Combination Therapies Make Significant Impact on Advanced RCC Treatment Across Lines of Therapy

Christopher W. Ryan, MD

A diagnosis of stage IV renal cell carcinoma in a 59-year-old- African American patient was the topic of a discussion led by Christopher W. Ryan, MD, professor of Medicine, Hematology & Oncology, Knight Cancer Institute, Oregon Health & Science University and executive officer, SWOG.

Targeted Oncology^TM: What guidelines does the National Comprehensive Cancer Network (NCCN) offer regarding first-line systemic therapy for clear cell RCC in instances of relapse or stage IV disease with poor- or intermediate-risk patients?

RYAN: [The NCCN] has 4 category 1 recommendations: axitinib [Inlyta] plus pembrolizumab [Keytruda], cabozantinib [Cabometyx] plus nivolumab [Opdivo], ipilimumab [Yervoy] plus nivolumab, and lenvatinib [Lenvima] plus pembrolizumab.¹ [The category 1 designation reflects] randomized phase 3 data that show an overall survival [OS] benefit. Cabozantinib [is also listed alone, although not as category 1] because it had a progression-free survival [PFS] advantage over sunitinib [Sutent] in an older, phase 2 trial [CABOSUN, NCT01835158].²

The VEGF tyrosine kinase inhibitors [TKIs] were the first drugs to be approved since interleukin 2, and they got their approvals beginning in late 2005: sorafenib [Nexavar],³ followed by sunitinib.⁴ We think these drugs work by inhibiting the VEGF receptor. We know that the VEGF ligand is often overexpressed in RCC due to patients’ [losing] function of the VHL gene.⁵ It is hypothesized that some of the newer generation TKIs, [such as] cabozantinib and lenvatinib, may have some additional activity because of additional tyrosine kinase inhibition of MET and AXL, or FGFR, [respectively]. Other, older treatments are the mTOR inhibitors, which inhibit mTOR complex 1; it’s unclear how mTOR inhibitors work, but there’s some rationale that they can affect hypoxia-inducible factor α, which is overexpressed in RCC. mTOR inhibition is falling out of favor in recent years, with the randomized trials, they’ve had worse outcomes than some of our newer [agents].

In the past 5 years, checkpoint immunotherapy treatments have [come to the forefront of] solid tumor oncology. There tends to be a [correlation between] mutational burden and the efficacy of these drugs. [However, in an analysis of anti–PD-1 or anti–PD-L1 therapy], RCC was a bit of an outlier [among targeted diseases]; its mutational burden is not high, but it’s [objective response rate (ORR)] was on the higher end [of the spectrum].⁶

What data support the use of the NCCN’s recommended therapies?

RYAN: All 4 trials [with category 1 data supporting the use of] checkpoint inhibitors [pembrolizumab, nivolumab, and ipilimumab] as first-line therapy showed a statistically significant and clinically relevant OS benefit over sunitinib. For axitinib plus pembrolizumab [KEYNOTE-426, NCT02853331], median OS was 45.7 months vs 40.1 months [HR, 0.73; 95% CI, 0.60-0.88; P < .001].⁷ For nivolumab plus cabozantinib [CheckMate 9ER, NCT03141177], the median OS was not reached [NR] vs NR [HR, 0.60; 98.89% CI, 0.40-0.89; P = .001],⁸ or ipilimumab plus nivolumab [CheckMate 214, NCT02231749], the mOS was NR vs 38.4 months [HR, 0.69; 95% CI, 0.59- 0.81].⁹ Finally, for lenvatinib plus pembrolizumab [CLEAR, NCT02811861], median OS was NR vs NR [HR, 0.66; 95% CI, 0.49-0.88; P = .005].¹⁰

All the studies showed higher response rates [for the experimental treatments vs the comparators]. For axitinib plus pembrolizumab, the ORR was 60.4% vs 39.6% [P < .0001].7 For cabozantinib plus nivolumab, the ORR was 55.7% vs 27.1% [P < .001].⁸ For ipilimumab plus nivolumab, the ORR was 39.1% vs 32.4% [P = .0134].⁹ For lenvatinib plus pembrolizumab, the ORR was 71.0% vs 36.1%, with a relative risk vs sunitinib of 1.97 [95% CI, 1.69-2.29].¹⁰

Was there anything distinguishing about any of the studies?

