Lenvatinib and Pembrolizumab Combo Breaks New Ground in Non–Clear Cell RCC

3D rendering of kidney cancer with organs and tumors: © Matthieu - stock.adobe.com

Researchers have been able to better identify the different subtypes of non–clear cell renal cell carcinoma (nccRCC) to provide effective treatment, which was the focus of a presentation by Laurence Albiges, MD, PhD, during the 2024 Kidney Cancer Research Summit held in Boston, Massachusetts, from July 11 to 12, 2024.¹ Albiges provided insight into effective treatments for specific nccRCC subtypes: papillary, chromophobe, translocation, fumarate hydratase (FH) deficient, renal medullary, collecting duct, and unclassified.

“The good news is that we have more and more specific information on the [approaches available] for different entities. The caveat is that these are small numbers of patients, and it’s not easy to draw any definitive conclusion,” Albiges, department head of oncology at Gustave Roussy in Villejuif, France, said in a presentation of the data.

Papillary RCC

For those with papillary RCC, Fitzgerald et al showed that 32 patients treated with the combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) had an overall response rate (ORR) of 47% and a median progression-free survival (PFS) of 13 months.² Similarly, the combination of lenvatinib (Lenvima) and pembrolizumab (Keytruda) resulted in an ORR of 54% and a median PFS of 17.4 months.³

“In terms of overall survival [OS], we are also seeing a difference, because 10 years ago the median OS was in the range of 1 to 1.5 years. With lenvatinib/pembrolizumab data at the 18-month mark, we have an OS rate that is above 70%,” Albiges explained. “I believe that even though these are not randomized data, we have a strong body of evidence on these combinations and have been able to push the bar for papillary RCC.”

In addition, when using the MET-driven approach for papillary RCC, the combination of durvalumab (Imfinzi) plus savolitinib (Orpathys) when administered to 27 patients resulted in an ORR of 53%, a median PFS of 12 months, and a median OS of 27.4 months.⁴ “We have been making progress in defining biomarker-based strategy, and the MET-driven approach has helped pave the road,” Albiges noted.

Chromophobe RCC

Regarding chromophobe RCC, Albiges showed data on the combinations of lenvatinib/everolimus (Afinitor) (n = 9) and lenvatinib/pembrolizumab (n = 29), which reported an ORR of 44% vs 34.5%, respectively, and a median PFS of 13.1 months and 26.2 months, respectively. In a retrospective analysis, investigators were able to pull together multi-institutional reports from 99 patients with metastatic chromophobe RCC receiving first-line systemic therapy.⁵ “The bottom line is that it’s very likely that [for] chromophobe [RCC], single agent may not be the [solution for] major results, and [instead] we want to work toward a combination,” Albiges said.

Translocation RCC

Treatment with immuno-oncology (IO) plus tyrosine kinase inhibitor (TKI) appears to provide the most efficacy for translocation RCC. When comparing cabozantinib (n = 31) vs an IO-IO (n = 18) vs an IO-TKI combination (n = 11), the ORR was 17%, 6%, and 36%, respectively, and the median OS was 17, 17.8, and 30.7 months, respectively.^6-8

“IO-TKIs, including [in] the lenvatinib/ pembrolizumab data, seem to be the ones that have the highest response rates in the range of 25%. We need to generate more data for this specific patient population, but I urge you to treat them with [a] combination approach,” Albiges said.

FH-Deficient RCC

Erlotinib (Tarceva) (150 mg daily) and bevacizumab (Avastin) (10 mg/kg every 2 weeks) resulted in an ORR of 64% and a median PFS of 21.1 months for those with FH-deficient (hereditary leiomyomatosis) RCC. Real-world data show that the median OS is 44 months; however, the field is moving toward triplets in a phase 2 study (NCT04981509), adding atezolizumab (Tecentriq) to erlotinib and bevacizumab, Albiges explained.⁹

Renal Medullary RCC

For patients with renal medullary RCC, platinum-based chemotherapy is standard and in a cohort of 45 patients receiving platinum- based therapy the ORR was 29% and the OS was 13 months.¹⁰ However, “there is more work [to do], especially here in the US,” Albiges noted.”

