Treating Renal Cell Carcinoma With Tyrosine Kinase Inhibition

POLL: What Frontline Treatment Would You Choose for Favorable- and Intermediate-Risk RCC?

Participants of a live, virtual case-based event discussed different scenarios for treatment of a patient with previously untreated clear cell renal cell carcinoma. Vote in the polls on what you would have chosen if this was your patient.

CASE 1 SUMMARY

A man, aged 61 years with an active lifestyle, had a history of metastatic renal cell carcinoma (mRCC), and was post‒left nephrectomy and adrenalectomy. He had clear cell RCC (ccRCC) with metastases in the adrenal​ gland. Four years later, he had a recurrence of lung nodules with biopsy consistent with ccRCC. In retrospect, they had been present on scans for at least 2 years prior​. Based on low volume, indolency of disease, and patient preference​, he underwent observation. Eighteen months later, there was continued indolent growth on scans, increased total tumor burden, and a new paratracheal lymph node metastasis (2.0 x 1.5 cm). His ECOG performance score was 0.

Vote in the polls below on what you would have chosen if this was your patient.

A decision was made to initiate systemic therapy. What first-line therapy are you most likely to choose for this favorable-risk patient?

RANA R. MCKAY, MD (moderator): This is where we stand with regards to the National Comprehensive Cancer Network [NCCN] guidelines for kidney cancer for favorable-risk disease: we have category 1 data for all 3 immuno-oncology [IO] plus VEGF–tyrosine kinase inhibitor [TKI] combinations that have demonstrated improvements in overall survival [OS].1 These include axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], and lenvatinib [Lenvima] plus pembrolizumab. Then under other recommendations axitinib/avelumab [Bavencio] is listed, cabozantinib alone is listed with a category 2B designation, nivolumab plus ipilimumab [Yervoy], and then single-agent TKI.1 These can be options for patients with favorable-risk disease.

With checkpoint inhibitor combinations like nivolumab/ipilimumab, the data there support the long-term durability of the regimen with long-term PFS at five years at around 30%.2 The Achilles heel of the CheckMate 214 [NCT02231749] data is that the primary progressive disease rate is 18%.3 At the present time we don’t have biomarkers to help us with the selection between IO/IO versus IO/VEGF-TKI.

What if this patient had 2 sites of distant metastasis (eg, lung and liver), what first-line therapy would you most likely recommend?

MCKAY: In that context it seems like no [participants at this roundtable event would] select single-agent TKI. More individuals selected nivolumab/ipilimumab as a potential option, and then some continuing to select the IO/VEGF-TKI combination.

TIMMY Q. NGUYEN, MD: I changed my treatment from single TKI to a TKI/IO because of the more aggressive presentation likely in the liver as well as the lung. The cancer now is progressing more and likely it's going to progress [even] more. We’ll gain more control of it. Patients need a more active treatment.

SIMON VINARSKY, MD: I selected nivolumab/ipilimumab because of the liver involvement and a clear cell morphology. All options, TKI plus nivolumab or pembrolizumab are absolutely acceptable options, but I chose this particular combination because of the aggressive pattern of metastases and liver involvement, which in this setting of RCC, tends to be a much more aggressive disease compared with pulmonary involvement.

MCKAY: That’s absolutely correct that those with liver metastases can behave more aggressively than those without those sites of metastases.

ROBERT ZAIDEN, MD: I picked lenvatinib plus pembrolizumab based on data from the CLEAR trial [NCT02811861]. I know that it has the longest response seen for any of the mRCC trials with a 71% objective response rate [ORR].4 The reason I didn’t go with cabozantinib plus nivolumab is that this patient did not have any bone metastases and we know cabozantinib/nivolumab is especially good in that subset of patients.

MAHENDER YELLU, MD: I picked the pembrolizumab/lenvatinib based on the complete response rate, quicker response, and personal experience. I have a few patients that did really well on this combination and having the disease in the liver, it's probably more aggressive. Also, if the patient is symptomatic, doing TKI with immunotherapy probably reasonable.

CASE 2 SUMMARY

A Black woman, aged 59 years, was diagnosed with a left renal mass ​and underwent left radical nephrectomy in December 2019​. Her diagnosis was ccRCC, T3aN0Mx, Fuhrman Grade 3​. Nine months later, she developed metastatic disease to the liver and retroperitoneal lymph nodes. Her radiographic diagnosis was stage IV RCC, with metastases to liver and retroperitoneum​. Her Karnofsky performance status was 90%. Her hemoglobin level was 11.1 g/dL​, and corrected calcium, neutrophils, and platelets were within normal limits.

A decision was made to initiate systemic therapy. What first-line therapy are you most likely to choose for this patient?

MCKAY: A fair bit of participants would choose nivolumab/ipilimumab, some lenvatinib/pembrolizumab, some nivolumab/cabozantinib. There were not many people selecting pembrolizumab/axitinib or single-agent cabozantinib.

If it was determined that ipilimumab was not appropriate for this patient, what regimen would you recommend instead of nivolumab plus ipilimumab?

MCKAY: In the updated NCCN guidelines for treatment for patients with poor- and intermediate-risk disease, all the IO/VEGF-TKI combinations are fair game and so is nivolumab/ipilimumab.1

[We can compare] the granular data regarding OS, progression-free survival, and ORR for the intermediate- and poor-risk population compared with the intent-to-treat population across these trials. I would keep in mind the number of patients with poor-risk disease that were enrolled across all of these trials, but based on topline data, every single one of these regimens is effective for patients with intermediate- and poor-risk disease.

Looking at the hazard ratio [HR] for OS, with the long-term follow-up of 67.7 months for nivolumab/ipilimumab is holding steady at 0.68 and for pembrolizumab/axitinib, 0.63.2,5 For cabozantinib/nivolumab, the HR for the intermediate-risk patients is 0.74; for the poor-risk patients it is 0.45.6 Then similarly for lenvatinib/pembrolizumab, the HR for intermediate-risk patients is 0.72 and for poor-risk patients is 0.39, so these are highly effective regimens.7 The ORR in the intermediate- and poor- risk patients, range from over 50% with the IO/VEGF combinations and 72% with lenvatinib/pembrolizumab, whereas for nivolumab/ipilimumab it's 42%.2,5-7

References:

1. NCCN. Clinical Practice Guidelines in Oncology. Kidney cancer, 2.2023. Accessed August 23, 2022. https://bit.ly/2TAx1m3

2. Motzer RJ, McDermott DF, Escudier B, et al. Conditional survival and long-term efficacy with nivolumab plus ipilimumab vs sunitinib in patients with advanced renal cell carcinoma. Cancer. 2022;128(11):2085-2097. doi:10.1002/cncr.34180

3. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290. doi:10.1056/NEJMoa1712126

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

5. Powles T, Plimack ER, Soulières D, et al. Pembrolizumab plus axitinib vs 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

6. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ-specific target lesion assessments with two-year follow-up in CheckMate 9ER: nivolumab plus cabozantinib vs 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. Choueiri TK, Powles T, Porta C, et al. A phase 3 trial of lenvatinib plus pembrolizumab vs sunitinib as a first-line treatment for patients with advanced renal cell carcinoma: overall survival follow-up analysis (the CLEAR study). Presented at: Kidney Cancer Research Summit 2021; October 7-8, 2021; Philadelphia, PA. Abstract E41. Accessed August 23th, 2022. https://bit.ly/3yRcxMx