Survival Benefit Not Seen When ICI is Added to Cabozantinib in mccRCC

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Among patients with metastatic clear cell renal cell carcinoma (mccRCC), findings from a from real-world Flatiron database showed similar survival with the addition of a PD-L1 inhibitor to cabozantinib (Cabometyx, Cometriq) vs cabozantinib alone in the second-line setting, following PD-(L)1 in the first line.¹

These results align with what was found in the phase 3 CONTACT-03 trial (NCT04338269) and strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors.

"The study showed that there is no additional benefit of adding PD-1/L1 inhibitor to cabozantinib compared to cabozantinib alone in second line following PD-1/L1-based therapies in first-line," Umang Swami, MD, assistant professor in the division of oncology, Department of Internal Medicine at Huntsman Cancer Institute, University of Utah, told Targeted Oncology^TM. "These results validate the CONTACT-03 results from a large real-world database and strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors in this setting."

In this study, which researchers note as “the first and largest real-world study to evaluate the effectiveness of adding a PD-1/L1 inhibitor to cabozantinib in patients who have experienced disease progression on prior immune checkpoint inhibitor-based therapies,” investigators aimed to see if the addition of a PD-(L)1 inhibitor to cabozantinib offers any additional benefit in those with mccRCC.

Deidentified patient-level data from a large real-world US-based database was utilized in the study. Those included were those with mccRCC who received any PD-(L)1-based combination in the first line, followed by second-line treatment with cabozantinib monotherapy or with PD-1/L1 inhibitors. The data set consisted of 12,285 patients with metastatic RCC, 348 of whom met eligibility and were therefore included in the analysis.

The end points evaluated in the study included real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by second line.

The study adjusted for patient characteristics and found that combining cabozantinib with PD-(L)1 inhibitors showed similar results to cabozantinib alone as a second-line treatment. The hazard ratios for progression-free survival and overall survival were 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively, meaning there was no statistically significant difference in benefit between the 2 groups.

From the start of second-line therapy, the median rwTTNT was 7.5 months (95% CI, 6.9-8.7) among those given cabozantinib alone vs 12 months (95% CI, 10-not estimable [NE]) for those given a PD-(L)1 inhibitor in addition to cabozantinib. Following propensity score matching weighting, 8.5 months was the median rwTTNT (95% CI, 7.1-12) in the cabozantinib monotherapy arm vs 12 months (95% CI, 10-NE) in the PD-(L)1 inhibitor plus cabozantinib arm.

The median rwOS from the initiation of second-line therapy was 17 months (95% CI, 14-22) and 21 months (95% CI, 12-NE) in the cabozantinib alone and PD-(L)1 inhibitor with cabozantinib arm, respectively. After propensity score matching weighting, the median rwOS was 20 months (95% CI, 16-25) and 21 months (95% CI, 12-31) between arms, respectively.

"The next steps will be to evaluate what other therapies can provide additional or synergistic benefits in combination with VEGF-TKIs in second line after prior treatment with PD-1/L1 based therapies. Some potential strategies may be combining them with HIF inhibitors, other TKIs and antibodies which have activity in clear cell renal cell carcinoma," added Swami.

REFERENCE:

Gebrael G,Jo Y,Mathew Thomas V, et al. Cabozantinib with immune checkpoint inhibitor versus cabozantinib monotherapy in patients with metastatic clear cell renal cell carcinoma progressing after prior immune checkpoint inhibitor. Cancer. 2024;1-8. doi:10.1002/cncr.35302