Collecting Duct Carcinoma

Regarding collecting duct carcinoma, Albiges concluded, “We had the prospective trial [that] took us 4 years and 18 centers to enroll 34 patients…. The study did not meet the predefined end points that adding bevacizumab [to gemcitabine (Gemzar) plus platinum-based chemotherapy] would increase both the PFS and OS. Today, there is no added value of bevacizumab to combination chemotherapy.”¹

Unclassified RCC

3D render of genitourinary system: © Leo Viktorov - stock.adobe.com

In unclassified RCC, patients treated with both cabozantinib/nivolumab and lenvatinib/pembrolizumab combinations reported 50% ORR rates, Albiges said. “We want to make sure they get access to at least 2 different classes of drugs,” she added.

There are remaining gaps in papillary RCC that data from 3 pending trials hope to fill: the phase 3 PAPMET2 trial (NCT05411081), the phase 2 PAXIPEM trial (NCT05096390), and the phase 3 SAMETA trial (NCT05043090). For all patients with nccRCC, there are 2 pending trials that are expected to report soon: the phase 2 SUNNIFORECAST trial (NCT03075423) and the phase 3 STELLAR-304 trial (NCT05678673).¹

“Although we have pending trials, I think we need more information about adjuvant strategies and how we should treat patients beyond a single TKI. I have not shown second-line data because we don’t have these, and there are many questions about the strategy we should adopt regarding primary treatment for these patients,” Albiges concluded.

REFERENCES:

1. Albiges L. Strategies for patients with non–clear cell RCC. Presented at: 2024 Kidney Cancer Research Summit; July 11-12, 2024; Boston, MA.

2. Fitzgerald KN, Lee CH, Voss MH, et al. Cabozantinib plus nivolumab in patients with non-clear cell renal cell carcinoma: updated results from a phase 2 trial. Eur Urol. doi:10.1016/j.eururo.2024.04.025

3. Voss MH, Gurney H, Atduev V, et al. First-line pembrolizumab plus lenvatinib for non–clear cell renal carcinomas (nccRCC): extended follow-up of the phase 2 KEYNOTE-B61 study. J Clin Oncol. 2024;42(suppl 4):2. doi:10.1200/JCO.2024.42.4_suppl.2

4. Suárez C, Larkin JMG, Patel P, et al. Phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). J Clin Oncol. 2023;41(14):2493-2502. doi:10.1200/JCO.22.01414

5. Doshi SD, Dizman N, Knezevic A, et al. A multi-institution analysis of outcomes with first-line systemic therapy for 99 patients with metastatic chromophobe renal cell carcinoma. J Clin Oncol. 2024;42(suppl 16):4512. doi:10.1200/jco.2024.42.16_suppl.4512

6. Thouvenin J, Alhalabi O, Carlo M, et al. Efficacy of cabozantinib in metastatic MiT family translocation renal cell carcinomas. Oncologist. 2022;27(12):1041-1047. doi:10.1093/oncolo/oyac158

7. Alhalabi O, Thouvenin J, Négrier S, et al. Immune checkpoint therapy combinations in adult advanced MiT family translocation renal cell carcinomas. Oncologist. 2023;28(5):433-439. doi:10.1093/oncolo/oyac262

8. Bakouny Z, Sadagopan A, Ravi P, et al. Integrative clinical and molecular characterization of translocation renal cell carcinoma. Cell Rep. 2022;38(1):110190. doi:10.1016/j.celrep.2021.110190

9. Montenegro GLB, Sharon E, Pickett-Gies CA, et al. A phase 2 study of bevacizumab, erlotinib, and atezolizumab in subjects with advanced hereditary leiomyomatosis and renal cell cancer (HLRCC) associated or sporadic papillary renal cell cancer (pRCC). J Clin Oncol. 2022;40(suppl 16):TPS4604. doi:10.1200/jco.2022.40.16_suppl.tps4604

10. Shah AY, Karam JA, Malouf GG, et al. Management and outcomes of patients with renal medullary carcinoma: a multicentre collaborative study. BJU Int. 2017;120(6):782-792. doi:10.1111/bju.13705