RYAN: All these studies included all risk groups, but in the study of ipilimumab plus nivolumab the primary analysis was limited to intermediate- and poor-risk patients, and the FDA labels this combination specifically for intermediate- and poor-risk patients.11 [In this same study], [while] there was an OS benefit with the experimental treatment, there was not a median PFS benefit vs the comparator [12.2 months vs 12.3 months; HR, 0.89; 05% CI, 0.76-1.05].⁹ All the other trials showed a significant median PFS benefit: for axitinib plus pembrolizumab, 15.7 months vs 11.1 months [HR 0.68; 95% CI, 0.58-0.80; P < .0001];⁷ for cabozantinib plus nivolumab, 16.6 months vs 8.3 months [HR, 0.51; 95% CI, 0.41-0.64; P < .001];⁸ and for lenvatinib plus pembrolizumab, 23.9 months vs 9.2 months [HR, 0.39; 95% CI, 0.32-0.49; P < .001].¹⁰

Can you expand on the data from the CheckMate 9ER trial that support the use of nivolumab plus cabozantinib?

RYAN: Nivolumab plus cabozantinib was approved by the FDA in January 2021 based on this trial.12 This was a first-line study; it randomly assigned patients with metastatic ccRCC to [receive either] nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was PFS, and, [as stated above], there was nearly a doubling of median PFS with the experimental treatment after a median follow-up of 18.1 months.⁸ Upon more recent [2-year] follow-up, the data didn’t change much: 17.0 months vs 8.3 months [HR, 0.52; 95% CI, 0.43-0.64].¹³ PFS across all subgroups (including subgroups defined by International Metastatic RCC Database Consortium prognostic risk and by PD-L1 expression) favored the experimental combination.⁸ The secondary end point was OS. Median OS was not reached in the primary analysis; at the 2-year follow-up, median OS was not estimable [NE] vs 29.5 months [HR, 0.66; 95% CI, 0.50-0.87].¹³

Like many of these combinations, this one has robust response rate data vs sunitinib. Complete responses [CRs] occurred in 8.0% of the experimental group and in 4.6% of the comparator group.⁸ At the 23.5-month follow-up, the ORR was 54.8% vs 28.4%; the CR rate was 9.3% vs 4.3%.13 And responses were durable with this combination. Median duration of response was 20.2 months [95% CI, 17.3-NE] with the combination vs 11.5 months [95% CI, 8.3-18.4] with the comparator.⁸

Treatment discontinuation due to adverse events [AEs] was somewhat higher with the combination than with sunitinib [15.3% vs 8.8%].¹³ Dose reductions, though, were similar in both arms; a minimum of 1 dose reduction was required by 56.3% of patients in the experimental group and 51.6% of patients in the comparator arm. That’s [consistent with my] clinical experience. Comparative toxicities between the nivolumab plus cabozantinib [combination] and sunitinib look relatively similar, but there’s a suggestion of some more AEs in the combination arm: somewhat more diarrhea [57% vs 43%] and more elevation of aspartate aminotransferase [23% vs 9%] and alanine aminotransferase [25% vs 6%].

When giving combined checkpoint inhibitor and TKI therapy, do you have problems distinguishing AEs that are immune related vs those attributable to the TKI? How do you manage those?

KEISER: [I use] time of onset [to distinguish them]. I would expect a little later [onset of AEs caused by checkpoint inhibitor immunotherapy] and an [earlier onset of AEs caused by] the TKI. [It’s] not a perfect [system], but [there is] a little bit of a [distinction in time of onset], I think.

