During a Targeted Oncology™ Case-Based Roundtable™ event, Sandy Liu, MD, discussed the frontline tyrosine kinase inhibitor/immune checkpoint inhibitor regimens and how to manage toxicities related to these regimens.
What study provided the first data to support the use of an immunotherapy (IO) agent in combination with a tyrosine kinase inhibitor (TKI) for the treatment of clear cell renal cell carcinoma (ccRCC)?
LIU: The KEYNOTE-426 study [NCT02853331] investigated the first IO plus TKI regimen that was approved.1 It enrolled patients with newly diagnosed or recurrent stage IV ccRCC. The patients had to be treatment naïve and have a Karnofsky performance status score of at least 70, measurable disease, and good organ function.
They were stratified according to International Metastatic RCC Database Consortium [IMDC] risk group and geographic region. They were randomly assigned 1:1 to receive either sunitinib [Sutent] 50 mg once daily—4 weeks on, 2 weeks off—or the combination of pembrolizumab [Keytruda] 200 mg every 3 weeks plus axitinib [Inlyta] 5 mg orally twice daily. The key primary end points were overall survival [OS] and progression-free survival [PFS] per RECIST in the intent-to-treat population. The key secondary end point was objective response rate [ORR], and they looked at patient-reported outcomes and safety.2
The OS in the intent-to-treat population, at a median follow-up of 42.8 months, was 45.7 months with pembrolizumab plus axitinib vs [40.1] months with sunitinib, and the HR was 0.73 [95% CI, 0.60-0.88; P < .001]. The PFS for the combination was 15.7 months compared with 11.1 months with sunitinib, and the HR was 0.68 [95% CI, 0.58-0.80; P < .0001].3
Which study provided data on the use of cabozantinib (Cabometyx) plus nivolumab (Opdivo)?
The CheckMate 9ER study [NCT03141177] compared cabozantinib plus nivolumab vs sunitinib. This study enrolled patients with previously untreated, advanced [or metastatic] RCC with a clear cell component, in any IMDC risk group. Patients were randomly assigned 1:1 to receive nivolumab 240 mg every 2 weeks plus cabozantinib at a dose of 40 mg [daily].
This dosing of 40 mg vs the monotherapy dosing of 60 mg makes [cabozantinib] much more tolerable. Sunitinib was given at the traditional dosing [50 mg daily; 4 weeks on, 2 weeks off]. The primary end point was PFS, and the secondary end points were OS, ORR, and safety.4
At a median follow-up of 44.0 months, the combination group had a median PFS of 16.6 months compared with the sunitinib group, which had a median PFS of 8.4 months [HR, 0.59; 95% CI, 0.49-0.71]. The benefits were sustained with additional follow-up; this was the longest follow-up of any IO plus TKI combination.5 The combination of nivolumab plus cabozantinib had a median OS of 49.5 months vs sunitinib at 35.5 months, [which is] a 14-month OS difference. The Kaplan- Meier curves separated early and remained separated.
Which study investigated the most recently approved IO plus TKI combination?
The CLEAR study [NCT02811861] investigated the latest IO plus TKI combination to be approved: first-line lenvatinib [Lenvima] plus pembrolizumab6 vs everolimus [Afinitor] plus lenvatinib or single-agent sunitinib. The key eligibility criteria were the same [as the other studies I have discussed].
This was a 3-arm study; patients were randomly assigned to receive lenvatinib 20 mg daily plus pembrolizumab, lenvatinib at 18 mg daily plus everolimus, or sunitinib at the traditional dosing. The primary end point was PFS, and the secondary end points were OS, ORR, safety, and health-related quality of life. They also looked at biomarkers.7
PFS was looked at a median follow-up of 33.7 months. The lenvatinib plus pembrolizumab group had a median PFS of 23.3 months compared with 9.2 months with sunitinib [HR, 0.42; 95% CI, 0.34-0.52]. [Regarding] prognostic risk factor scores for lenvatinib plus pembrolizumab vs sunitinib, the HR was strongest for patients with poor risk, followed by intermediate and favorable risk, [in that order]. The median OS for the lenvatinib plus pembrolizumab group and for the sunitinib group [was] not reached. The OS rate at 12 months was 91.4% vs 80.2% for those groups, respectively. The OS rate at 24 months was [80.2% vs 69.7%], respectively.8
What are some key features of the studies that investigated immune checkpoint inhibitor (ICI) combination regimens indicated for the first-line treatment of favorable-risk metastatic RCC?
