ASCO 2023: Discussant: Combination Therapies Come of Age in Kidney Cancer

( The 2023 ASCO annual meeting included a kidney cancer session, featuring a discussant presentation by Dr. David Braun discussing combination therapies coming of age in kidney cancer. Dr. Braun started by highlighting that that there has been an evolving landscape of systemic therapies for RCC over the last 3 decades, highlighted by the cytokine era of the early 1990s, the molecularly targeted therapy era of the early 2000s, the immune checkpoint inhibitor era in the mid 2010s, followed by the combination therapy era starting in the late 2010s:

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As such, there are several first-line and subsequent line therapy options for metastatic RCC available, which are also stratified by favorable and intermediate/poor risk:

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As part of his discussant presentation, Dr. Braun highlighted two abstracts in the mRCC first-line systemic therapy space, including “Pembrolizumab + axitinib versus sunitinib as first-line therapy for advanced clear cell RCC: 5-year analysis of KEYNOTE-426” presented by Dr. Brian Rini, and “Final prespecified overall survival analysis of CLEAR: 4-year follow-up of lenvatinib + pembrolizumab vs sunitinib in patients with advanced RCC” presented by Dr. Thomas Hutson. There is a biological rationale for immunotherapy + VEGF TKI, given that VEGF TKIs T cells decrease Treg cells and increase effector CTL cells, whereas VEGF TKI myeloid cells decrease M2-like TAMs and increase mature dendritic cells:

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Based on the current data, is immunotherapy + TKI superior to TKI alone for front-line clear cell RCC treatment? Dr. Braun states that yes, it is, given the increased objective response rate as shown in the extended results of the KEYNOTE-426 and CLEAR trials, in addition to a low progressive disease rate. 

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Additionally, there is the added benefit of significantly improved progression free survival and overall survival as demonstrated in KEYNOTE-426 and CLEAR. However, Dr. Braun cautions that although OS is positive, there is questions regarding durability of response with these immunotherapy + TKI combinations. If we look at the CheckMate 214 trial1 with regards to overall survival, there is evidence that in this trial there is more prominent and durable splitting of the curves: 

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The second question is whether immunotherapy + TKI responses are durable? Dr. Braun states that the answer is maybe. In the current trials, the median duration of response was ~2 years, however there is a lack of CTLA-4 blockade (which Dr. Braun states may be quite important), and the anti-PD-1 agent is discontinued at 2 years. Again, based on the CheckMate-214 trial, there is evidence of better duration of response, with >50% of IO + IO responses being durable:

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The third question is whether immunotherapy + TKI therapy improves overall survival for patients with IMDC favorable risk RCC? According to Dr. Braun, the answer is probably not, given that in the extended follow-up of both KEYNOTE-426 and CLEAR, there was no overall survival benefit for IMDC favorable patients. Dr. Braun then provided the following concluding statements for this first part of his discussant presentation:

  • Do updated results from CLEAR and KEYNOTE-426 chance practice? No, but they re-affirm it as a treatment option for IMDC intermediate and poor risk patients
  • How do we treat patients with IMDC favorable risk disease? There is no clear answer, which means that this is an important area of additional investigation (IO + TKI, TKI alone, and pure IO being potential options in this disease space)
  • Does IO + TKI lead to durable responses or cures? Not for most patients

Currently, Dr. Braun provided his front-line clear cell RCC treatment paradigm, highlighting the durability of IO + IO therapy:

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According to Dr. Braun, the next steps in therapy are potentially triplet therapy (including the COSMIC-313 and MK-6482-012 trials), as well as adaptive trial designs (ie. PDIGREE).

Dr. Braun then discussed the third abstract in his discussant presentation “Efficacy and safety of atezolizumab + cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor treatment in metastatic RCC: Primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study” presented by Dr. Toni Choueiri. The clinical question from this abstract is: Does “re-challenge” with immune checkpoint inhibitor + TKI improve outcomes vs TKI alone in patients previously treated with immune checkpoint inhibitor therapy? Based on a pre-ASCO Twitter poll, Dr. Braun notes that ~1/3 of participants would potentially re-challenge patients with immunotherapy after previously having received immunotherapy.

