The CONTACT-03 is the first randomised, phase III study conducted in patients with cancer to examine the safety and efficacy of rechallenge with a PD-L1 inhibitor following progression on previous PD-(L)1 therapy. The results show an absence of clinical benefit and increased toxicity with continuation of PD-L1 inhibitor use in patients receiving tyrosine kinase inhibitor (TKI) therapy for immune checkpoint inhibitor (ICI)-resistant renal cell carcinoma (RCC), suggesting that routine use of ICI rechallenge outside of clinical trials should be discouraged.

The results are reported at 2023 ASCO Annual Meeting on 5 June in Chicago, IL, US along with a simultaneous publication in The Lancet by Prof. Toni K Choueiri of the Dana-Farber Cancer Institute, Harvard Medical School in Boston, MA, USA, and colleagues.

In patients with advanced RCC, a combination of a PD1 inhibitor and either a second ICI, an antibody against CTLA4, or one of several small molecule inhibitors of the VEGF receptor, have improved clinical outcomes including overall survival (OS). Across many malignancies, the ICI introduction in the frontline setting has led to questions around optimal second-line therapy. In patients with advanced RCC, prospective evidence supports the use VEGF-TKI; cabozantinib has shown potent activity in patients previously treated with contemporary ICI-based regimens while maintaining a manageable safety profile.

VEGF-TKIs seem to be the mainstay of therapy in patients with RCC following progression after ICI, but a potential option is ICI continuation after initial progression. This option is not limited to patients with RCC, as multiple published series document retreatment with ICI after progression in other cancers despite the absence of sufficient evidence from clinical studies. To rigorously assess retreatment with ICI after progression, the study team conducted a phase III study comparing cabozantinib with or without ICI with the PD-L1 inhibitor atezolizumab in the post-ICI setting. Although atezolizumab does not have an approved indication in RCC, it has shown activity as monotherapy in previously untreated patients with advanced RCC and in combination with cabozantinib in patients with RCC previously treated with ICIs.

The CONTACT-03 study evaluated the safety and efficacy of atezolizumab–cabozantinib compared with cabozantinib alone in patients with metastatic RCC who had disease progression during or after previous ICI treatment. It was a multicentre, randomised, open-label, phase III study, performed in 135 study sites in 15 countries in Asia, Europe, North America, and South America. Patients aged 18 years or older with locally advanced or metastatic RCC whose disease had progressed with ICIs were randomly assigned (1:1) to receive atezolizumab (1200 mg intravenously every 3 weeks) plus cabozantinib (60 mg orally once daily) or cabozantinib alone. Randomisation was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk group, line of previous ICI therapy, and RCC histology.

The two primary endpoints were progression-free survival (PFS) per blinded independent central review and OS. The primary endpoints were assessed in the intention-to-treat population and safety was assessed in all patients who received at least one dose of study drug. The study is closed to further accrual.

From 28 July 2020 to 27 December 2021, 692 patients were screened for eligibility, 522 of whom were assigned to receive atezolizumab-cabozantinib (263 patients) or cabozantinib (259 patients). In total, 401 patients (77%) were male and 121 patients (23%) were female. At data cut-off on 3 January 2023, median follow-up was 15.2 months; 171 patients (65%) receiving atezolizumab-cabozantinib and 166 patients (64%) receiving cabozantinib had disease progression per central review or died.

Median PFS was 10.6 months (95% confidence interval [CI] 9.8–12.3) with atezolizumab-cabozantinib and 10.8 months (10.0–12.5) with cabozantinib (hazard ratio [HR] for disease progression or death 1.03, 95% CI 0.83–1.28; p = 0.78). 89 (34%) patients in the atezolizumab–cabozantinib group and 87 (34%) in the cabozantinib group died. Median OS was 25.7 months (95% CI 21.5–not evaluable) with atezolizumab-cabozantinib and was not evaluable (21.1–not evaluable) with cabozantinib (HR for death 0.94 [95% CI 0.70–1.27]; p = 0.69).

Serious adverse events occurred in 126 of 262 patients (48%) treated with atezolizumab-cabozantinib and 84 of 256 patients (33%) treated with cabozantinib; adverse events leading to death occurred in 17 patients (6%) in the atezolizumab-cabozantinib group and 9 (4%) in the cabozantinib group.

The authors concluded that these results should discourage sequential use of ICIs in patients with RCC outside of clinical trials. In an accompanied comment, Drs. Kathryn E Beckermann and Brian I Rini of the Vanderbilt Ingram Cancer Center in Nashville, TN, US wrote that CONTACT-03 was a well conducted randomised study that addressed a clinically relevant question in patients with advanced RCC and used a standard of care control group. The enrolled participants were representative of those with ICI-refractory RCC. One limitation is the small number of patients with previous adjuvant immunotherapy, an emerging population for whom the role for further immunotherapy is in question.

Salvage immunotherapy with alternative mechanisms might be of benefit but will require prospective testing. However, it is possible that individual patient tumours are initially hard-wired as immunotherapy-susceptible or not, suggesting an approach of maximising initial immunotherapy (e.g., combinations of multiple immunotherapy drugs with different mechanisms) rather than sequencing. Consequently, testing novel immunotherapy in a refractory setting might be suboptimal. For example, previous studies in RCC did not show benefit of adding CTLA4 inhibition in patients who did not respond to PD-1 inhibitor monotherapy, but the combination of CTLA4 and PD-1 inhibition is clearly active in immunotherapy-naive patients.

In order not to prematurely reject potentially active novel immunotherapy, the RCC community of investigators, sponsors, patients, and regulatory bodies must accept frontline RCC study designs that incorporate novel drugs and regimens.

There are no wider data from other cancers to support sequenced immunotherapy. Therefore, this rechallenge approach, which was being increasingly adopted in clinical practice, should be avoided until and unless positive data are available. A deeper understanding of immunotherapy resistance mechanisms is needed to design rational studies in this setting.

This study was sponsored by F Hoffmann-La Roche and Exelixis was a study collaborator.