Atezolizumab/Cabozantinib Fails to Elicit Benefit Over SOC in Second-line Metastatic NSCLC

Enriqueta Felip, MD, PhD

Second-line treatment with the combination of atezolizumab (Tecentriq) plus cabozantinib (Cabometyx) did not generate a clinical benefit over standard-of-care docetaxel in patients with metastatic non–small cell lung cancer (NSCLC) previously treated with immune checkpoint inhibitors (ICIs) and chemotherapy, according to findings from the phase 3 CONTACT-01 trial (NCT04471428) presented at the 2023 European Lung Cancer Congress.¹

A total of 366 patients were enrolled in CONTACT-01 and randomly assigned to receive 1200 mg of atezolizumab once every 3 weeks plus 40 mg of cabozantinib taken orally once a day, or 75 mg/m² of docetaxel intravenously once every 3 weeks. Crossover was not allowed and the primary end point was overall survival (OS) including key secondary end points progression-free survival (PFS), confirmed objective response rate (ORR), duration of response (DOR), and safety.

Eligible patients had to have an ECOG performance status of 0 or 1, progression on or after an ICI and platinum-based chemotherapy, and the absence of a sensitizing EGFR mutation or ALK fusion oncogene.

In the treatment arm, median OS was 10.7 months (95% CI, 8.8-12.3) vs 10.5 in the control arm (95% CI, 8.6-13.0). Risk of death or progression was 12% (OS HR, 0.88; 95% CI, 0.68-1.16); P = .3668). Median PFS in the treatment arm was 4.6 months (95% CI, 4.1-5.5) vs 4.0 months in the control arm (95% CI, 3.1-4.4). Risk of progression was 26% (PFS HR, 0.74; 95% CI, 0.59-0.92).

Investigators reported a similar ORR in both arms: in the treatment arm, ORR was 11% vs 13.3% in the control arm. Median DOR was 5.6 months in the treatment arm vs 4.3 months in the control arm.

“We have observed no differences in response rate between the 2 arms and no differences in the median duration of response,” Enriqueta Filip, MD, head of the lung cancer unit in the Department of Oncology of Vall d’Hebron University Hospital, Barcelona, Spain, said during a discussion about second-line approaches at the 2023 European Lung Cancer Congress.¹

Safety signals were also similar between the 2 arms, with treatment-related grade 3/4 adverse events (AEs) in the atezolizumab plus cabozantinib arm at 39% vs 13.3% in the docetaxel arm and serious treatment-related AEs at 20% in the atezolizumab plus cabozantinib arm vs 17% in the docetaxel arm.

When reviewing the subgroup analysis of OS, Filip noted that the HR in females was 1.70 vs 0.72 in males. “Is there a similar trend for the PFS hazard ratio in males vs females, and is there more squamous cell carcinoma in males?” asked Filip, noting these subgroups could be investigated further.

Additional analysis also suggested that prior treatment with an ICI for 6 months or more led to a HR of 0.78 vs 1.06 in patients on ICI treatment for less than 6 months.

Reviewing trials in the pre-immunotherapy era, Filip highlighted 2 randomized trials in the second line in patients with NSCLC, which evaluated docetaxel plus nintedanib (Ofev) vs docetaxel (LUME-Lung 1; NCT00805194)² and docetaxel plus ramucirumab (Cyramza) vs docetaxel (NCT01168973),³ respectively.

In LUME-Lung 1, the median OS for the treatment arm was 10.1 months vs 9.1 months in the control arm and in NCT01168973, the median OS in the treatment arm was 10.5 months vs 9.1 months in the control arm.

In the Lung-MAP trial (NCT03971474),⁴ patients were randomized to receive either ramucirumab plus pembrolizumab or investigator's choice standard of care. These patients previously received at least 1 line of anti–PD-1 or anti–PD-L1 therapy, with 100% of patients receiving ICIs for 84 days or more. Median OS was 14.5 months in the treatment arm vs 11.6 months in the control arm.

“In the study presented today, over 60% of patients had been treated with immunotherapy for 6 months or more prior to enrollment,” Filip said. Median OS was 10.7 months in the treatment arm vs 10.5 months in control arm. Emerging strategies in NSCLC are undergoing evaluation in clinical trials in patients who have been previously treated with ICIs and chemotherapy.^5,6

When patients with NSCLC progress on first-line immunotherapy and platinum-based chemotherapy, treatment options remain limited.

“Cabozantinib plus docetaxel did not improve outcomes when compared to docetaxel, so docetaxel or docetaxel plus an anti–angiogenic agent remains the standard of care,” Filip concluded. In the post-ICI and platinum-based chemotherapy scenario, ongoing phase 3 trials are evaluating the role of retreatment with ICI combinations and antibody-drug conjugates while the benefit of prior ICI could be explored further.

References

1. Felip E. Metastatic lung cancer (NSCLC & SCLC): Which 2L Strategy After 1L? Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 60
2. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol. 2014;15(2):143-155. doi:10.1016/S1470-2045(13)70586-2
3. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673. doi:10.1016/S0140-6736(14)60845-X
4. Reckamp KL, Redman MW, Dragnev KH, et al. Phase II Randomized Study of Ramucirumab and Pembrolizumab Versus Standard of Care in Advanced Non-Small-Cell Lung Cancer Previously Treated With Immunotherapy-Lung-MAP S1800A. J Clin Oncol. 2022;40(21):2295-2306. doi:10.1200/JCO.22.00912
5. He K, Berz D, Gadgeel SM, et al. MRTX-500 Phase 2 Trial: Sitravatinib With Nivolumab in Patients With Nonsquamous NSCLC Progressing On or After Checkpoint Inhibitor Therapy or Chemotherapy. J Thorac Oncol. 2023;S1556-0864(23)00158-2. doi:10.1016/j.jtho.2023.02.016
6. Falchook GS, Ribas A, Davar D, et al. Phase 1 trial of TIM-3 inhibitor cobolimab monotherapy and in combination with PD-1 inhibitors nivolumab or dostarlimab (AMBER). J Clin Oncol. 2022;40(suppl 16):2504-2504. doi: 10.1200/JCO.2022.40.16_suppl.2504