Approximately 30% of the population in the CLEAR trial of lenvatinib plus pembrolizumab had favorable risk.5 The study of axitinib plus pembrolizumab was similar.3 The CheckMate 214 study [NCT02231749] of ipilimumab [Yervoy] plus nivolumab9 and the CheckMate 9ER study of cabozantinib plus nivolumab each enrolled 23% [favorable-risk patients].4 The median follow-up was the longest for the CheckMate 214 study, [at 67.7 months].9 The studies of axitinib plus pembrolizumab and of cabozantinib plus nivolumab each had similar follow-up—[42.8 months3 and 44.0 months,5 respectively].
The ORR ranged from 39% [with ipilimumab plus nivolumab]9 all the way to 71% [with lenvatinib plus pembrolizumab].8 The rate of progressive disease was 18% with ipilimumab plus nivolumab9 compared with a low 5% with lenvatinib plus pembrolizumab7 and 6% with cabozantinib plus nivolumab.4
Q:What notable safety data came from these studies?
In the KEYNOTE-426 study, the most common treatment-related adverse events [TRAEs] at the 42.8-month median follow-up were diarrhea, hypertension, palmar-plantar erythrodysesthesia, and hypothyroidism. Approximately 96% of the patients in the experimental arm had TRAEs of any grade, and approximately 60% had TRAEs of grade 3 or greater.3 In the CheckMate 9ER study, the toxicities were very similar: diarrhea, palmar-plantar erythrodysesthesia, hypertension, fatigue, and hypothyroidism; most of it was of grade 1 or 2.4 The TRAEs associated with lenvatinib plus pembrolizumab were very similar: diarrhea, hypertension, stomatitis, hypothyroidism, and fatigue—this could be a TKI phenomenon—and most of these were of grade 1 and 2.7
Q:How do the different VEGF TKI agents compare with one another?
This is a heterogeneous class of drugs. They have distinct pharmacokinetic and pharmacodynamic profiles, selectivities, and drug-drug interactions. However, looking at the first-generation TKIs, sunitinib and sorafenib [Nexavar], vs those in higher generations, there has been an increase in potency and/or VEGF receptor selectivity.
The third-generation agents were axitinib and tivozanib [Fotivda]. The second-generation agents were pazopanib [Votrient], cabozantinib, and lenvatinib. Tivozanib and axitinib have the highest selectivity; they are what I call pure VEGF receptor inhibitors. Then we have pazopanib, lenvatinib, cabozantinib, as well as sunitinib and sorafenib; they are TKIs that can inhibit not only the VEGF receptor but also other targets. Axitinib has the shortest half-life—approximately 2 to 5 hours—compared with lenvatinib and cabozantinib, which have long half-lives.10
A decision was made to initiate axitinib plus pembrolizumab.
What is an advisable treatment algorithm for the management of AEs, such as diarrhea and hepatitis, with the axitinib combination treatment?
You should monitor and continue both agents with supportive care if the patient has grade 1 diarrhea. If they don’t have any improvement and they go to grade 2, hold axitinib for 24 to 48 hours and continue the ICI. If they improve, consider an intermittent schedule or dose reduction for axitinib. If they don’t have improvement with grade 2, you should hold the ICI and start steroids.
If they improve, consider restarting axitinib followed by an ICI rechallenge. If they develop diarrhea of grade 3 or 4, or the presence of alarming signs, you should hold both agents and consider hydration or hospitalization. If they improve, consider restarting axitinib and rechallenging with the ICI. If they have diarrhea of grade 4, I would permanently discontinue the ICI and consider monotherapy TKI.11
For grade 1 hepatitis, you should monitor and continue both agents. If there is no improvement [or the patient has hepatitis of] grade 2, hold axitinib for 48 to 72 hours and continue the ICI, but monitor the patient’s enzymes 1 to 2 times weekly. If they have improvement, consider restarting axitinib at a lower dose.
