Anti-PD-L1 Plus Targeted Agent No Better Than Chemo for Resistant NSCLC

Non-small lung cancer (NSCLC) that progressed on immunotherapy did not benefit from the combination of a PD-L1 inhibitor and a targeted agent versus chemotherapy, a randomized trial showed.

After a minimum survival follow-up of 10.9 months, patients assigned to docetaxel had a median overall survival (OS) of 10.5 months versus 10.7 months with atezolizumab (Tecentriq) and cabozantinib (Cabometyx). Median progression-free survival (PFS) was 4.0 months with docetaxel and 4.6 months with the chemotherapy-free doublet.

Serious adverse events (SAEs), grade 3/4 AEs, and fatal AEs also did not differ significantly between treatment groups, reported Joel Neal, MD, PhD, of Stanford Cancer Institute in California, and co-authors in the Journal of Clinical Oncology.

“The phase III CONTACT-01 study in CPI [checkpoint inhibitor]-experienced metastatic NSCLC investigated whether a tyrosine kinase inhibitor (TKI) could reinvigorate immune response with a cancer immunotherapy after previous treatment failure,” the authors stated. “This study did not meet its primary endpoint of OS.”

“CONTACT-01 does not support the combination of atezolizumab plus cabozantinib after progression on previous CPI and platinum-based chemotherapy,” they added. “We await results of ongoing trials in CPI-refractory NSCLC.”

Patients with squamous NSCLC appeared to benefit from atezolizumab and cabozantinib more than patients with nonsquamous NSCLC, similar to a previous study of pembrolizumab (Keytruda) and ramucirumab (Cyramza), the authors noted. In addition, OS differed between men and women, but imbalances in prognostic factors might have contributed to the difference.

Understanding of resistance mechanisms in NSCLC continues to evolve, and patterns of primary and acquired resistance have emerged, according to the authors of an accompanying editorial.

“Distinguishing these populations is an important first step in designing clinical trials for patients after tumor progression and assessing the efficacy of novel therapies,” noted Ticiana Leal, MD, of Emory University in Atlanta, and co-authors.

Prognostic and predictive biomarkers, beyond PD-L1 are needed, Leal and colleagues continued.

“Several other agents, including monoclonal antibodies … and multikinase inhibitors … have been tested in patients with ICI [immune checkpoint inhibitor]-resistant NSCLC,” they continued. “Given encouraging preliminary activity, this led to the development of phase III trials investigating these combinations with ICI in previously treated patients. Unfortunately, disappointing results of multikinase TKIs plus ICI in patients with NSCLC previously treated with platinum chemotherapy and ICI are consistent across trials versus docetaxel.”

“The results of CONTACT-01 add to the body of evidence that the strategy of combining multikinase inhibitors plus ICI is not efficacious,” Leal and co-authors concluded.

The introduction of immunotherapies has improved survival outcomes in metastatic NSCLC, leading to approval of several agents as first-line treatment, Neal and co-authors noted in their introduction. When disease progresses on anti-PD1/L1 and platinum-containing therapy, options include single-agent chemotherapy or combination treatment with docetaxel and ramucirumab or nintedanib (Ofev).

Cabozantinib is a potent multikinase inhibitor, they continued. In preclinical models, cabozantinib promotes an immune-permissive environment suggesting potential synergistic activity with checkpoint inhibitors. The combination of cabozantinib and atezolizumab produced encouraging preliminary clinical activity in NSCLC with previous CPI exposure.

Continuing the line of research, investigators conducted the CONTACT-01 trial to expand and confirm the preliminary evidence. Eligible patients had radiologic progression of NSCLC after treatment with platinum-containing chemotherapy and an anti-PD1/L1 inhibitor. They were randomized to cabozantinib and atezolizumab or docetaxel, and the primary endpoint was OS.

Data analysis included 352 patients. The results showed a nonsignificant 12% reduction in the survival hazard for the combination arm (95% CI 0.68-1.16, P=0.3668). The 1-year OS was 43.3% with atezolizumab and cabozantinib and 44.1% with docetaxel. In general, treatment effects observed in the intention-to-treat analysis were consistent across most subgroups.

Analysis of PFS revealed a 26% reduction in the PFS hazard favoring the combination but with overlapping confidence intervals. PFS at 6 months (39.5% vs 23.7%) and 12 months (14.7% vs 8.4%) also favored atezolizumab and cabozantinib. Objective response rates were 11.8% with the combination and 13.3% with docetaxel. Duration of response showed another numerical advantage for the combination, 5.6 months versus 4.3 months.

The authors acknowledged several limitations of the study, including use of archival tissue to assess PD-L1 expression (which was not predictive of OS benefit) and the likely combined inclusion of patients with primary and acquired resistance to CPI.