Updated Data Supports Use of Nivolumab + Cabozantinib in Advanced ccRCC

CASE

• Patient is a 61-year-old male, married, father of 2 grown children and 5 grandchildren who live nearby, active lifestyle (daily walks, golfs regularly)​.
• History of low-volume, indolent metastatic clear-cell renal cell carcinoma (RCC), status post‒left nephrectomy and adrenalectomy.​
• Patient was observed based on low-volume and indolence of disease and patient preference​.
• Three years after nephrectomy: continued indolent growth on scans, increased total tumor burden, new paratracheal lymph node (2.0 x 1.5 cm) and greater than 10 pulmonary nodules seen on CT scan. ​
• Lung biopsy confirms metastatic clear-cell RCC​.
• Laboratory results within normal limits
• ECOG performance status of 0.

Targeted Oncology^TM: What are the current National Comprehensive Cancer Network guidelines for treating these patients?

RANA MCKAY, MD: The preferred regimens for [patients with] favorable-risk disease includes immunotherapy [IO] plus a VEGF inhibitor as category 1 recommendations.¹ [For patients with poor-risk disease, the recommended treatments] include all the approved IO and VEGF combinations, in addition to nivolumab [Opdivo] plus ipilimumab [Yervoy], and also cabozantinib [Cabometyx] monotherapy based on [data from the BREAKPOINT] phase 2 study [NCT03463681].² For other recommended regimens [for patients with] favorable risk, nivolumab plus ipilimumab is listed as an option and TKIs without a category designation, except for cabozantinib, [which] has a 2B designation in that context.

Rana McKay, MD​

Medical Oncologist

Associate Professor of Medicine

University of California San Diego​

San Diego, CA​

What other combinations can be used for a patient like this?

There are 4 FDA approved IO and VEGF combinations that have demonstrated improvements in overall survival [OS] for this patient population, [which include CheckMate 214 (NCT02231749), KEYNOTE-426 (NCT02853331), CheckMate 9ER (NCT03141177), and the CLEAR study (NCT02811861)].^3-6 These trials were all a little bit different, regarding the proportion of patients that had favorable, intermediate, and poor risk disease across them. The KEYNOTE-426 and CLEAR studies enrolled almost a third of patients who had favorable risk disease, so that is going to certainly impact the data and how they look.^4,6

[Between these trials], the median follow-up was longest in patients in the CheckMate 214 study [at 67.7 months, and the combination of ipilimumab plus nivolumab] demonstrated a statistically significant improvement in OS [at 55.7 months] in the intent-to-treat population.³ When we look at progression-free survival [PFS] in the intent-to-treat population it is a borderline improvement, which is not atypical for IO-based regimens.

I think looking at landmark PFS is more suitable for assessing that endpoint…. In general, the IO and VEGF combinations have a more profound effect on PFS and have a more dramatic up front objective response rate [ORR]. The primary progressive disease [PD] rate is generally 10% or less across these trials. In the short term those drugs tend to be more beneficial.

What did the updated data for the CheckMate 9ER study show clinicians?

Keeping in mind that the cabozantinib dosing [in this trial is] at 40 mg, which is different than the standard monotherapy dosing at 60 mg, the primary end point here was PFS.⁷ The updated data were presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium and had a median follow-up of 44 months. [Patients were still] continuing to demonstrate a statistically significant improvement in PFS in the combination arm compared to sunitinib [Sutent] at 16.6 months [95% CI, 12.8-19.8] vs 8.4 months [95% CI, 7.0-9.7], respectively, with a HR of 0.58 [95% CI, 0.48-0.71), so [it was] almost a 50% improvement in PFS between the 2 arms.

In the updated data for OS, the medians have now been reached for both arms. The median OS for nivolumab plus cabozantinib in the intend-to-treat population is 49.5 months [95% CI, 40.3-NE) and 35.5 months [95% CI, 29.2-42.3] for those on sunitinib. That’s a delta of 14 months in the intent-to-treat population, which includes all comers with favorable-, intermediate-, and poor-risk disease.⁷

In a subset analysis for OS looking at all the subgroups of interest by age, region, race, sex, performance status, IMDC [International Metastatic RCC Database Consortium] risk category…the HR is trending towards nivolumab and cabozantinib.⁸ The patients that seem to derive the most benefit are when we look at the IMDC risk groups. Certainly, those poor-risk patients with an HR of 0.49 [95% CI, 0.31-0.79] then 0.74 [95% CI, 0.54-1.01] for the intermediate group, but right at 1.03 [0.55-1.92] for the favorable risk patients. Probably as these patients are followed over time they will get subsequent lines of therapies that can dilute the OS signal over time.

In a continuation of the subgroup analysis, [including patients with previous nephrectomy or radiotherapy, a baseline PD-L1 status of 1% at cutoff, sarcomatoid features, diagnosis stage, and if they had either bone or liver metastasis], the direction of the HR is still favoring nivolumab and cabozantinib.

At 44.0 months of follow up, how did the PFS and OS among the different IMDC risk groups change?

The intermediate-/poor-risk patients seem to be deriving the most benefit. You can certainly see [a benefit in the PFS] in favor of patients on nivolumab plus cabozantinib compared with sunitinib for favorable risk at 21.4 months [95% CI, 13.2-24.8] vs 13.9 months [95% CI, 9.6-18.5], respectively. However, in OS…I think we need to follow the favorable risk patients a lot longer. These patients live a lot longer and the event rate is a lot lower for these patients and happen later. So, over time, we have to continue to follow and see what happens to those individuals.⁷

What was the updated response data in this trial?

The confirmed ORR in the intend-to-treat population was 55.7% [95% CI, 50.1%-61.2%] and the complete response [CR] rate is now 12.4%, with a partial response rate of 43.3%. The primary PD rate is low at 6.2% and the ORR favored the combination therapy over sunitinib across all the subgroups including based off IMDC risk status.⁷

The response rate in the favorable risk group of patients was much higher compared with sunitinib. Updated ORR data was seen at the ASCO symposium at 52.6% on the combination therapy in the intermediate/poor group, not in the intent-to-treat population, vs 23.8% on sunitinib with a CR rate of 12% [with the combination vs 5.2% with sunitinib].⁸

^References

^{1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, version 1.2024. Accessed August 9, 2023. https://tinyurl.com/h2y8hfef}

^{2. Procopio G, Claps M, Pircher C, et al. A multicenter phase 2 single arm study of cabozantinib in patients with advanced or unresectable renal cell carcinoma pre-treated with one immune-checkpoint inhibitor: The BREAKPOINT trial (Meet-Uro trial 03). Tumori. 2023;109(1):129-137. doi:10.1177/03008916221138881}

^{3. Motzer R, Tannir N, McDermott D, et al. Conditional survival and 5-year follow-up in CheckMate 214: First-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). Annal Oncol. 2021;32(5):S678-S724. doi:10.1016/annonc/annonc675}

^{4. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from 42-month follow-up of KEYNOTE-426. J Clin Oncol. 2021;39(suppl 15):4500. doi:10.1200/JCO.2021.39.15_suppl.4500}

^{5. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841. doi:10.1056/NEJMoa2026982}

^{6. Motzer R, Alekseev B, Rha SY, et al; CLEAR Trial Investigators. Lenvatinib plus pembrolizumab or everolimus for advanced renal cell carcinoma. N Engl J Med. 2021;384(14):1289-1300. doi:10.1056/NEJMoa2035716}

^{7. 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(6):603-603. doi:10.1200/JCO.2023.41.6_suppl.603}

^{8. 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. 2022l;23(7):888-898. doi:10.1016/S1470-2045(22)00290-X}