CONTACT-03 enrolled 522 patients with histologically confirmed, inoperable, locally advanced or metastatic clear cell or non-clear cell RCC, regardless of PD-L1 status, that progressed on or after immune checkpoint inhibitor treatment. Randomization was 1:1 to atezolizumab (1200 mg IV q3w) + cabozantinib (60 mg oral QD) or cabozantinib alone. The primary efficacy endpoints were centrally reviewed RECIST 1.1 progression free survival and overall survival. Key secondary endpoints were investigator-assessed progression free survival, centrally reviewed RECIST 1.1 objective response rate and duration of response and safety. Of note, ~3/4 of these patients were clear cell RCC without sarcomatoid features with very few post-adjuvant immunotherapy patients (based on the timing of enrollment, adjuvant immunotherapy was not yet approved). IO + IO (nivolumab + ipilimumab) was the most common previous first-line therapy (30.5% among patients subsequently receiving atezolizumab + cabozantinib vs 27.1% for patients subsequently receiving cabozantinib). IO monotherapy was the most common second line therapy (87.% in the atezolizumab + cabozantinib arm vs 92.8% in the cabozantinib arm). There was no difference between atezolizumab + cabozantinib vs cabozantinib with regards to response, primary progressive disease rate, disease control, or duration of response:

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However, cabozantinib did prove to be effective after immune checkpoint inhibitor therapy, with an objective response rate of 40.9% (per central review), which compares favorably to METEOR (objective response rate 21%) [2], and CaboPoint (GU ASCO 2023). Additionally, there was no benefit to atezolizumab + cabozantinib for progression free survival (HR 1.03, 95% CI 0.83-1.28) and overall survival (HR 0.94, 95% CI 0.70-1.27). Of additional concern is that re-challenge with immune checkpoint inhibitor + TKI is more toxic than TKI alone. There were: (i) higher grade 3-4 adverse events, (ii) three treatment related deaths, (iii) two immune-related deaths, (iv) double the rate of serious adverse events, and (v) double the rate of withdrawal from cabozantinib:


Dr. Braun notes that there are several limitations of CONTACT-03:

  • This trial used an anti-PD-L1 instead of an anti-PD-1, whereby anti-PD-L1 may be less active in RCC
  • Immunotherapy rechallenge is given immediately after prior immunotherapy
  • Very few patients were treated after adjuvant pembrolizumab, thus this does not answer the question of optimal treatment after adjuvant immunotherapy (trials are needed for this. 

Thus, we are able to conclude that the addition of atezolizumab + cabozantinib did not improve response or progression free survival versus cabozantinib alone. Furthermore, atezolizumab + cabozantinib was significantly associated with higher grade 3-4 adverse events. Cabozantinib was shown to be an effective therapy for immune checkpoint inhibitor-refractory RCC, with an objective response rate of 40%. Perhaps immunotherapy post-immunotherapy could still be an effective approach in RCC with the use of an anti-PD-1 inhibitor or the use of other immunotherapy agents, such as anti-CTLA-4. Dr. Braun emphasized that whatever the next step is, it needs to continue taking into account patient preferences. Based on a survey from KCcure, most patients are looking for a cure of their disease:


Thus, aiming for a cure requires novel therapeutic approaches in RCC: requiring an understanding of RCC immunobiology, and perhaps antigen-specific approaches as a next generation immunotherapy.

Dr. Braun concluded this section of his presentation with the following take-home points from CONTACT-03:

  • Does CONTACT-03 change practice? Yes, anti-PD-(L)1 should not be used after progression on prior PD-(L)1 (at least until TiNivo-2). There is more toxicity and the potential to compromise dosing of the TKI
  • Next steps include: (i) trials to optimize clinical outcomes (increasing objective response rate, progression free survival and overall survival), (ii) novel targets aiming for a cure, and (iii) always listening to the patient perspective

Presented by: David A. Braun, MD, PhD, School of Medicine, Yale University, New Haven, CT

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, June 2 – Tues, June 6, 2023. 


  1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carinoma. N Engl J Med 2018;378(14):1277-1290.
  2. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1814-1823.