Lenvatinib/Pembrolizumab/Chemo Induces Inferior OS vs Pembrolizumab/Chemo in Previously Untreated NSCLC

Lenvatinib (Lenvima) plus pembrolizumab (Keytruda), pemetrexed, and carboplatin or cisplatin did not improve treatment outcomes compared with placebo plus pembrolizumab, pemetrexed, and carboplatin or cisplatin when given as first-line therapy in patients with stage IV nonsquamous non–small cell lung cancer (NSCLC) without targetable EGFR or ALK alterations, according to data from the final analysis of the phase 3 LEAP-006 trial (NCT03829319) presented at the 2023 ESMO Immuno-Oncology Annual Congress.

At a data cutoff of August 11, 2023, and a median follow-up of 36.8 months (range, 28.4-46.4), the median overall survival (OS) in the patients who received lenvatinib plus pembrolizumab, pemetrexed, and carboplatin or cisplatin (n = 375) was 21.8 months (95% CI, 18.6-24.0), and the median OS in those who received placebo plus pembrolizumab, pemetrexed, and carboplatin or cisplatin (n = 373) was 22.1 months (95% CI, 19.7-24.2). The 36-month OS rate was 33.0% for patients treated with lenvatinib plus pembrolizumab, pemetrexed, and carboplatin or cisplatin and 22.1% for those treated with placebo plus pembrolizumab, pemetrexed, and carboplatin or cisplatin. The HR was 1.05 (95% CI, 0.88-1.26) with a 1-sided P value of .708.

The median progression-free survival (PFS) at the final analysis was 12.2 months (95% CI, 10.5-15.0) and 9.2 months (95% CI, 8.3-10.7) in patients in the lenvatinib and placebo arms, respectively. The 36-month PFS rate was 21.9% for patients in the lenvatinib arm and 21.5% for those in the placebo arm. The HR was 0.88 (95% CI, 0.74-1.04).

“The efficacy of pembrolizumab, pemetrexed, and carboplatin or cisplatin was consistent with that observed in the pivotal [phase 3] KEYNOTE-189 study [NCT02578680],” Roy S. Herbst, MD, PhD, explained in a presentation of the data. “Pembrolizumab plus pemetrexed and carboplatin or cisplatin remains a standard of care for this population.”

Herbst is an ensign professor of medicine (Medical Oncology), a professor of pharmacology, and deputy director of the Yale Cancer Center in New Haven, Connecticut, as well as chief of Medical Oncology and director of the Center for Thoracic Cancers at Yale Cancer Center and Smilow Cancer Hospital. He also serves as assistant dean for translational research at the Yale School of Medicine.

In KEYNOTE-189, patients with previously untreated stage IV nonsquamous NSCLC without targetable EGFR or ALK alterations derived significant OS, PFS, and overall response rate (ORR) benefits from treatment with pembrolizumab added to pemetrexed and carboplatin or cisplatin vs treatment with pemetrexed and carboplatin or cisplatin alone.

This investigation shifted the treatment paradigm for this patient population, though investigators are still looking to provide better outcomes for patients, Herbst noted in the presentation of the data. The hypothesis that the oral TKI lenvatinib may modulate the tumor microenvironment to an immune-stimulatory state prompted the investigation of this agent in combination with pembrolizumab, pemetrexed, and carboplatin or cisplatin.

Patients were eligible for enrollment onto the randomized, double-blind trial if they presented with histologically or cytologically confirmed stage IV nonsquamous NSCLC; had no indication for EGFR-, ALK-, or ROS1-directed therapy; no prior therapy for stage IV NSCLC; no prior PD-1, PD-L1, or CTLA-4 inhibitor in any setting; provision of a tumor sample for PD-L1 evaluations; and an ECOG performance status (PS) of 0 or 1.

Approximately 714 patients were randomly assigned to the lenvatinib or placebo arms. Patients in the lenvatinib arm received 8 mg of lenvatinib orally once daily, 200 mg of pembrolizumab intravenously every 3 weeks, and 500 mg/m² of pemetrexed intravenously every 3 weeks, plus carboplatin at an AUC of 5 mg/mL/min or cisplatin at 75 mg/m² intravenously every 3 weeks for up to 4 cycles, followed by 8 mg of oral lenvatinib daily plus 200 mg of pembrolizumab intravenously every 3 weeks and 500 mg/m² of pemetrexed intravenously every 3 weeks until disease progression or intolerable toxicity for up to 35 total cycles of pembrolizumab. Patients in the placebo arm received daily oral placebo given with the same pemetrexed and carboplatin or cisplatin therapy combination for up to 4 cycles, followed by daily oral placebo plus 200 mg of pembrolizumab intravenously every 3 weeks and 500 mg/m² of pemetrexed intravenously every 3 weeks, with the same cutoff criterion as the lenvatinib arm.

Notably, patients were stratified by their PD-L1 tumor proportion score (TPS < 50% vs ≥ 50%), geographic region (East Asia vs not east Asia, and ECOG PS (0 vs 1).

The dual primary end points of the study were PFS per RECIST v1.1 criteria by blinded independent central review (BICR) and OS. The secondary end points of the study were ORR and duration of response (DOR) per RECIST v1.1 criteria by BICR; health-related quality of life; and safety.

