Risk Group Data Raises Questions on Choice of Frontline Therapy in RCC

Manojkumar Bupathi, MD, MS (Moderator)

Associate Director

Genitourinary Cancer Research

Sarah Cannon Research Institute at Rocky Mountain Cancer Centers I The US Oncology Network

Denver, CO

DISCUSSION QUESTION

• What are your perspectives on the final overall survival (OS) data and the updated analysis by renal cell carcinoma (RCC) risk group of CheckMate 9ER (NCT03141177)?

BENJAMIN TEPLY, MD: This OS benefit is driven by [patients with] intermediate or poor risk, and so this is a great option for those patients.¹ In the subgroup that was presented with favorable risk, the HR was greater than 1.0 for cabozantinib [Cabometyx] plus nivolumab [Opdivo], so it's unclear whether…it's required for the favorable-risk patients. But certainly for immediate or poor risk, [there is] substantial survival benefit.

MANOJKUMAR BUPATHI, MD, MS: If…you look at the [patients by their] baseline IMDC [International Metastatic RCC Database Consortium] prognostic group, in the forest plot it crosses 1.0 for patients with [a score of] 0.2 There was benefit in patients who have…[a score of] 1 to 2 as well as 3 to 6 in terms of risk status for cabozantinib/nivolumab, comparing it with sunitinib. All the other features seem to be pretty similar overall otherwise.

[For] OS by subgroup, at the 33-month median follow up in the final OS, most of these categories it seems like it favors cabozantinib/nivolumab in general, and this is according to the predefined or the post-hoc subgroup at baseline.²

Looking at the PFS [progression-free survival] and OS by IMDC risk group at the 44-month follow up, the combined data for the intermediate-risk groups is new. How did the PFS amd OS HRs for favorable risk impact your opinion on TKI [tyrosine kinase inhibitor] plus immune checkpoint inhibitor [ICI] versus TKI alone? Dr Teply has commented on this highlighting the point that [these data may suggest] you may not need doublet therapy all the time in patients who have favorable risk. Does anyone else have thoughts?

RADHAKRISHNA VEGUNTA, MD: Do you have data for other combinations like lenvatinib [Lenvima] plus pembrolizumab [Keytruda] and axitinib [Inlyta] plus pembrolizumab?

BUPATHI: It was all broken down by subgroup analysis that it showed benefit. It seems to be all these trials were slightly different, but it seems like there could be some benefit across all 3 [risk groups] in using pembrolizumab/axitinib as well as pembrolizumab/lenvatinib [Lenvima].^3,4

SHAKER DAKHIL, MD: The NCCN [National Comprehensive Cancer Network] guidelines did not recommend a TKI alone.⁵

BUPATHI: No. The NCCN guideline for this is a category 1 recommendation for using IO/TKI.

DAKHIL: Even for the favorable-risk group?

BUPATHI: For favorable risk, that’s correct. This [subgroup analysis] was presented at ASCO GU [2023 American Society of Clinical Oncology Genitourinary Cancers Symposium].¹

DAKHIL: Unless they changed the NCCN Guidelines [I would not use single agent]; in our group, we follow NCCN.

RABIH FAHED, MD: It’s a subgroup analysis, so the study was not powered to prove or disprove the benefit in each single group. I’ll take it as hypothesis generating. When it comes to all-comers, the intent-to-treat [ITT] population, supported by NCCN guidelines, the combination is approved in all risk groups and that’s what we see.

BUPATHI: That is fair. This was presented [at 2023 ASCO GU] so it’s hard to say. It sounds like no one will change their pattern or practice or anything just based on what we’re showing from these data.

SAKEER HUSSAIN, MD: Is there any disadvantage of using single-agent TKI when the patient’s disease progresses, and you have to choose.

BUPATHI: I don’t know that there’s a specific disadvantage of using a TKI up front. It just comes down to which TKI you’re using, and what the adverse events look like. I think you’re going to see a difference of opinion in terms of which TKI would be the go-to in that sense. I don’t know that there’s a specific disadvantage.

ROMEO MANDANAS, MD: In this particular trial…it didn’t use a combination TKI [as a comparator], so I don’t know if it’s worth using that particular TKI [instead of cabozantinib/nivolumab] because the comparator was [sunitinib].

BUPATHI: I don’t know the last time I’ve used sunitinib in RCC. I think we have many better drugs than sunitinib. Certainly I’ve used cabozantinib as a single agent, I’ve used axitinib as a single agent, but I haven’t used sunitinib in a long time.

[Another analysis] showed that…there was a 27.3% [numerical] improvement in response over sunitinib.² The duration of response was 23.1 months, which is about 8 months improvement over sunitinib, and there’s a low rate of progressive disease as best rate response in general.⁶

This is consistent with the ITT, looking at the PFS and OS by site of metastasis. This was a post-hoc analysis and was consistent with the ITT analysis, which was basically showing a benefit with nivolumab/cabozantinib, regardless of IMDC status, organ site of metastases, extent of tumor.⁷

_References:

_{1. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib vs sunitinib for first-line treatment of advanced renal cell carcinoma (aRCC): 3-year follow-up from the phase 3 CheckMate 9ER trial. J Clin Oncol. 2023;41(suppl_6):603. doi:10.1200/JCO.2023.41.6_suppl.603}

_{2. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first-line treatment for advanced renal cell carcinoma (CheckMate 9ER): long-term follow-up results from an open-label, randomised, phase 3 trial. Lancet Oncol. 2022;23(7):888-898. doi:10.1016/S1470-2045(22)00290-X}

_{3. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial. Lancet Oncol. 2020;21(12):1563-1573. doi:10.1016/S1470-2045(20)30436-8}

_{4. Porta CG, Eto M, Motzer RJ, et al. Updated efficacy of lenvatinib (LEN) + pembrolizumab (PEMBRO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CLEAR study. Ann Oncol. 2022;33(suppl_7):S660:S680. doi:10.1016/annonc/annonc1072}

_{5. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer; version 4.2023. Accessed June 6, 2023. https://bit.ly/3tcwJXG}

_{6. Powles T, Choueiri TC, Mauricio B, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. J Clin Oncol. 2022;40(suppl_6):350. doi:10.1200/JCO.2022.40.6_suppl.350}

_{7. Apolo AB, Powles T, Burotto M, et al. Nivolumab plus cabozantinib (N+C) versus sunitinib (S) for advanced renal cell carcinoma (aRCC): outcomes by baseline disease characteristics in the phase 3 CheckMate 9ER trial. J Clin Oncol. 2021;39(suppl 15):4553. doi:10.1200/JCO.2021.39.15_suppl.4553}