- Systemic therapy for metastatic RCC (mRCC): JAVELIN 101. Of course, the big news at the meeting was the Presidential Session devoted to JAVELIN 101, presented by Dr. Robert Motzer from MSKCC.1 The study randomized patients with metastatic RCC to either sunitinib or the combination of axitinib with avelumab. Avelumab is an anti-PD-L1 antibody, administered intravenously every two weeks. Sunitinib and axitinib fall into the category of vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKIs) – this was the first phase III to read out amongst several comparing the TKI plus immunotherapy approach to TKI alone. The study was designed to show an improvement in progression-free survival (PFS) and overall survival (OS) in the PD-L1 positive group, with key secondary endpoints evaluating the overall population. The study showed a statistically significant improvement in PFS in the PD-L1 positive group (13.8 mos vs 7.2 mos; P<0.001) and in the overall population (13.8 mos vs 8.4 mos; P=0.0001), but a difference in OS was not yet observed (these data were admittedly premature.
- Systemic therapy for mRCC: PD-L1 subsets in CABOSUN and METEOR. A poster discussion session highlighted an update from CABOSUN and METEOR by Dr. Toni Choueiri and colleagues.2 I won’t go through the details of CABOSUN or METEOR, since I’ve discussed it on previous posts, but the two studies evaluated cabozantinib against relevant comparators in the first- and post-first-line setting, respectively. Cabozantinib appeared to demonstrate benefit against comparators, irrespective of PD-L1 status.
- Adjuvant therapy for localized RCC: ATLAS. The ATLAS trial follows the paradigm of previous adjuvant studies assessing a VEGF-TKI versus placebo (e.g., ASSURE, S-TRAC and PROTECT).3 Now, I’ve long held the notion that the amalgam of existing data doesn’t support the use of adjuvant therapy. ATLAS is no different. The study compared axitinib to placebo, and differed from the design of other studies in that patients were allowed to continue axitinib for up to 3 years if recurrence didn’t occur. With 724 patients accrued overall, no difference in disease-free survival was observed. This is yet another nail in the coffin of adjuvant VEGF-TKI therapy, in my opinion.
Options like axitinib/avelumab may not be in our hands for the short term, but when regimens such as this and bevacizumab/atezolizumab become available, it will present quite a conundrum for the practicing clinician. My suggestion is that regimens like cabozantinib alone could still be relevant for particular subsets of patients – those with really aggressive, bony disease. Regimens such as nivolumab/ipilimumab could be used in circumstances where surgical considerations exist – for example, if a patient has de novo metastatic disease and has indications for cytoreductive nephrectomy, I’ve started nivolumab/ipilimumab in close proximity to surgery. For the remaining cases, we could consider axitinib/avelumab or bevacizumab/atezolizumab. While the magnitude of benefit may be higher with axitinib/avelumab, I am impressed by the higher frequency of complete responses seen with bevacizumab/atezolizumab – furthermore, the toxicity profile of bevacizumab/atezolizumab is exceptional (and I have used both). The data for axitinib/avelumab may get overshadowed by axitinib/pembrolizumab. We know from press release that a phase III study comparing axitinib/pembrolizumab to sunitinib met primary endpoints for PFS and OS. I think we may see a tidal wave of new approvals. I’m particularly intrigued by the data Dr. Neeraj Agarwal and I presented for the combination of cabozantinib with atezolizumab. This takes the most active VEGF-TKI we have at our disposal and combines it with immunotherapy. It will be interesting to see where that combination heads.
And what about adjuvant therapy? Well, ESMO 2018 doesn’t change much for us. With the negative results from ATLAS, my vote is still for clinical trials of immunotherapy in the adjuvant setting. I’m running the phase III IMmotion 010 trial, comparing atezolizumab and placebo, with Drs. Rob Uzzo and Axel Bex. This is one of a handful of adjuvant studies that we in the RCC community have to get behind. For now, I discuss the data for adjuvant TKIs with my patients comprehensively. I have yet to have a patient who wishes to undergo adjuvant treatment.
Thank you for joining me for an ESMO 2018 wrap-up and looking forward to hearing your thoughts on my thoughts!
1. Motzer, R. J., Penkov, K., Haanen, J. B. A. G. et al.: LBA6_PRJAVELIN renal 101: A randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Annals of Oncology, 29: mdy424.036, 2018
2. Choueiri, T. K., Hessel, C., Halabi, S. et al.: LBA38Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): Cabozantinib versus sunitinib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC). Annals of Oncology, 28: mdx440.032, 201
3. Gross-Goupil, M., Kwon, T. G., Eto, M. et al.: Axitinib Versus Placebo as an Adjuvant Treatment for Renal Cell Carcinoma: Results From the Phase III, Randomized ATLAS Trial. Annals of Oncology: mdy454, 2018
Written by: Sumanta Kumar Pal, MD