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Expert Analysis: ASCO GU 2023

CME

CCO Independent Conference Highlights of the 2023 ASCO Genitourinary Cancers Symposium

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: April 28, 2023

Expiration: April 27, 2024

Daniel P. Petrylak
Daniel P. Petrylak, MD
Elizabeth R. Plimack
Elizabeth R. Plimack, MD, MS, FASCO
CME/CE Information

Activity

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Course Completed

CheckMate 9ER: 3-Yr Update of First-line Nivolumab Plus Cabozantinib vs Sunitinib in Advanced RCC

Elizabeth R. Plimack, MD, MS:
Long‑term outcomes from several pivotal frontline trials in RCC were presented this year at ASCO GU. There were 3 trials with TKIs in combination with immunotherapy, 1 with triplet therapy, and then of course CheckMate-214, which is historic. We are seeing durable long‑term outcomes in a subset of patients with RCC after first-line therapy and learning whether there are differences between the studies over time. One of the updates that was presented was the 3‑year follow‑up of CheckMate 9ER. CheckMate 9ER is a phase III trial evaluating nivolumab in combination with cabozantinib vs sunitinib as first-line treatment for advanced or metastatic RCC.41,42 PFS, OS, and ORR benefits were seen at the primary analysis and subsequent follow-up.

Dr Mauricio Burotto and colleagues presented updated PFS, OS and ORR after a median follow up of 44 months (range 36.5-56.5 months).43 The follow-up time is important to keep in mind when we look at the various curves. The current report also includes subgroup analyses by International Metastatic RCC Database Consortium (IMDC) risk category and among patients completing 2 years of nivolumab treatment.

CheckMate 9ER enrolled 651 patients with previously untreated advanced or metastatic RCC with a clear-cell component from any IMDC risk group. Patients were randomized to receive nivolumab 240 mg IV every 2 weeks in combination with cabozantinib 40 mg orally once daily or sunitinib 50 mg orally once daily with 4 weeks on and 2 weeks off. Stratification was based on IMDC risk score, tumor PD-L1 expression, and geographic region. Treatment continued until disease progression per RECIST v1.1 or intolerable toxicity.

The primary endpoint was PFS by BICR and secondary endpoints included OS, ORR by BICR, and safety.

It is important to note that sunitinib is now an outdated control. Comparing the experimental arm to sunitinib, keep in mind that the control arm OS varied over time as novel therapies were approved.

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CheckMate 9ER: Updated PFS and OS in ITT Population and by IMDC Risk Subgroup

Elizabeth R. Plimack, MD, MS:
In the ITT population, the median OS and PFS benefit with the combination of nivolumab and cabozantinib remains consistent with longer follow-up.43  Patients had an OS and PFS benefit regardless of IMDC risk status at baseline, with the greatest benefit observed among patients with poor risk disease.

The performance of the sunitinib arm varies slightly across frontline RCC trials, so I would argue that HR is not the best metric to use when comparing across trials. Since medians are 1 point in time, I would also argue they are not the best metric to compare, either. I favor landmark analyses for these common endpoints to assess performance of the experimental arms across trials.

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CheckMate 9ER 3-Yr: Response in ITT Population

Elizabeth R. Plimack, MD, MS:
The ORR benefit with nivolumab plus cabozantinib was similar to what was reported before, at 55.7% vs 28.4% with sunitinib.43

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CheckMate 9ER 3-Yr: Response by IMDC Risk Subgroup

Elizabeth R. Plimack, MD, MS:
The ORR with combination therapy was better than with single agent sunitinib across risk groups, noting again that we do not use sunitinib anymore in this setting.43

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CheckMate 9ER 3-Yr: TRAEs

Elizabeth R. Plimack, MD, MS:
There were no new treatment‑related deaths since the previous analysis and no new safety signals were reported.43 Corticosteroid treatment to manage immune-mediated AEs was administered to 22% of patients in the nivolumab plus cabozantinib arm. The study defined high-dose steroids as >40mg of prednisone daily or equivalent. 

