Motzer Examines Impact of IO/TKI Combination Trials for Non–Clear Cell RCC

Robert J. Motzer, MD

Section Head, Kidney Cancer, Genitourinary Oncology Service

Jack and Dorothy Byrne Chair in Clinical Oncology

Memorial Sloan Kettering Cancer Center

New York, NY

CASE SUMMARY

• A 57-year-old man presented to the emergency department with new onset gross hematuria, right flank pain, and weight loss.

Medical History

• Hypertension, well controlled on angiotensin-converting enzyme inhibitor once daily
• No prior history of malignancy
  

Social History

• Employed as a bank teller
• Nonsmoker

Family History

• Father died of colon cancer at age 60 years; mother underwent hysterectomy for uterine fibroids at age 37 years. No other family history of malignancy.

Diagnostic Workup

• Abdominal CT: 7-cm solid mass in right kidney; liver and lung metastases detected
• Laboratory test results: normal complete blood cell count + differential and comprehensive metabolic panel
• Histopathology: core needle biopsy, papillary architecture consistent with non–clear cell renal cell carcinoma (nccRCC)
• Molecular testing: awaiting results

Treatment

• The patient proceeds to a right radical nephrectomy.
• Pathology: renal cell carcinoma, papillary nccRCC; stage I

Peers & Perspectives in Oncology: What are the challenges of selecting treatment for patients with nccRCC?

Robert Motzer, MD: There haven’t been a lot of data to support high-level recommendations. There has been a lack of phase 3 trials. The evidence has also been hindered by the variety of cell types. For the most part, these tumor types are grouped together, and they have very different underlying biology, and very different natural history. It’s been difficult to establish specific programs for non–clear cell tumors. For the most part, the drugs are studied in [patients with ccRCC], and either they have a label for [all] kidney cancer and so physicians use them for nccRCC, or these drugs are extrapolated and tried in the non–clear cell types. For the most part, with the exception of the immunotherapies [IO], the response rates are lower with the nccRCC than they are with ccRCC, but there may be some activity and there is a lack of options.

What data support the use of cabozantinib (Cabometyx) as a single agent in this population?

Cabozantinib [is preferred] based on its activity in a randomized trial, providing a higher level of evidence. It was compared with sunitinib [Sutent] in the phase 2 PAPMET trial [NCT02761057]….There were 2 other drugs that were included [crizotinib (Xalkori) and savolitinib], which were specific MET inhibitors. They lacked activity from the beginning, and so those arms were shut down and the trial ended by comparing sunitinib and cabozantinib. There is an interest in trying those drugs as MET inhibitors, as well as cabozantinib, which targets MET, because of the fact that there are some patients with type 1 papillary RCC who have activating MET mutations and…to a certain extent, we are targeting that MET mutation that has been reported in type 1 papillary RCC.

Although it was a relatively modest randomized phase 2 trial, there were approximately 150 patients, almost 50/50 for sunitinib [n = 46] and cabozantinib [n = 44], and then the other 2 drugs were [taken] out of the trial based on a lack of activity…. This was published in The Lancet, which has very high impact factor, showing the need for randomized trials in nccRCC.¹ They had type 1, type 2, [or papillary not otherwise specified]. Type 2 is now referred to as FH-deficient tumors because they’re characterized by mutations in fumarate hydratase, which is within the Krebs cycle.

The median progression-free survival [PFS] for cabozantinib was approximately double that of sunitinib [9.0 months vs 5.6 months, respectively]. The overall response rate [ORR] was higher as well [23% vs 4%]. There wasn’t a benefit in overall survival [(OS) median, 20.0 months vs 16.4 months]. Some people defend sunitinib because they say there wasn’t a benefit in OS. But clearly the PFS and the ORR were higher in favor of cabozantinib and this was a phase 2 trial, not a phase 3 trial, so it wasn’t powered to show a benefit in OS. It appears to show improvement in efficacy for cabozantinib compared with sunitinib, and the toxicity profile was the same for both drugs.

What role does the addition of nivolumab (Opdivo) to cabozantinib have in patients with nccRCC?

This was based on a large phase 2 trial [NCT03635892] that was done at Memorial Sloan Kettering Cancer Center. It was an investigator-initiated trial. There were 2 trials: One was specific to chromophobe tumors, and the other was supposed to be directed to papillary or unclassified tumors that have papillary features. The chromophobe tumor trial closed after [enrolling] fewer than 10 patients because there was no activity that was seen. Chromophobe tumors are felt to be a resistant tumor to immunotherapy, but cabozantinib/nivolumab in papillary or unclassified tumors was a study that showed the efficacy in the 40 patients who were treated on the trial.²

Our hurdle here was that some of the patients got this as a second-line [therapy]. They had already [experienced disease progression] on sunitinib, so they probably [lowered] the response rate a little. But the ORR is between 40% and 50% with this program, which is high. There were 2 patients who [were enrolled] with translocation-associated RCC. I think these patients had initially been characterized as a papillary RCC but had been reread by pathologists and reclassified as translocation.

The median PFS was 12 months, but it is very difficult to interpret in a single-arm trial. OS is even more difficult to interpret in a single-arm trial and is not particularly meaningful.

