Cabozantinib/Atezolizumab Combo Misses PFS, OS End Points in ICI-Treated, Advanced RCC

Toni K. Choueiri, MD

The addition of atezolizumab (Tecentriq) to cabozantinib (Cabometyx) did not improve progression-free survival (PFS) or overall survival (OS) compared with cabozantinib alone in patients with advanced renal cell carcinoma (RCC) who previously received treatment with an immune checkpoint inhibitor (ICI), missing the primary end points of the phase 3 CONTACT-03 trial (NCT04338269) that was presented during the 2023 ASCO Annual Meeting.^1,2

Results showed that through central review, the median PFS with the combination was 10.6 months (95% CI, 9.8-12.3) compared with 10.8 months (95% CI, 10.0-12.5) with cabozantinib alone (HR, 1.03; 95% CI, 0.83-1.28; P = .784). The 12-month PFS rates were 44% (95% CI, 38%-50%) and 48% (95% CI, 42%-54%, respectively).

An interim analysis of OS showed a similar trend; the median OS was 25.7 months (95% CI, 25.1-not evaluable [NE]) with the doublet vs NE (95% CI, 21.1-NE) with the monotherapy (HR, 0.94%; 95% CI, 0.70-1.27; P = .690).

“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,” said Toni K. Choueiri, MD, who is the lead study author, director of the Lank Center for Genitourinary Oncology, and medical director of International Strategic Initiatives, at Dana-Farber Cancer Institute, as well as the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, in an oral presentation of the findings. “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 RCC and potentially in other tumor types.”

The use of ICIs in the frontline setting has led to questions surrounding sequencing for the second-line setting, Choueiri explained. Cabozantinib, among other VEGFR TKIs, have demonstrated activity in previously treated patients with ICI-based regimens.^3,4 Rechallenge of PD-1/PD-L1 inhibitors following initial disease progression is becoming an emerging practice in mRCC therapy but this has not been studied in a phase 3 setting.

To assess this practice, investigators launched the phase 3 CONTACT-03 trial, which compared atezolizumab plus cabozantinib with cabozantinib alone in patients with metastatic or advanced clear cell or non–clear cell RCC with or without a sarcomatoid component who had radiographic progression on or after a prior ICI. The immunotherapy must have been given in the immediately preceding line of therapy and could have been given in the adjuvant, first-, or second-line setting as a single agent or for use in combination with another permitted agent.

A total of 522 patients were randomly assigned 1:1 to receive atezolizumab at 1200 mg intravenously (IV) every 3 weeks with cabozantinib at 60 mg daily orally or cabozantinib alone.

Stratification factors included International Metastatic RCC Database Consortium (IMDC) risk group (0 vs 1 to 2 vs 3 or higher), histology (dominant clear cell without sarcomatoid vs dominant non–clear cell without sarcomatoid vs any sarcomatoid), and the most recent line of ICI (adjuvant vs frontline vs second line).

The coprimary end points were independent centrally assessed PFS, and OS. Key secondary end points were investigator-assessed PFS, objective response rate (ORR) both per central review and via investigator, duration of response (DOR) via central review and investigator, and safety.

Regarding baseline characteristics, the median age was 62.5 years (18-89), and 76.9% of patients were male. Most patients were White (82.8%), while 10.7% and 6.6% were Asian and other, respectively. The most recent line of ICI therapy was given in the frontline locally advanced or metastatic setting (52.9%), followed by the second-line setting (46.4%), and in the adjuvant setting (0.4%).

Most patients had dominant clear cell RCC without sarcomatoid histology (78.0%) vs non–clear cell without sarcomatoid (11.7%) and any sarcomatoid (10.2%). A total 62.3% of patients had an IMDC score of 1 to 2 vs 22.6% with a score of 0 and 14.8% with a score of 3 or greater. Patients previously received 0 (36.1%), 1 (62.3%), or 2 prior VEGR TKIs (1.7%).

The most common frontline treatment was nivolumab (Opdivo) plus ipilimumab (Yervoy; 28.8%), followed by sunitinib (Sutent; 28.7%), pazopanib (Votrient; 15.2%), axitinib (Inlyta) plus pembrolizumab (Keytruda; 12.3%), nivolumab (3.1%), avelumab (Bavencio) plus axitinib (2.5%), bempegaldesleukin (Bempeg) plus nivolumab (2.3%), lenvatinib (Lenvima) plus pembrolizumab (1.8%), and sorafenib (Nexavar; 0.8%).

The most common second-line treatment was nivolumab (90.1%), nivolumab plus ipilimumab (2.9%), and axitinib plus pembrolizumab (2.1%). Sunitinib was the sole adjuvant treatment (37.5%).

The lack of PFS difference between the 2 arms was seen across most prespecified subgroups. Although there was a benefit with the combination seen in patients who had a complete or partial response to their prior ICI (HR, 0.76; 95% CI, 0.40-1.43), this was not significant as the confidence interval crossed 1.

The confirmed ORRs via RECIST 1.1 criteria and per central review were 40.5% (95% CI, 34.5%-46.8%) with the combination and 40.9% (95% CI, 34.8%-47.3%) with cabozantinib alone; the complete response (CR) rates were 0% and 2%, respectively. The partial response (PR), stable disease (SD), progressive disease (PD), and not evaluable/missing rates were 40.5% vs 40.2%, 50.6% vs 47.6%, 4.2% vs 5.1%, and 4.6% vs 6.3%, respectively.

