Cemiplimab Plus Chemotherapy Approaches EU Approval for PD-L1+ NSCLC

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of cemiplimab-rwlc (Libtayo) in combination with platinum-based chemotherapy as frontline treatment for adult patients with advanced non–small cell lung cancer (NSCLC) with PD-L1 expression of 1% or higher in the European Union.¹

The approval would include patients who are not candidates to receive definitive chemoradiation, whose tumors are metastatic or locally advanced, and who do not harbor EGFR, ALK, or ROS1 aberrations.

The positive opinion is based on data from the phase 3 Study 16113/EMPOWER-Lung 3 trial (NCT03409614). Of the 466 patients enrolled to the trial, 327 had tumors with a PD-L1 expression of at least 1%. In this subgroup, cemiplimab plus chemotherapy (n = 217) resulted in a median overall survival (OS) of 22 months vs 13 months with chemotherapy alone (n = 110) at a median follow-up of 16 months; this translated to a 45% relative reduction in the risk of death (HR, 0.55; 95% CI, 0.39-0.78). With a longer median follow-up of 28 months, cemiplimab/chemotherapy continued to showcase a meaningful survival benefit in this group (HR, 0.51; 95% CI, 0.38-0.69).

The European Commission is anticipated to make a final decision in the coming months.

In November 2022, the FDA approved cemiplimab in combination with platinum-based chemotherapy for adult patients with advanced NSCLC without EGFR, ALK, or ROS1 aberrations.² The decision was also supported by findings from the randomized, multicenter, phase 3 EMPOWER-Lung 3 trial, which enrolled 466 patients with locally advanced NSCLC who were not eligible for surgical resection or definitive chemoradiation or those with metastatic disease who had not received prior systemic treatment for metastatic disease.3 Notably, patients were eligible irrespective of PD-L1 status.

Key exclusion criteria included tumors harboring EGFR, ALK, or ROS1 aberrations; a medical condition in need of systemic immunosuppression; or ongoing or recent autoimmune disease that needed systemic treatment. Those with a history of brain metastases were able to participate if they received adequate treatment and had returned to baseline for at least 2 weeks before undergoing randomization on the trial.

Study participants were randomly assigned 2:1 to receive intravenous (IV) cemiplimab at 350 mg every 3 weeks for 108 weeks in combination with platinum-based chemotherapy every 3 weeks for 4 cycles or IV placebo every 3 weeks plus chemotherapy every 3 weeks for 4 cycles.

Chemotherapy in either arm was comprised of carboplatin area under the curve (AUC) 5 or 6 and paclitaxel at 200 mg/m2; cisplatin at 75 mg/m2 and paclitaxel at 200 mg/m2; carboplatin at AUC 5 or 6 and pemetrexed at 500 mg/m2; or cisplatin at 75 mg/m2 and pemetrexed at 500 mg/m2. Patients with nonsquamous disease who received a pemetrexed-containing regimen were required to have maintenance pemetrexed for the first 4 cycles.

Key stratification factors included histology (squamous vs nonsquamous) and PD-L1 expression (<1% vs 1% to 49% vs ≥50%).

OS served as the major efficacy outcome measure, and additional measures comprised progression-free survival (PFS) and overall response rate (ORR) per blinded independent central review (ICR).

Of the patients enrolled to the trial, 43% had squamous disease, 15% had locally advanced disease, and 7% had a history of brain metastases.¹

The trial was stopped early due to a recommendation issued by the independent data monitoring committee, as it met preset criteria for OS efficacy. Data from the primary analysis published in Nature Medicine in August 2022 showed that at a median duration of follow-up of 16.3 months (interquartile range [IQR], 13.9-19.1) in the investigative arm and 16.7 months (IQR, 14.2-19.0) in the control arm, the addition of cemiplimab chemotherapy (n = 312) resulted in significantly improved OS over chemotherapy alone (n = 154) in the overall population, translating to a 29% relative reduction in the risk of death (HR, 0.71; 95% CI, 0.53-0.93; 2-sided P = .0140).^1,4

The median OS in the investigative and control arms was 21.9 months (95% CI, 15.5-not evaluable [NE]) and 13.0 months (95% CI, 11.9-16.1), respectively. The estimated proportion of patients who were alive at 12 months was 65.7% (95% CI, 59.9%-70.9%) and 56.1% (95% CI, 47.5%-63.8%), respectively.⁴

The study was not powered to evaluate efficacy within predefined subgroups, but numerical improvements in OS were observed in those with squamous and nonsquamous disease. In the squamous subset, the median OS in the cemiplimab and placebo arms was 21.9 months vs 13.8 months, respectively (HR, 0.56); in the nonsquamous subset, these numbers were 15.8 months vs 13.0 months (HR, 0.79). However, follow-up was notably shorter in the nonsquamous group.

The median PFS with cemiplimab plus chemotherapy was 8.2 months (95% CI, 6.4-9.3) vs 5.0 months (95% CI, 4.3-6.2) with chemotherapy alone (HR, 0.56; 95% CI, 0.44-0.70; P < .0001). The estimated proportion of patients receiving cemiplimab who were alive and did not have progressive disease at 12 months was 38.1% (95% CI, 32.4%-43.8%) vs 16.4% (95% CI, 10.5%-23.4%) with chemotherapy alone.

Moreover, cemiplimab plus chemotherapy elicited an ORR of 43.3% (95% CI, 37.7%-49.0%) by ICR vs 22.7% (95% CI, 16.4%-30.2%) with chemotherapy alone. Of those who responded in the investigative arm, 2.6% (n = 8/312) achieved a complete response and 40.7% (n = 127) had a partial response. The median duration of response in the investigative and control arms was 15.6 months (95% CI, 12.4-NE) and 7.3 months (95% CI, 4.3-12.6), respectively.

In 465 patients evaluated for safety in the trial, the toxicities reported in at least 10% of patients included anemia (44%), alopecia (37%), musculoskeletal pain (27%), nausea (25%), fatigue (23%), peripheral neuropathy (21%), hyperglycemia (18%), decreased appetite (17%), increased alanine aminotransferase (16%), increased aspartate aminotransferase (15%), neutropenia (15%), constipation (14%), dyspnea (13%), rash (13%), thrombocytopenia (13%), vomiting (12%), diarrhea (11%), insomnia (11%), decreased weight (11%), and hypoalbuminemia (10%).¹

Twenty-five percent of patients experienced serious toxicities; 5% of these adverse effects led to treatment discontinuation.

References

1. Libtayo (cemiplimab) in combination with chemotherapy receives positive CHMP opinion for the treatment of advanced PD-L1 positive non-small cell lung cancer (NSCLC). News release. Regeneron Pharmaceuticals, Inc. February 24, 2023. Accessed February 24, 2023. https://investor.regeneron.com/news-releases
2. FDA approves cemiplimab-rwlc in combination with platinum-based chemotherapy for non-small cell lung cancer. News release. FDA. November 8, 2022. Accessed February 24, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
3. Libtayo (cemiplimab-rwlc). Prescribing information. Regeneron. November 2022. Accessed February 24, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761097s014lbl.pdf
4. Gogishvili M, Melkadze T, Makharadze T, et al. Cemiplimab plus chemotherapy versus chemotherapy alone in non-small cell lung cancer: a randomized, controlled, double-blind phase 3 trial. Nat Med. 2022;28(11):2374-2380. doi:10.1038/s41591-022-01977-y