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CheckMate 9ER 3-Yr: Treatment Exposure and Subsequent Therapies

Elizabeth R. Plimack, MD, MS:
Only 31% of patients in the sunitinib arm who received subsequent systemic therapy went on to receive a PD‑1/PD‑L1 inhibitor, which is what we now would consider standard of care for RCC.43 If patients went through their treatment course without receiving one, it would certainly have a detrimental impact on OS in the control arm. The median duration of treatment was significantly longer with nivolumab plus cabozantinib, at 21.8 months vs 8.9 months, and the rate of treatment discontinuations was slightly lower (82.2% vs 90.0%).

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CheckMate 9ER 3-Yr: Clinical Implications

Elizabeth R. Plimack, MD, MS:
The data show that long‑term follow-up is important. We try to choose frontline therapies with an eye toward both short‑ and long‑term patient benefit. Long‑term benefit needs to be visualized through frequent updates, so we are grateful to the authors for presenting this. I would urge that we stop comparing the various combinations with sunitinib, as again the control arm is different over time, options are different for patients, and it does not reflect our current clinical practice. I think a better metric to look at is landmark OS and PFS values, with a clear focus on which patients are censored vs confirmed progression-free or alive at specific points in time. The nuance of the curves is important to understand as we look across trials.

CaboPoint: Second-line Cabozantinib Post CPI-Based Combination Therapy in Advanced RCC

Elizabeth R. Plimack, MD, MS:
CaboPoint is an ongoing, phase II trial evaluating cabozantinib in patients whose RCC has progressed on checkpoint inhibitor (CPI)-based combination therapy.44  The study aims to address the question of how cabozantinib performs after current standard frontline therapies such as CPI combinations or TKI/CPI combinations. The current planned interim analysis, presented by Dr Laurence Albiges and colleagues at ASCO GU 2023, reports the response rate after 80% of cohort A received at least 3 months of treatment (data cutoff: July 12, 2022).

CaboPoint enrolled 127 patients with histologically confirmed advanced or mRCC with a clear-cell component whose RCC progressed after CPI-based first-line therapy. Patients could not have previously received cabozantinib. Cabozantinib is administered at the standard dosing of 60 mg daily. Patients were assigned cohorts based on their first‑line therapy, with patients progressing after dual CPI therapy (nivolumab plus ipilimumab) enrolled in cohort A and after CPI plus VEGF TKI (avelumab or pembrolizumab plus axitinib) in cohort B.

Treatment with cabozantinib continues until disease progression, unacceptable toxicity, or study end (18 months after the last patient starts treatment). The primary endpoints are ORR by ICR in cohort A, and secondary endpoints include ORR by ICR in cohort B, ORR by investigator assessment in both cohorts, PFS, OS, and safety.

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CaboPoint: Baseline Characteristics

Elizabeth R. Plimack, MD, MS:
The baseline characteristics are consistent with what we see in RCC among patients who survive first-line therapy.45

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CaboPoint: Interim ORR by Investigator Assessment

Elizabeth R. Plimack, MD, MS:
In cohort A, which has 60 patients who progressed after dual CPI therapy, the ORR was 31.7%.45 In cohort B, which has 28 patients who progressed on CPI plus VEGF TKI, the ORR was 25.0%. There were no CRs in cohort A and 1 CR in cohort B (4.0%). The subgroup of patients with 1 metastasis had an ORR of 51.9% (95% CI: 32.0-71.3) vs 15.8% (95% CI: 6.0-31.3) for patients with ≥3 metastatic sites.

These results indicate that even if patients have previously received a TKI, there are still some nice responses.

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Your patient with advanced renal cell carcinoma (RCC) has progressed on first-line therapy with pembrolizumab plus axitinib. Based on the results of the CaboPoint study examining cabozantinib in patients with progressive disease after previous therapy with immune checkpoint inhibitor (ICI)-based therapy presented at ASCO 2023, what would you tell your patient about the efficacy of cabozantinib as second-line therapy?

CaboPoint: Clinical Implications

Elizabeth R. Plimack, MD, MS:
The CaboPoint results underscore what we are already doing in practice, which is using cabozantinib as a second‑line agent after doublet immunotherapy. This study allows us to understand what to expect with cabozantinib in this space.

Daniel P. Petrylak, MD:
These results are also consistent with what we previously saw in retrospective data looking at TKIs after CPI.

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