At the data cutoff, 50.5% in the combination arm were still responding to treatment vs 52.9% of those in the monotherapy arm. The median DOR was 12.7 months (range, 2.1+ to 22.9+) and 14.8 months (range, 2.3+ to 25.6+), respectively.

When evaluated via investigator review, the ORRs were 38.0% (95% CI, 32.1%-44.2%) with the combination and 41.7% (95% CI, 35.6%-48.0%) with cabozantinib alone; the complete response (CR) rates were 1.5% and 0.8%, respectively. The PR, SD, PD, and not evaluable/missing rates were 36.5% vs 40.9%, 48.3% vs 46.3%, 9.1% vs 6.6%, and 4.6% vs 5.4%, respectively. At the data cutoff, 58.0% of patients who received the combination were still responding to treatment vs 44.4% of those who received cabozantinib alone. The median DOR was NE (range, 2.1+ to 23.2+) and 12.2 months (range, 2.1+ to 25.6+), respectively.

The most common subsequent systemic anticancer treatment was a TKI/VEGF inhibitor in the combination (23.2%) and cabozantinib-alone (24.7%) arms, followed by an mTOR inhibitor (12.9% vs 10.0%, respectively) with everolimus (Afinitor; 12.5% and 10.0%), another ICI (4.6% and 9.3%), chemotherapy (0.8%, each), and an investigational/other agent (0.4% and 1.2%).

Regarding safety, the incidence of any-grade treatment-related adverse effects (TRAEs) was similar in both arms, at 96.2% and 97.3%, respectively. However, grade 3/4 TRAEs occurred in 55.3% of those in the cabozantinib/atezolizumab arm vs 47.3% of those in the cabozantinib-alone arm; deaths due to adverse effects (AEs) occurred in 6.5% and 3.5% of patients, respectively. Three of the deaths in the combination arm were related to treatment; these TRAEs included immune-mediated enterocolitis and renal failure, which were tied to atezolizumab, and intestinal perforation, which was related to cabozantinib. Serious TRAEs occurred in 24.0% of combination-treated patients and 11.7% of those who received the monotherapy.

The most common all-grade AEs were diarrhea (65.3% with the combination vs 70.7% with cabozantinib alone), palmar-plantar erythrodysesthesia syndrome (38.5% vs 41.0%), decreased appetite (38.2% vs 37.9%), hypothyroidism (36.3% vs 37.9%), nausea (29.4% vs 35.9%), asthenia (29.4% vs 29.3%), hypertension (27.5% vs 34.0%), fatigue (27.5% vs 23.8%), increased alanine aminotransferase (23.7% vs 22.3%), increased aspartate aminotransferase (22.9% vs 23.8%), anemia (20.2% vs 18.8%), and decreased weight (17.6% vs 25.0%).

AEs resulted in treatment withdrawal for 15.6% of those on the doublet arm vs 3.9% of those on the monotherapy arm. Toxicities resulted in dose interruption of atezolizumab in 60.7% of patients. AEs resulted in interruption or reduction of cabozantinib in 89.3% of those on the combination arm vs 87.1% of those on the monotherapy arm.

Editor’s Note: Choueiri listed the following disclosures: stock ownership and honoraria with Curesponse, Osel, Pionyr, Precede Bio, and Tempest Therapeutics; consulting or advisory roles with Alkermes, Analysis Group, Aravive, Arcus Biosciences, ASCO, AstraZeneca, Bayer, Bristol-Myers Squibb, Clinical Care Options, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, Gilead Sciences, GlaxoSmithKline, Harborside Press, Infinity Pharmaceuticals, Ipsen, Janssen Oncology, Kanaph Therapeutics, Lancet Oncology, Lilly, Merck, MJH Life Sciences, Navinata Health, NCCN, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Precede Bio, Prometheus, Roche/Genentech, Sanofi/Aventis, Scholar Rock, Tempest Therapeutics, The New England Journal of Medicine, and UpToDate; research funding from Agensys, Arcus Biosciences, AstraZeneca, AVEO, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Eisai, Exelixis, GlaxoSmithKline, Ipsen, Merck, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharma; patents and royalites from Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, ctDNA technologies, and PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response; travel expenses from Alexion Pharmaceuticals, Allegiant, Analysis Group, AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, Merck, MJH Life Sciences, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, The New England Journal of Medicine, and UpToDate; and that medical writing and editorial assistance support may have been funded by communications companiesfunded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, and Parexel.

References

1. Choueiri TK, Albiges L, Tomczak P, et al. Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study. J Clin Oncol. 2023;41(suppl 17):LBA4500. doi:10.1200/JCO.2023.41.17_suppl.LBA4500
2. Atezolizumab plus cabozantinib versus cabozantinib monotherapy for patients with renal cell carcinoma after progression with previous immune checkpoint inhibitor treatment (CONTACT-03): a multicentre, randomised, open-label, phase 3 trial. The Lancet. Published June 5, 2023. doi:10.1016/S0140-6736(23)00922-4
3. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927. doi:10.1016/S1470-2045(16)30107-3
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