05Jun

Setback in RCC Treatment: CABOMETYX and TECENTRIQ Combo Misses PFS and OS Endpoint in ICI-Treated Patients

Phase III CONTACT-03 trial

During the 2023 ASCO Annual Meeting, the results of the Phase III CONTACT-03 trial (NCT04338269) were presented. This multicenter, randomized, open-label trial aimed to evaluate the efficacy of adding TECENTRIQ (atezolizumab) to CABOMETYX (cabozantinib) in patients with advanced renal cell carcinoma (RCC) who had previously received treatment with an immune checkpoint inhibitor (ICI). Unfortunately, the trial did not meet its primary endpoints, as the addition of atezolizumab did not improve progression-free survival (PFS) or overall survival (OS) compared to treatment with cabozantinib alone.

The trial involved 135 study sites across 15 countries in Asia, Europe, North America, and South America. Eligible patients were 18 or older with locally advanced or metastatic RCC that had progressed with ICIs. The patients were randomly assigned in a 1:1 ratio to receive either atezolizumab (1200 mg intravenously every 3 weeks), cabozantinib (60 mg orally once daily), or cabozantinib alone. The primary endpoints of the trial were assessed in the intention-to-treat population, while safety was evaluated in all patients who received at least one dose of the study drug.

Between July 28, 2020, and December 27, 2021, a total of 692 patients were screened for eligibility, with 522 patients assigned to receive either atezolizumab-cabozantinib (263 patients) or cabozantinib alone (259 patients). Among the patients, 401 (77%) were male, and 121 (23%) were female. At the data cutoff on January 3, 2023, the median follow-up period was 15.2 months (interquartile range 10.7-19.3).

The results showed that 65% of patients receiving atezolizumab-cabozantinib and 64% of patients receiving cabozantinib alone experienced disease progression or died according to the central review. The median progression-free survival was 10.6 months in the atezolizumab-cabozantinib group and 10.8 months in the cabozantinib group. In terms of overall survival, the median was 25.7 months in the atezolizumab-cabozantinib group and not evaluable in the cabozantinib group.

Regarding safety, serious adverse events occurred in 48% of patients treated with atezolizumab-cabozantinib and 33% of patients treated with cabozantinib alone. Adverse events leading to death were reported in 6% of patients in the atezolizumab-cabozantinib group and 4% in the cabozantinib group.

These findings indicate that the addition of atezolizumab to cabozantinib did not provide significant improvements in PFS or OS compared to cabozantinib alone in patients with advanced Renal Cell Carcinoma who had previously received ICI treatment.

 

Atezolizumab + Cabozantinib 

(n = 263)

Cabozantinib

(n = 259)

Centrally reviewed PFS events, n (%)

171 (65)

166 (64)

Median PFS (95% CI), mo

10.6 (9.8, 12.3)

10.8 (10.0, 12.5)

OS events, n (%)

89 (34)

87 (34)

Median OS (95% CI), mo

25.7 (21.5, NE)

NE (21.1, NE)

KOL insights

“The addition of atezolizumab to cabozantinib did not result in improved clinical outcomes in patients with mRCC who progressed on or after prior ICI treatment. These data in my opinion, and the opinion of the investigators, highlight the importance of randomized, prospective assessment of re-challenge with checkpoint inhibitors in Renal Cell Carcinoma and potentially in other tumor types.” –Expert Opinion.

“The information gleaned from CONTACT-03 is the reason phase 3 randomized trials should be done. Atezolizumab may not have been the ideal checkpoint inhibitor to partner with cabozantinib, given its lack of success in multiple randomized phase 3 trials in the metastatic and adjuvant settings. In the end, the takeaway is you may have one effective shot potentially at anti–PD-1 therapy leading to durable benefit in Renal Cell Carcinoma, and it is, therefore, critical to make the most of it as upfront therapy—but it’s not necessarily effective post-progression” –Expert Opinion.

Conclusion

The addition of atezolizumab to cabozantinib did not improve clinical outcomes and led to increased toxicity. These results highlight the importance of randomized, prospective assessment or re-challenge with checkpoint inhibitors in Renal Cell Carcinoma and other tumor types.

In mRCC, prospective evidence supports the use of VEGF receptor tyrosine kinase inhibitors (TKIs), including cabozantinib, in patients previously treated with immune checkpoint inhibitor–based regimens. Although CONTACT-03 failed to meet its primary endpoint, it is nevertheless informative and highlights the importance of randomized, prospective assessment or re-challenge with checkpoint inhibitors in Renal Cell Carcinoma and other tumor types