Frontline Pembrolizumab Plus Cabozantinib Elicits Responses in Cisplatin-Ineligible Urothelial Carcinoma

Rohit K. Jain, MD, MPH

The combination comprised of pembrolizumab (Keytruda) and cabozantinib (Cabometyx) was efficacious and had a manageable toxicity profile when used in the first-line treatment of patients with advanced urothelial carcinoma, including those who were ineligible for cisplatin, according to data from the phase 2 PemCab trial (NCT0334804) presented at the 2024 Genitourinary Cancers Symposium.¹

The doublet elicited an objective response rate (ORR) of 45.7% (95% CI, 30.5%-61.8%) in evaluable patients (n = 36), which was comprised of a complete response rate of 14.2% and a partial response rate of 31.4%; 25.7% of patients had a best response of stable disease, 28.5% experienced disease progression, and 1 patient was not evaluable. The clinical benefit rate was 71.4% with the regimen, and 80% of patients experienced tumor shrinkage.

The median time to response was 2.7 months, and at a median follow-up of 20.2 months, the median duration of response (DOR) was 14.7 months. As of their last follow-up in clinic, 8 patients were still in response to treatment. At a median follow-up of 14.3 months, the median progression-free survival (PFS) was 7.6 months (95% CI, 5.3-12.6) and the median overall survival (OS) was 17.1 months (95% CI, 12.6-not reached).

“In this hard-to-treat population consisting of cisplatin-ineligible with high PD-L1 score, cisplatin-refusing, and platinum-ineligible patients [with urothelial carcinoma,] cabozantinib plus pembrolizumab showed encouraging efficacy,” said Rohit K. Jain, MD, MPH, who is assistant member in the Department of Genitourinary Oncology at Moffitt Cancer Center in Tampa, Florida, in a presentation of the data. “However, the trial did not attain the required 17 responses to exclude the 32% lower-bound 95% confidence interval for the ORR.”

There are limited therapeutic options available to patients with cisplatin- and platinum-ineligible locally advanced or metastatic urothelial carcinoma, underscoring an area of unmet need. VEGFR TKIs like cabozantinib, pazopanib (Votrient), and sunitinib (Sutent) have exhibited response rates ranging from 7% to 19% in patients with pretreated metastatic urothelial carcinoma, according to Jain. He added that although phase 3 trial data have indicated that regimens like bevacizumab (Avastin) paired with cisplatin and gemcitabine and ramucirumab (Cyramza) plus docetaxel can prolong PFS, they have not led to significant improvements in OS.

Cabozantinib is a multiple receptor TKI targeting MET, VEGFR2, RET, KIT, and TIE-2, as well as the TAM family of kinases, which comprises TYRO2, AXL, and MER. Preclinical data have indicated that the agent can alter the tumor microenvironment through the downregulation of regulatory T cells and myeloid-derived suppressor cells. Clinical studies have demonstrated that combining cabozantinib with immunotherapy is safe and efficacious in pretreated metastatic urothelial carcinoma and other genitourinary malignancies.

“This investigator-initiated trial was designed in 2017-2018 when pembrolizumab monotherapy was approved for all cisplatin-ineligible patients,” Jain noted. “This later changed to cisplatin ineligible with a high PD-L1 score, defined as a combined positive score [CPS] of 10 or higher, and platinum-ineligible patients. The label was later revised and is now available only to select platinum-ineligible patients. Also, during the conduct of this trial, there were no specific guidelines to determine the platinum ineligibility.”

The study enrolled patients with histologically confirmed, locally advanced or metastatic urothelial carcinoma who had an ECOG performance status of 0 to 2 and a measurable target lesion per RECIST v1.1 criteria. Patients needed have cisplatin-ineligible disease with a PD-L1 CPS of 10 or higher. Cisplatin ineligibility was based on at least 1 of the following: having an estimated creatinine clearance between at least 30 but less than 60 mL/min, an ECOG performance status of greater than 1, hearing loss, or baseline neuropathy that is higher than grade 1. Patients with platinum ineligibility, irrespective of PD-L1 expression, and those who refused cisplatin-based chemotherapy, were also eligible.

Study participants were given pembrolizumab at 200 mg every 3 weeks plus cabozantinib at a daily dose of 40 mg until disease progression, intolerable toxicities, or for up to 2 years.

The primary end point of the study was investigator-assessed ORR utilizing RECIST v1.1 criteria and secondary end points included PFS, OS, DOR, disease control rate, and safety.