AMBIKA: We can stop the TKI first and see whether [the AE] improves. If it doesn’t improve, it’s more [likely to be due to] immunotherapy [IO].

RYAN: I’ve run into this recently with some patients; it’s a chronic question, [involving] diarrhea in some cases and elevated liver function test results as well. Obviously, if you see severe hepatitis, you’re probably going to be more worried about therapy. But, I agree, outside of severe examples, [it’s a good idea to] stop the TKI and see if [the symptoms] settle down, and not jump into steroid treatment unless [absolutely necessary].

Do you think there is a reason to switch patients who are receiving axitinib plus pembrolizumab to nivolumab plus cabozantinib instead?

FANG: I’m eager to try this new combination for my next patient. Axitinib tends to be quite toxic. Most patients will experience some degree of [palmar-plantar erythrodysesthesia]. [I have also seen] hemoglobin go very high. I [have had] a better experience with cabozantinib.

AMBIKA: Do you know why the [rate of] subsequent therapy was low in the CheckMate 9ER study? I think only 40% [of the patients in the sunitinib arm] got subsequent systemic therapy; only 29% of patients in that arm got subsequent immunotherapy.8 That skews the data, right?

RYAN: That is a good question. There can be a lot of factors, including geographic location, [that affect subsequent therapy]; certain therapies might not be available [to some patients].

KEISER: I like this study, [though] I haven’t used [this combination] a lot yet. But if I remember right, [patients in] CheckMate 9ER had a worse [prognosis at baseline compared to patients in other studies].^8,10 So I think some of those patients just never got to a crossover point. In other words, they were too sick. I think the deck was stacked against the CheckMate 9ER trial, and yet it still performed pretty well.

RYAN: Yes. It certainly performed well. I think people’s personal experience with various TKIs influence which one they’re comfortable using, although a lot of these things can be idiosyncratic.

What are some of the NCCN recommendations for second-line therapy for relapse or stage IV ccRCC?

RYAN: The category 1 recommendations1 [are the result of] randomized trials of axitinib vs sorafenib [Nexavar],¹⁴ nivolumab vs everolimus [Afinitor],¹⁵ cabozantinib vs everolimus,16 and lenvatinib plus everolimus vs lenvatinib or everolimus.¹⁷ All these studies were done mostly in patients previously treated with sunitinib. They all showed PFS advantages over their comparators. For axitinib [AXIS, NCT00678392], median PFS was 6.7 months vs 4.7 months [HR, 0.665; 95% CI, 0.544- 0.812; 1-sided P < .001].¹⁴ For nivolumab [CheckMate 025, NCT01668784], median PFS was 4.6 months vs 4.4 months [HR, 0.88; 95% CI, 0.75-1.03; P < .11].¹⁵ For cabozantinib [METEOR, NCT01865747], the HR was 0.51 [95% CI, 0.41-0.62; P < .0001].¹⁶ Finally, for lenvatinib plus everolimus [NCT01136733], a PFS advantage was demonstrated vs everolimus alone [14.6 months vs 5.5 months; HR, 0.40; 95% CI, 0.24-0.68; P = .0005] but not vs lenvatinib alone.¹⁷

RYAN: So, what I’m seeing is a good half of you would jump to this as second-line therapy, like in this case, but a lot of people are probably saving it for third-line therapy. The thing is, we just talked about the changing landscape by using IO/ TKI therapy, and using cabozantinib potentially in the first-line setting with nivolumab. People are looking for something different, maybe moving this up to a second-line treatment.

Can you elaborate on the data that support the use of lenvatinib plus everolimus?

