Cabozantinib Plus Atezolizumab Does Not Prolong PFS in Advanced RCC

Ming Yin, MD

Cabozantinib (Cabometyx) in combination with atezolizumab (Tecentriq) failed to demonstrate improvement in progression-free survival (PFS) among patients with locally advanced or metastatic clear cell or non-clear cell renal cell carcinoma (mRCC) who progressed during or after immune checkpoint inhibitor (ICI) therapy.¹

The primary end point of the phase 3 CONTACT-03 trial (NCT04338269) was not met with this result. However, the safety profile of the combination was consistent with the known safety of each agent individually. Full findings from the study will be presented during an upcoming medical meeting.

"It is expected that patients may not have good response to ICI after exposure to a prior ICI. It is disappointing to see that adding cabozantinib in this situation did not improve the outcomes compared with cabozantinib alone because there are some evidence that cabozantinib can help to overcome some ICI resistance, Ming Yin, MD, a medical oncologist at the James Comprehensive Cancer Center at The Ohio State University told Targeted Oncology^TM. "It is not known at present how many patients have already received both ICI and TKI prior to randomization. Indeed, if the cancer is already resistant to both ICI and TKI, further treatment with a different ICI or TKI-based therapy may not be very effective due to possible cross-resistance."

An important question raised as a result of the PFS finding of CONTACT-03, is whether PFS is a strong end point for ICI therapy. Moreover, there is intrigue about the pending presentation of results.

Scott Tykodi, MD, PhD

"A role for continued PD1/PDL1 blockade in RCC patients who fail a front-line immune checkpoint inhibitor-containing regimen in not clear in the field. A provocative single arm phase II study of lenvatinib plus pembrolizumab in PD1/PDL1 inhibitor refractory patients showed a provocatively high ORR encouraging speculation there could be synergy between TKI and ICI agents in the ICI refractory setting. The CONTACT-03 study and similarly designed ongoing TiNivo-2 are therefore of high interest. The press release for a negative PFS outcome for CONTACT-03 is certainly disappointing for the synergy concept. However, PFS is often a weak endpoint for ICI therapy and a more complete presentation of the data including response rate, response duration, and ultimately OS will still be interesting to see, Scott Tykodi, MD, PhD, associate professor, Clinical Research Division, Fred Hutch, told Targeted Oncology^TM.

Prior research by Yin et al has shown that combining an ICI like atezolizumab with a tyrosine kinase inhibitor (TKI) like cabozantinib is feasible and safe in patients with later-line RCC. Prior treatment was shown to affect the efficacy of ICI/TKI therapy but had little impact on safety and tolerability.²

In the study, 85 adult patients with RCC were treated with one of 4 ICI regimens, including pembrolizumab (Keytruda), nivolumab (Opdivo), avelumab (Bavencio), or nivolumab plus ipilimumab (Yervoy in combination with 1 of 5 TKIs; sunitinib (Sutent), axitinib (Inlyta), pazopanib (Votrient), lenvatinib (Lenvima), or cabozantinib. Of the 85 patients, 33 patients were treated in the frontline setting and 52 were second-line line or beyond.

"The ICI combinations in mRCC include ICI plus VEGFR TKI or ICI plus ipilimumab (another type of ICI). Both combinations have been approved as 1st line therapy. At least three different ICI/TKI combinations are available, which can be used in all mRCC patients, said Yin. "Although they have not been compared head-to head in clinical trials, they are similar in efficacies but may differ a bit in the toxicity profiles due to the different TKI partners. Nivolumab/ipilimumab provide a different solutions for intermediate/high-risk mRCC patients, which can be better tolerated and may induce long-term remission in patients who achieve complete response."

The median PFS with ICI/TKI therapy was 11.6 months (95% CI, 8.5-14.5 months). In terms of objective response rate (ORR), the rate decreased as prior line of therapy increased. Patients treated in the first-line had a 56.7% ORR while it was 37.5% for second-line, 21.4% for third-line, and 21% for fourth-line and beyond.²

Fifty-two percent of patients who received at least 2 lines of ICI/TKI therapy had grade 3 or 4 adverse events (AEs). The most common grade 3 or higher AEs were anorexia, (13.5%) diarrhea and hypertension (11.5% each), and fatigue (9.6%).

These findings warranted further investigation, which is the rationale behind the global, multicenter, randomized, phase 3, open-label CONTACT-03 study.

"The optimal treatment after the above ICI combinations have not been well established. There is some evidence that ICI/TKI may retain a good efficacy after nivolumab/ipilimumab, but not vice versa," explained Yin.

A total of 522 patients with locally advanced or mRCC. Patients had histologically confirmed disease, measurable disease per RECIST v1.1, archival tumor specimen for biopsy, a Karnofsky performance score of at least 70, as well as adequate hematologic and end-organ function.

In the experimental arm, patients are treated with intravenous (IV) atezolizumab 1200 mg in combination with cabozantinib 60 mg. Atezolizumab is given at a fixed dose on day 1 of each 21-day cycle, every 3 weeks, and cabozantinib is administered orally once daily. In the comparator arm, patients received cabozantinib 60 mg orally once daily.^1,3

As a coprimary end point, CONTACT-03 is assessing overall survival (OS). The key secondary end points being explored in the study include PFS by investigator assessment, ORR by investigator assessment, ORR by independent review facility, duration of ORR by investigator assessment, duration of response by investigator assessment, and safety. The study is also evaluating atezolizumab concentrations, cabozantinib concentrations, the prevalence of anti-drug antibodies, and the incidence of anti-drug antibodies to atezolizumab during the study.

"ICI/TKI regimens have been very successful in the front-line space with 3 separate commonly used ICI/TKI doublets that all have shown survival benefit vs TKI monotherapy [sunitinib]. The question for CONTACT-03 is to explore a role for ICI in the salvage setting. PD1 plus CTLA4 blockade with nivolumab plus ipilimumab has some activity in PD1 blockade refractory patients," explained Tykodi.

"In my mind, that data encouraged a look at other PD-1 combinations in the ICI refractory space. More thorough analyses of the CONTACT 03 data and outcomes for TiNivo-2 will be valuable datasets to help guide best approach to manage RCC patients failing front line doublet regimens," Tykodi added.

_REFERENCES:

_{1. Exelixis provides update on phase 3 CONTACT-03 trial evaluating cabozantinib in combination with atezolizumab in patients with previously treated advanced kidney cancer. March 2, 2023. Accessed March 3, 2023. https://ir.exelixis.com/news-releases/news-release-details/exelixis-provides-update-phase-3-contact-03-trial-evaluating}

_{2. Yang Y, Psutka SP, Parikh AB, et al. Combining immune checkpoint inhibition plus tyrosine kinase inhibition as first and subsequent treatments for metastatic renal cell carcinoma. Cancer Med. 2022;11(16):3106-3114. doi: 10.1002/cam4.4679.}

_{3. A study of atezolizumab in combination with cabozantinib compared to cabozantinib alone in participants with advanced renal cell carcinoma after immune checkpoint inhibitor treatment (CONTACT-03). ClinicalTrials.gov. Updated February 24, 2023. Accessed March 3, 2023. https://clinicaltrials.gov/ct2/show/NCT04338269}