“Historically, the ORR of first-line chemotherapy has been around 36% to 38% and 26% [with pembrolizumab] in [patients with] metastatic urothelial carcinoma. Based on these data, we used the 95% [one-sided] exact binomial confidence interval to calculate ORR,” Jain explained. “We estimated that with 35 evaluable patients, the lower bound of the 95% confidence interval [would] extend no more than 26% from the observed proportion. If there [were] 17 or more objective responses in 35 patients, the study [would] be considered positive, and the confidence interval would exclude 32%. We estimated that a total of 39 patients [would need to] be enrolled to get 35 evaluable patients.”

Between December 2018 and April 2023, a total of 36 patients were enrolled in the phase 2 study. The median patient age was 72.5 years (range, 47-82). Most patients were male (77.8%) and more than half of patients had an ECOG performance status of 1 (58.3%). Regarding primary tumor location, 52.8% had upper tract disease and 47.2% had disease in the bladder. Most patients had pure urothelial histology (77.7%) and 22.2% had mixed histology.

Notably, 77.8% of patients had visceral metastases, with 13.8% of patients having liver metastases. Regarding PD-L1 expression, 47.2% of patients had a CPS lower than 10, 22.2% had a CPS of 10 or higher, and this information was not available for 30.6% of patients. “Sixty-nine percent [of patients] were considered cisplatin ineligible due to renal dysfunction,” Jain said. Almost 20% of patients (19.4%) had refused cisplatin-based chemotherapy.

At the time of data cutoff in November 2023, 1 patient was still on treatment. The most common reason for discontinuation was radiological or clinical disease progression (50%), followed by adverse effects (AEs; 22.2%), patient decision (13.8%), death because of disease progression (5.5%), and treatment completion per protocol (5.5%). The median number of cycles of pembrolizumab and cabozantinib received was 10 (range, 1-18) and 7.5 (range, 1-18), respectively.

No new safety signals were observed with the doublet. Most patients (91.6%) experienced at least 1 treatment-emergent AE (TEAE) and 50% had TEAEs that were grade 3 or higher. Two instances of grade 4 AEs related to cabozantinib were observed; these effects included gastrointestinal bleeding and colonic perforation. Moreover, 83% of patients had immune-related AEs (irAEs) with 11% needing high-dose steroids. There were no treatment-related deaths.

Cabozantinib dose interruptions and reductions were needed in 47.2% and 33.3% of patients, respectively; 16.6% of patients discontinued the agent.

The most common TEAEs reported with cabozantinib plus pembrolizumab were fatigue (any grade, 63.9%; grade ≥3, 2.8%), diarrhea (58.3%; 2.8%), palmar-plantar erythrodysesthesia syndrome (41.7%; 5.6%), pruritus (38.9%; 0%), anorexia (33.3%; 5.6%), nausea (33.3%; 2.8%), hypophosphatemia (27.8%; 0%), hypomagnesemia (25.0%; 0%), hypothyroidism (25.0%; 0%), mucositis oral (25.0%; 2.8%), vomiting (25.0%; 0%), hoarseness (22.2%; 0%), proteinuria (13.9%; 5.6%), and a thromboembolic event (8.3%; 8.3%).

“Lenvatinib plus pembrolizumab did not improve outcomes in the phase 3 LEAP-011 trial [NCT03898180] against pembrolizumab. This could suggest that [a selective] TKI with immune-modulating activity targeting the TAM kinases might have better activity in this disease. Indeed, the phase 3 MAIN-CAV trial [NCT05092958] is evaluating the combination of cabozantinib and maintenance avelumab [Bavencio],” Jain concluded. “Further evaluation of cabozantinib and pembrolizumab may be warranted informed by principles of precision medicine. Potentially, a more tolerable and potent VEGF TKI [that is] similar to cabozantinib, zanzalintinib, may be an important direction of investigation to improve the therapeutic index.”

Editor’s Note: Dr Jain disclosed receiving honoraria from Curio Science, DAVA Oncology, FLASCO, and MJH Life Sciences; having a consulting or advisory role for Aveo, Bristol-Myers Squibb, EMD Serono, Gilead Sciences, and Sanofi; being on the Speakers' Bureau for Seattle Genetics/Astellas; receiving research funding from Bristol-Myers Squibb, Gilead Sciences, and the NCI; and having travel expenses paid by DAVA Oncology, FLASCO, and Sanofi.

Reference

Jain RK, Swami U, Bilen MA, et al. Cabozantinib plus pembrolizumab as first-line therapy for cisplatin-ineligible advanced urothelial carcinoma (PemCab). J Clin Oncol. 2024;42(suppl 4):539. doi:10.1200/JCO.2024.42.4_suppl.539