RYAN: The trial that led to the approval of [this combination]18 was a phase 2, randomized, 3-arm trial of lenvatinib (18 mg) plus everolimus (5 mg), single-agent lenvatinib (24 mg), and single-agent everolimus (10 mg). The primary end point was PFS.17

Single-agent lenvatinib [showed a] significant PFS [advantage over everolimus] [HR, 0.61; 95% CI, 0.38-0.98; P = .048].17 But the difference between the combination and everolimus with respect to PFS was profound and highly significant, [as mentioned above]. The combination also showed a superior response rate over everolimus [43% vs 6%; P < .0001]. Finally, analysis of OS data showed a significant advantage in the post-hoc, 24.2-month follow-up [HR, 0.51; 95% CI, 0.30-0.88; P = .024].10

KEISER: Are there any data on the number of patients [who] tolerated [those doses]? I don’t think I’ve ever been able to use those doses [for single-agent lenvatinib], much less in combination. On this trial, where [the patients] were carefully nurtured along, what [doses] did they really end up on?

RYAN: The toxicity [data here will] probably echo what you’re trying to say, that there was a fair amount of toxicity.

Among the grade 3 and grade 4 toxicities, 19% of patients experienced diarrhea. Among all grades, vomiting and nausea [affected about] half of the patients. Stomatitis, an everolimus-associated AE, was about the same in both arms [for all grades, 44% with the combination, 50% with single-agent everolimus]. The combination group also had more oral pain [23% vs 4%] and more abdominal pain [37% vs 8%], [though these were] mostly lower grade. Additionally, the combination group exhibited more decreased appetite [53% vs 18%], renal failure [18% vs 12%], and hypertension [42% vs 10%]. Some of the main laboratory abnormalities that you see with everolimus are metabolic, and in this study, hyperglycemia of grade 3 or grade 4 was actually higher in the single-agent everolimus group [16%, vs 3% in the combination arm], probably because [those patients received a] higher dose of everolimus.¹⁷

What is your experience using lenvatinib plus everolimus?

RYAN: I haven’t used [that combination] a lot. Most of my experience has been [using it in the] third line [or later], where you don’t get to see results sometimes.

RYAN: This patient did quite well, but I think most of us have concerns that the studies did show a relatively high rate of numerous AEs.

_REFERENCES

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_{9. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab vs sunitinib for first-line treatment of advanced renal cell carcinoma: extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open. 2020;5(6):e001079. doi:10.1136/esmoopen-2020-001079}

_{10. 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;384:1289-1300. doi:10.1056/NEJMoa2035716}

_{11. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. News release. US Food and Drug Administration; April 16, 2018. Accessed August 2, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-ipilimumab-combination-intermediate-or-poor-risk-advanced-renal-cell}

_{12. FDA approves nivolumab plus cabozantinib for advanced renal cell carcinoma. News release. US Food and Drug Administration. January 22, 2021. Accessed July 31, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-plus-cabozantinib-advanced-renal-cell-carcinoma}

_{13. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab + cabozantinib (NIVO+CABO) vs sunitinib (SUN) for advanced renal cell carcinoma (aRCC): outcomes bay sarcomatoid histology and updated trial results with extended follow-up of CheckMate 9ER. Paper presented at: American Society of Clinical Oncology Genitourinary Cancers Symposium; February 11-13, 2021; virtual. Accessed August 2, 2021. https://meetinglibrary.asco.org/record/195192/abstract}

_{14. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib vs sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378(9807):1931-1939. doi:10.1016/S0140-6736(11)61613-9 Published correction appears in Lancet. 2012;380(9856):1818}

_{15. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 investigators. Nivolumab vs everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665}

_{16. Choueiri TK, Escudier B, Powles T, et al; METEOR investigators. Cabozantinib vs everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917-927. doi:10.1016/S1470-2045(16)30107-3}

_{17. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473-1482. doi:10.1016/S1470-2045(15)00290-9 Published correction appears in Lancet Oncol. 2016;17 (7):e270. Published correction appears in Lancet Oncol. 2018;19(10):e509.}

_{18. Lenvatinib in combination with everolimus. News release. FDA. May 13, 2016. Updated May 16, 2016. Accessed August 3, 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/lenvatinib-combination-everolimus}