If they don’t have improvement, hold the ICI and start steroids. If they improve, consider restarting axitinib and rechallenging with their ICI. If the patient develops hepatitis of grade 3 or 4, hold both agents and start steroids. If they improve, you should do a risk-benefit assessment and consider restarting. However, if there is concomitant bilirubin elevation with any grade, it should prompt a full workup, stopping both drugs and referring to hepatology.
Q:How do you manage fatigue and hypertension in this type of treatment in ccRCC?
For fatigue of grade 1, monitor and continue both agents. For grade 2, hold axitinib for 48 to 72 hours and continue the ICI. If the patient improves, consider dose reduction for axitinib. If there is no improvement, do an endocrine assessment. I would typically check their levels of thyroid-stimulating hormone, free T3, and T4. I would also check their levels of cortisol and total testosterone to complete my endocrine assessment. If it is abnormal, you should continue both agents and start hormone replacement. If the patient has severe fatigue of grade 3 or 4, sudden onset, or rapid deterioration, hold both agents and do the endocrine assessment. If it is normal, with no improvement, check other reversible causes and consider cancer-related fatigue. If there is improvement, consider dose reduction.11
For an initial cardiovascular assessment, you should see [whether] the patient has cardiovascular disease, diabetes, left ventricular hypertrophy or carotid [artery] wall thickness, [high-risk] age, a history of smoking, or a family history of early cardiovascular disease. [If so], do a physical examination—[blood pressure] and waist circumference. You should [do laboratory assessments of] their creatinine level, 24-hour protein excretion, and lipid profile. If the patient has a systolic blood pressure of less than 140 mm Hg, a diastolic blood pressure of less than 90 mm Hg, or both, you can start the TKI and then monitor their blood pressure.
You should keep a close eye on the patient—weekly during the first cycle, then every 2 to 3 weeks. You should also consider daily blood pressure monitoring at home if there are more than 2 risk factors. However, if they have a baseline systolic blood pressure of greater than 140 mm Hg, a diastolic blood pressure of greater than 90 mm Hg, or both, treat the hypertension and start the TKI once it is controlled. If it is uncontrolled, refrain from starting the TKI, decrease the dose, or discontinue the [antiangiogenic] drug.12
1. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. April 19, 2019. Updated April 22, 2019. Accessed May 22, 2023. https://bit.ly/44zRrAG
2. 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
3. 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
4. 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
5. 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
6. FDA approves lenvatinib plus pembrolizumab for advanced renal cell carcinoma. FDA. August 10, 2021. Updated August 11, 2021. Accessed May 22, 2023. https://bit.ly/3pHcJ0s
7. 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
8. 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
9. Motzer RJ, Tannir NM, McDermott DF, 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). Ann Oncol. 2021;32(suppl 5):S685-S687. doi:10.1016/j.annonc.2021.08.057
10. Fogli S, Porta C, Del Re M, et al. Optimizing treatment of renal cell carcinoma with VEGFR-TKIs: a comparison of clinical pharmacology and drug-drug interactions of anti-angiogenic drugs. Cancer Treat Rev. 2020;84:101966. doi:10.1016/j.ctrv.2020.101966
11. Grünwald V, Voss MH, Rini BI, et al. Axitinib plus immune checkpoint inhibitor: evidence- and expert-based consensus recommendation for treatment optimisation and management of related adverse events. Br J Cancer. 2020;123(6):898-904. doi:10.1038/s41416-020-0949-9
12. de Jesus-Gonzalez N, Robinson E, Moslehi J, Humphreys BD. Management of antiangiogenic therapy-induced hypertension. Hypertension. 2012;60(3):607-615. doi:10.1161/HYPERTENSIONAHA.112.196774