a range of 2–5% of patients achieved a complete response, while none in the placebo arm achieved such a response (9).
The safety profile of cemiplimab in combination with chemotherapy was comparable to many trials involving ICIs in conjunction with platinum doublets. Notably, Grade 3 or higher treatment-emergent adverse events (TEAEs) were observed in 48.7% of the cemiplimab group and 32.7% in the placebo arm. Cytopenias emerged as the most common side effect in both treatment arms. Sponsor-identified immune-mediated adverse events were recorded in 18.9% of patients receiving cemiplimab, with 2.9% of these events classified as Grade 3 or higher. Within the cemiplimab-treated group, 8.7% of patients succumbed to TEAEs, while 9.2% in the placebo arm. More specifically, in the treatment and control arms, 1.3% and 1.0% of patients, respectively, succumbed to treatment-related adverse events (TRAEs) (9).
How does EMPOWER-Lung 3 Part 2 fit into clinical practice?
EMPOWER-Lung 3 Part 2 added cemiplimab as another choice for ICI therapy in conjunction with platinum-doublet chemotherapy for NSCLC. The benefits of cemiplimab combination therapy were consistent with the outcomes observed in trials that involved the combination of a single ICI agent with platinum-doublet studies. Notably, these trials include Keynote-189 (non-squamous), Keynote-407 (squamous), and IMpower 130 (non-squamous). While direct comparison is lacking, it is reasonable to infer that cemiplimab presents a comparable efficacy and safety profile to pembrolizumab and atezolizumab when combined with histology-specific platinum doublets. It is worth noting that in most phase III trials where a single ICI agent was combined with chemotherapy, there was a consistent and disappointing lack of survival benefit observed in patients with PD-L1-negative tumors (9-11). Additionally, it is also important to mention that these trials were not adequately powered to study the PD-L1 subgroups.
It is crucial to exercise caution when interpreting subgroup analyses and cross-trial comparisons. Interestingly, patients with squamous histology displayed numerically longer median OS in both the cemiplimab and placebo arms, in comparison to those with non-squamous histology. When compared with Keynote-407’s squamous-only patients at the 5-year update, the HR for OS in this study, at 0.61 (95% CI: 0.42–0.87) at 2-year, was numerically lower than Keynote-407’s HR of 0.71 (95% CI: 0.59–0.85) (10). In addition, HR for PFS in EMPOWER-Lung 3 Part 2 was slightly lower at 0.56 (95% CI: 0.41–0.78), compared to the treatment arm in Keynote-407’s HR of 0.62 (95% CI: 0.52–0.74) (9,10). When evaluating patients with squamous NSCLC based on tumor PD-L1 expression, no significant improvement in OS was observed in the PD-L1-negative population. Notably, this study also revealed no significant OS benefit in the population with PD-L1 expression ≥50% (HR =0.77; 95% CI: 0.40–1.45). The subgroup analysis in this study presents a challenge in interpretation, and further research with a larger cohort is necessary to better understand this intriguing signal.
Beyond the single ICI and chemotherapy combination, nivolumab in combination with ipilimumab with or without platinum doublets has displayed a numerically longer OS for patients with squamous histology compared to those with non-squamous histology in Checkmate-227 and Checkmate-9LA. It is plausible that specific combinations of ICIs and chemotherapy could potentially offer greater benefits to patients with squamous histology.
One distinctive demographic characteristic of the EMPOWER-Lung 3 trial was that out of the 466 patients enrolled, a remarkable 391 (83.9%) were male. The high proportion of male participants remained significant when considering the histological composition along with the known association between squamous cell carcinoma in lung cancer and the male sex. Specifically in this trial, squamous histology accounted for 200 (42.9%) of the patients (12). Keynote-407, which exclusively featured patients with squamous histology, had a comparable percentage of male participants at 81.3%. Meanwhile, in Keynote-189 with only non-squamous NSCLC participants, 58.9% of the cohort was male (6). Regarding OS, males in both the Keynote-189 and Keynote-407 trials demonstrated higher HRs compared to females (6,7). However, in the EMPOWER-Lung 3 Part 2 trial, the OS benefit from cemiplimab was only observed in the male subgroup (HR =0.55; 95% CI: 0.42–0.71). The lack of an OS benefit observed in females (HR =0.98; 95% CI: 0.54–1.78) was likely due to the small number of female participants.
In clinical practice, patients harboring sensitizing mutations in EGFR, ALK, and ROS1 should receive appropriate front-line targeted therapy as responses to single-agent ICI in these patients are low (1,13). For those with PD-L1 expression ≥50%, preferred first-line options include monotherapy with pembrolizumab, atezolizumab, or cemiplimab (14-16), allowing patients to avoid the toxicities of chemotherapy. Employing a single ICI in combination with a platinum-doublet regimen is a prudent approach for patients lacking high PD-L1 expression or those facing a high disease burden necessitating swift disease control (1).