Of the patients in the lenvatinib arm, the median age was 63 years (range, 18-85); most were male (67.7%); 30.9%, 66.1%, and 0.5% were Asian, White, or other, respectively; 29.6% were from East Asia and 70.4% were from the rest of the world; 36.0% had an ECOG PS of 0; 85.3% were current or former smokers; 13.3% had brain metastases; 16.8% had liver metastases; 1.3% had received prior neoadjuvant therapy; 5.6% had received prior adjuvant therapy; 24.8% had received prior radiotherapy; 6.4% had received prior thoracic radiotherapy; 24.0% had a PD-L1 TPS of 50% or greater; and 82.9% and 16.5% had received prior carboplatin and cisplatin chemotherapy, respectively.

Among the patients in the placebo arm, the median age was 64 years (range, 28-87); most were male (66.2%); 30.6%, 63.5%, and 1.3% were Asian, White, or other, respectively; 30.0% were from East Asia and 70.0% were from the rest of the world; 35.7% had an ECOG PS of 0; 81.0% were current or former smokers; 9.9% had brain metastases; 9.9% had liver metastases; 1.3% had received prior neoadjuvant therapy; 4.3% had received prior adjuvant therapy; 18.5% had received prior radiotherapy; 4.8% had received prior thoracic radiotherapy; 24.4% had a PD-L1 TPS of 50% or greater; and 85.3% and 14.5% had received prior carboplatin and cisplatin chemotherapy, respectively.

In total, 1469 participants were screened, and 748 patients were randomly assigned and included in the intention-to-treat population.

Notably, of the 375 patients allocated to the lenvatinib arm, 373 received at least 1 dose of a study drug, 31 remained on at least 1 study drug at data cutoff, 14 completed the study treatment, and 328 discontinued all study drugs due to adverse effects (AEs; n = 103), complete response (n = 1), physician decision (n = 8), progression (n = 196), withdrawal of consent (n = 15), or another reason (n = 5).

Of the 373 patients allocated to the placebo arm, 372 received at least 1 dose of a study drug, 44 remained on at least 1 study drug at data cutoff, 12 completed the study treatment, and 316 discontinued all study drugs due to AEs (n = 78), physician decision (n = 10), progression (n = 210), withdrawal of consent (n = 16), or another reason (n = 2).

The ORRs were 60.0% (95% CI, 54.8%-65.0%) and 53.6% (95%, 48.4%-58.8%) in the lenvatinib and placebo arms, respectively. In the lenvatinib arm, 53.6% of patients had a partial response, and 6.4% of patients had a complete response. These rates were 44.8% and 8.8%, respectively, in the placebo arm.

The median DOR was 15.8 months (range, 1.6-41.7+) for patients on the lenvatinib arm and 13.7 months (range, 1.2+-41.6+) for those on the placebo arm. The 36-month DOR rates were 34.3% and 28.1% for patients in the lenvatinib and placebo arms, respectively.

Overall, the median duration of any therapy was 10.8 months (range, 0.03-44.5) in patients on the lenvatinib arm and 9.3 months (range, 0.03-44.7) in patients on the placebo arm. The median number of treatment cycles was 15 (range, 1-61) and 13 (range, 1-65) in each respective arm.

Regarding safety, 97.3% and 95.2% of patients on the lenvatinib and placebo arms, respectively, experienced any AEs. On the lenvatinib arm, 69.7% of patients experienced a grade 3, 4, or 5 AE; 37.5% of patients experienced a serious AE; 5.6% of patients experienced an AE that led to death; and 37.3% of patients experienced an AE that led to treatment discontinuation. On the placebo arm, 55.6% of patients experienced a grade 3, 4, or 5 AE; 26.9% of patients experienced a serious AE; 2.7% of patients experienced an AE that led to death; and 27.7% of patients experienced an AE that led to treatment discontinuation.

“There were no unexpected AEs for the combination of lenvatinib, pembrolizumab, pemetrexed, and carboplatin or cisplatin,” Herbst concluded.

Editor’s Note: Dr Herbst has disclosed consulting roles with AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Biodesix, Bolt Biotherapeutics, Bristol Myers Squibb, Cybrexa Therapeutics, eFFECTOR Therapeutics, Eli Lilly, EMD Serono, Genentech/Roche, Genmab, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Loxo Oncology, MSD, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Oncternal Therapeutics, Pfizer, Sanofi, Seattle Genetics, Shire, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Symphogen, Takeda, Tesaro, Tocagen, and WindMIL Therapeutics; advisory board membership with AstraZeneca, Bolt Biotherapeutics, Cybrexa Therapeutics, EMD Serono, I-Mab Biopharma, Immunocore, Infinity Pharmaceuticals, Neon Therapeutics, Novartis, and STCube Pharmaceuticals; research support from AstraZeneca, Eli Lilly, Genentech/Roche, and MSD; and non-executive board membership with Junshi Pharmaceuticals and Immunocore. The LEAP-006 study, as well as medical writing and editorial assistance in support of this presentation, were funded by Eisai Inc. and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

Reference

Herbst RS, Cho BC, Zhou C, et al. Lenvatinib plus pembrolizumab, pemetrexed, and a platinum (len + pembro + chemo) as first-line therapy for metastatic nonsquamous non-small cell lung cancer (NSCLC): phase 3 LEAP-006 study. Ann Oncol. 2023;20(suppl 1):100535. doi:10.1016/iotech/iotech100535