Immunotherapy/TKI Combos Continue to Advance RCC Paradigm

Claud M. Grigg, Jr, MD

With the emergence of immunotherapy/TKI combinations in the treatment paradigm of renal cell carcinoma (RCC), patients are deriving significant benefit with improved survival outcomes, said Claud M. Grigg Jr, MD.

“The take-home message is that these combinations targeting VEGF and either PD-1 or PD-L1, are very, very active,” added Grigg. “Certainly, in patients who are symptomatic, I believe it will be a no-brainer to incorporate one of these combinations into the first-line [setting].”

For example, the combination of pembrolizumab (Keytruda) and axitinib (Inlyta) was found to induce a significantly longer progression-free survival (PFS) and overall survival (OS) versus sunitinib (Sutent) in treatment-naïve patients with clear cell metastatic RCC, as per the phase III KEYNOTE-426 trial.¹ In April 2019, the FDA approved pembrolizumab in combination with axitinib for the frontline treatment of patients with advanced RCC, based on these data.

Secondly, results of the pivotal phase III JAVELIN Renal 101 trial demonstrated that the combination of avelumab (Bavencio) and axitinib led to a 31% reduction in disease progression or death versus sunitinib in treatment-naïve patients with advanced RCC, regardless of PD-L1 expression.² These data led to the May 2019 FDA approval of the combination for frontline use.

Furthermore, data from a subgroup analysis of JAVELIN Renal 101 were presented at the 2019 ASCO Annual Meeting. Data showed that PD-L1 expression ≥1% appeared to be the greatest predictor of benefit from the combination.³ It was associated with longest PFS in those who received the combination and shortest PFS those who received sunitinib (HR, 0.63; 95% CI, 0.49-0.81).

Combinations currently under investigation in this space include durvalumab (Imfinzi) plus savolitinib, as well as bevacizumab (Avastin) combined with atezolizumab (Tecentriq), Grigg added.

In an interview with OncLive, Grigg highlighted data from pivotal trials with combinations in both clear cell and non-clear cell RCC, as well as challenges with identifying biomarkers for immunotherapy.

OncLive: What key advances have been made with immunotherapy/TKI combinations in RCC?

Grigg: There were 2 major themes [at the 2019 Genitourinary Cancers Symposium] for RCC involving immunotherapy. The first, and probably the most high profile [advance], was in the first-line setting of clear cell RCC. There, we saw results from 2 studies.

The first one was the KEYNOTE-426 trial, which looked at the combination of pembrolizumab and axitinib versus sunitinib. That study met its primary endpoints of both improvement in OS and PFS, with a remarkable benefit. If you look at the OS at 1 year, it was an absolute improvement of over 10%, and that benefit seems to be extended out to at least 18 months. The other abstract that was presented contained the updated results from the JAVELIN Renal 101 trial. Data presented at the 2018 ESMO Congress showed an improvement in PFS with the combination of axitinib plus avelumab, which is a PD-L1 inhibitor over sunitinib in the first-line setting. Now, we’re seeing that the benefit in PFS, as well as very high response rates, seem to be consistent across all subgroups.

The other big theme had a little bit lower profile; there were advances made in non-clear cell RCC. We heard from 3 presenters who looked at 3 different immunotherapies or immunotherapy combinations in single-arm, phase II trials. One was the KEYNOTE-427 trial, which looked at pembrolizumab monotherapy. Then we saw the combination of durvalumab, which is a PD-L1 inhibitor, plus savolitinib, which is a MET inhibitor, as well as the combination of bevacizumab and atezolizumab.

While we shouldn't probably take away too much from single-arm, phase II trials, and we shouldn't be comparing across them, what is most noteworthy is that the objective response rates (ORR) in all 3 studies are virtually identical, around 25%. Historically, the response rates with single-agent TKIs are in the single digits or perhaps low double digits. I would argue that immunotherapy should probably in the immediate future be a part of first-line therapy, whatever we do or don’t combine it with for patients with non-clear cell RCC.

Are the toxicities associated with these immunotherapy/TKI combinations manageable?

Thus far, I don't believe we've seen the full results, but we haven't seen any unforeseen toxicities outside of what we would expect from either drug alone. Certainly, with some of the earlier studies that have been done—for example, with pazopanib (Votrient)—we did see some signals of possibly synergistic toxicity. In that case, it was hepatic toxicity. However, we haven't seen that yet with any of these newer combinations.

Some challenges exist in terms of interpreting [the source of] some toxicities. For example, diarrhea we can see with either [a TKI or an immunotherapy agent] alone. If the toxicity is related to the TKI versus if it’s an immune-related toxicity, it would be managed very differently. Therefore, there will be many challenges in terms of interpreting those toxicities in the future.

What future challenges do you foresee in terms of deciding between these regimens?

It's going to be really hard. I don’t believe we’re going to have any data for quite a while to compare between different TKI and immunotherapy combinations. Certainly, we still have the combination of ipilimumab (Yervoy) and nivolumab (Opdivo) that's approved for first-line use as well. We’ll have to bear in mind the toxicity profiles of the individual agents, but only time is going to tell. There are at least 4 phase II clinical trials ongoing that are attempting to address the role of ipilimumab in patients who have failed single-agent PD-1/PD-L1 [therapy], which may help us in thinking about how to incorporate that agent as we start to see these immunotherapy/TKI combinations become [FDA] approved.

Where do we stand in terms of biomarkers for immunotherapy?

The PD-L1 story has been equally as complex in RCC as it has been in other disease types. At this point, I don't believe that PD-L1 plays any role as a biomarker for RCC. There are certainly several other biomarkers. We're hearing about mutations in DNA repair defects, as well as PBRM1 and BAP1. There are several gene expression profiles that are being evaluated, but [currently] there are probably no biomarkers that are going to help us from that standpoint.

What is your take-home message for your colleagues working in the RCC space?

It’s a completely different landscape now than it was 5 years ago. We have so many new options. With these combinations, we're seeing that the vast majority of patients, at least in the first-line setting, derive significant benefit and can expect to live—in many cases—for years, which is something that we couldn't say 5 years ago.

References

1. Powles T, Plimack ER, Stus V, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for locally advanced or metastatic renal cell carcinoma (mRCC): a phase III KEYNOTE-426 study. J Clin Oncol. 2019;37(suppl 7; abstr 543). doi: 10.1200/JCO.2019.37.7_suppl.543.
2. Motzer RJ, Penkov K, Haanen JBAG, et al. JAVELIN renal 101: a randomized, phase III study of avelumab + axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma (aRCC). Ann Oncol. 2018;29(suppl 8; abstr LBA6_PR). doi: 10.1093/annonc/mdy424.036.
3. Choueiri TK, Albiges L, Haanen JB, et al. Biomarker analyses from JAVELIN Renal 101: avelumab + axitinib (A+Ax) versus sunitinib (S) in advanced renal cell carcinoma (aRCC). J Clin Oncol. 2019;37(suppl 15; abstr 101). doi: 10.1200/JCO.2019.37.15_suppl.101.