Cemiplimab when combined with histology-specific platinum-doublets in the front-line setting as underscored by EMPOWER-Lung 3 Part 2 offers a reasonable option for patients with PD-L1 positive tumors (9). However, the management of patients with NSCLC whose tumors are negative for PD-L1 expression remains a great unmet need. Thus far the only trials to show a consistent benefit in the PD-L1 negative cohort were the Keynote-189, Checkmate-227 and Checkmate 9-LA. Checkmate-227 evaluated ipilimumab and nivolumab, however, this was not the primary analysis population and Food and Drug Administration (FDA) approval for this regimen is limited to patients with positive PD-L1 expression (17). Checkmate-9LA’s evaluation of combined nivolumab and ipilimumab with chemotherapy and intriguingly, the OS for patients with PD-L1 negative tumors was numerically longer than for PD-L1 positive, with median OS 17.7 (95% CI: 13.7–20.3) and 15.8 (95% CI: 13.8–22.2) months, respectively (18). However, it is crucial to note that these trials lacked the sufficient statistical power required for a thorough examination of the PD-L1 subgroups.
Lastly, regimens including dual ICI combinations with chemotherapy in trials like Checkmate-9LA and Poseidon, along with the utilization of bevacizumab in combination with immunochemotherapy in EMPOWER150, have gained approval for patients with NSCLC (Table 1) (8,18,20). Notably, these intensified regimens often come with elevated toxicities (8,18,20,22). However, it is important to note that the target patient population for these regimens remains less clearly defined and often hinges on the expertise and clinical judgment of physicians and institutions.
Table 1
| Trials | Study drug [number of patients] | Histology | PD-L1 for OS | HR (95% CI) | 2-year OS rate vs. control |
|---|---|---|---|---|---|
| EMPOWER-Lung 3 Part 2 (9) | Cemiplimab and platinum-doublet [312] vs. Chemo [154] | Squamous, non-squamous | <1% | 0.94 (0.62–1.42) | 42.7% vs. 27.2% |
| 1–49% | 0.50 (0.34–0.74) | ||||
| ≥50% | 0.56 (0.36–0.86) | ||||
| Checkmate-9LA (18) | Nivolumab, ipiliumab, and platinum-doublet [361] vs. Chemo [358] | Squamous, non-squamous |
<1% | 0.67 (0.51–0.88) | 38% vs. 26% |
| 1–49% | 0.70 (0.53–0.93) | ||||
| ≥50% | 0.75 (0.53–1.07) | ||||
| Checkmate-227 (19) | Nivolumab and ipiliumab [583] vs. Chemo [583] | Squamous, non-squamous |
<1% | 0.62 (0.49–0.79) | 40% vs. 30% |
| 1–49% | 0.94 (0.75–1.18) | ||||
| ≥50% | 0.70 (0.55–0.90) | ||||
| IMpower 130 (5) | Atezolizumab and platinum-doublet [451] vs. Chemo [228] | Non-squamous | <1% | 0.81 (0.61–1.08) | 39.6% vs. 30.0% |
| 1–49% | 0.70 (0.45–1.08) | ||||
| ≥50% | 0.84 (0.51–1.39) | ||||
| IMpower 150 (20) | Atezolizumab, bevacizumab, and platinum-doublet [359] vs. bevacizumab and platinum-doublet [338] | Non-squamous | <1% | 0.90 (0.71–1.14) | 40.9% vs. 30.8%† |
| ≥1% | 0.73 (0.57–0.94) | ||||
| ≥50% | 0.70 (0.46–1.08) | ||||
| Keynote-189 (21) | Pembrolizumab and platinum-doublet [410] vs. Chemo [206] | Non-squamous | <1% | 0.52 (0.36–0.74) | 45.5% vs. 29.9% |
| 1–49% | 0.62 (0.42–0.92) | ||||
| ≥50% | 0.59 (0.39–0.88) | ||||
| Keynote-407 (10) | Pembrolizumab and platinum-doublet [278] vs. Chemo [281] | Squamous | <1% | 0.83 (0.61–1.13) | 36.0% vs. 30.8% |
| 1–49% | 0.61 (0.45–0.83) | ||||
| ≥50% | 0.68 (0.47–0.97) | ||||
| Poseidon (8) | Tremelimumab, durvalumab, and platinum-doublet [338] vs. Chemo [337] | Squamous, non-squamous |
<1% | 0.77 (0.58–1.00) | 32.9% vs. 22.1% |
| ≥1% | 0.76 (0.61–0.95) | ||||
| <50% | 0.82 (0.67–1.00) | ||||
| ≥50% | 0.65 (0.47–0.89) |
†, 2-year OS rate calculated from ITT-WT (no EGFR or ALK alternation). OS, overall survival; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1; HR, hazard ration; Chemo, chemotherapy; ITT-WT, intention-to-treat wild-type; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase.
Conclusions
EMPOWER-Lung 3 Part 2 has demonstrated that the combination of cemiplimab with histology-specific platinum-doublet chemotherapy stands as an efficacious chemoimmunotherapy regimen. This regimen provides a viable alternative to the use of pembrolizumab or atezolizumab when combined with histology-specific platinum-doublet chemotherapy.
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-23-30/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-23-30/coif). D.H.O. reports research funding (to institution) from BMS, Merk, Palobiofarma, Pfizer, Genentech and Onc.AI, which are outside the scope of the current work. G.A.O. served on DSMB member for Novocure LUNAR study, as a speaker of CME talks for OncLive, and also receives research support (to institution) from BMS, Genentech, AstraZeneca, Dizal, Apolomics, Abbvie, Merck and Pfizer. The other author has no conflicts of interest to declare.
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Cite this article as: Li M, Owen DH, Otterson GA. EMPOWER Lung-3 Part 2: empowering options for anti-PD-1 and chemotherapy in non-small cell lung cancer with current landscape and remaining challenges. AME Clin Trials Rev 2023;1:16.