The waterfall plot showed that [nearly all] the patients had disease stabilization and most had shrinkage to some degree, and so there was efficacy with this program. This could be challenged, and a point can be made for cabozantinib monotherapy followed by immunotherapy as a single agent in sequence, because there’s not a clear benefit in OS for this program. But the ORR and the degree of tumor shrinkage seems superior to single agent.

Safety profiles were quite similar to that of the large phase 3 CheckMate 9ER trial [NCT03141177].^2,3 There were more patients in this trial who came off for toxicity for this regimen [50% for either drug, 33% for both]. We don’t know why. This was a single-center study at our center, but more patients came off for toxicity compared with the CheckMate 9ER trial. [Safety was] otherwise quite similar…with cabozantinib/nivolumab in the ccRCC experience.

Could you describe the study design and outcomes for the trial of lenvatinib (Lenvima) plus pembrolizumab (Keytruda)?

The phase 2 KEYNOTE-B61 [NCT04704219] [trial investigated] lenvatinib/pembrolizumab in nccRCC. It was an industry-sponsored global trial. It was a single arm, not randomized, with over 150 patients with various histologies planned to get lenvatinib plus pembrolizumab….⁴ This trial took all comers, almost 160 patients. More than half had papillary histology; it’s the most common nccRCC. The next most common was chromophobe and then after that unclassified, so those 3 are the ones that you may very well see in your own practice.

The ORR was approximately 50%, which is pretty good [Figure⁴]. It’s become a choice now in first-line therapy for these patients with nccRCC. The chromophobe tumor has been discussed because all the studies using an IO therapy except for this one showed a lack of activity with immune checkpoint inhibitor therapy in chromophobe [histology]. This is the only one that’s shown activity…albeit it’s only 8 patients who had a response. Chromophobe tumor is one that has lesser activity associated with it, compared with either clear cell or papillary RCC. A few patients with translocation-associated RCC were included, but this is quite a rare tumor type in adults and activity was difficult to assess given the small numbers.

[Looking at] different factors that were involved in response… the important information was that there didn’t seem to be a distinguishing factor between favorable, intermediate, or poor risk in these patients with nccRCC. Those with papillary RCC did the best. Those with chromophobe RCC did the worst, and sarcomatoid features didn’t matter for these patients. Sarcomatoid features have been [seen] as important in the clear cell RCC particularly for response to drugs like nivolumab plus ipilimumab [Yervoy]. PD-L1–expressing tumors seemed to do better than those that lacked PD-L1 expression.

The waterfall plot shows that most patients have tumor response, and I think that’s probably one of the most important metrics. A number of patients are on this for more than a year, [and we are] still waiting for longer follow-up.

PFS was probably not that much different than cabozantinib/nivolumab, with a 63% PFS rate at 12 months, whereas the median for the cabozantinib/nivolumab was 12 months. But we can’t compare [2 different] single-arm trials, and the OS information is very limited.

Safety was [roughly] identical to that in the [phase 3] CLEAR trial [NCT02811861] for lenvatinib/pembrolizumab, confirming the toxicity profile for this particular [combination], showing it wasn’t different in these patients with rarer nccRCC than it was in the patients with ccRCC.^4,5

Could you summarize the trial data in nccRCC?

This is a high-level summary of [large] trials and trials that you should be aware of in nccRCC. There is the Eisai Study 221 phase 2 trial [NCT02915783] of lenvatinib plus everolimus. This is a combination that’s been used by many of us for chromophobe tumors. Chromophobe tumors seem to have better response rate to everolimus than they do to tyrosine kinase inhibitors; there was activity for lenvatinib/everolimus in chromophobe tumors.⁶ The problem with this study was that it was only 31 patients, and so I think that the [opportunity] was missed here by such a small study for this combination.

The outcome with nivolumab/ipilimumab in nccRCC [from the phase 4 CheckMate 920 trial; NCT02982954] was disappointing. The response rate was low, less than 20%.⁷ There weren’t complete responses with this, which was a surprise to most of us.

Nivolumab plus cabozantinib…and lenvatinib plus pembrolizumab are reasonable choices as first-line therapy based on response rate. These are the newer combinations; they haven’t been compared with monotherapy in a phase 3 trial, but the single-arm data look good.

REFERENCES:

1. Pal SK, Tangen C, Thompson IM Jr, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397(10275):695-703. doi:10.1016/S0140-6736(21)00152-5

2. Lee CH, Fitzgerald KN, Voss MH, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: updated results from a phase 2 trial. J Clin Oncol. 2023;41(suppl 16):4537. doi:10.1200/JCO.2023.41.16_suppl.4537

3. 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

4. Albiges L, Gurney H, Atduev V, et al. Pembrolizumab plus lenvatinib as first-line therapy for advanced non-clear-cell renal cell carcinoma (KEYNOTE-B61): a single-arm, multicentre, phase 2 trial. Lancet Oncol. 2023;24(8):881-891. doi:10.1016/S1470-2045(23)00276-0

5. 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

6. Hutson TE, Michaelson MD, Kuzel TM, et al. A single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Eur Urol. 2021;80(2):162-170. doi:10.1016/j.eururo.2021.03.015

7. Tykodi SS, Gordan LN, Alter RS, et al. Safety and efficacy of nivolumab plus ipilimumab in patients with advanced non-clear cell renal cell carcinoma: results from the phase 3b/4 CheckMate 920 trial. J Immunother Cancer. 2022;10(2):e003844. doi:10.1136/jitc-2021-003844