Limited Role for ICI Rechallenge in RCC Spurs Interest in More Tailored Later-Line Strategies

Evan T. Hall, MD, MPhil

Despite the lack of clinical benefit generated by immune checkpoint inhibitor (ICI) rechallenge for most patients with advanced renal cell carcinoma (RCC) who have progressed on prior immunotherapy, ongoing research is seeking to clarify the application of this strategy in select patient subgroups, according to Evan T. Hall, MD, MPhil, who added that increasingly tailored later-line RCC regimens are also of interest for this patient population.

Several clinical trials have studied the potential efficacy of checkpoint inhibitor rechallenge following progression on prior ICIs in patients with RCC. The phase 3 CONTACT-03 trial (NCT04338269) evaluated the efficacy and safety of atezolizumab (Tecentriq) plus cabozantinib (Cabometyx) in patients with metastatic RCC (mRCC) who had progressed on prior ICI.1 This study did not show a clinical benefit with atezolizumab plus cabozantinib (n = 263) vs cabozantinib alone (n = 259) and the median progression-free survival (PFS) in these respective populations was 10.6 months (95% CI, 9.8-12.3) and 10.8 months (95% CI, 10.0-12.5; stratified HR, 1.03 [95% CI, 0.83-1.28; P = .784]).

Additionally, the phase 3 TiNivo-2 trial (NCT04987203) employed a similar design to CONTACT-03, investigating the efficacy and safety of tivozanib (Fotivda) plus nivolumab (Opdivo) in patient with mRCC who had previously received an ICI.2 This trial showed that the addition of nivolumab to tivozanib did not improve clinical outcomes vs tivozanib alone in this combination, with respective median PFS durations of 5.7 months (95% CI, 4.0-7.4) and 7.4 months (95% CI, 5.6-9.2; HR, 1.10 [95% CI, 0.84-1.43; P = .49]).

Notably, no patient subgroups appeared to particularly benefit from ICI rechallenge in either trial.1,2

“There is nuance in different clinical scenarios, but for most patients who have received an immunotherapy-based treatment in the first-line setting, continuing that same drug beyond progression doesn’t seem to add benefit, as we’ve now seen in 2 large studies,” Hall said in an interview with OncLive®.

In the interview, Hall discussed the limited potential for immunotherapy rechallenge in patients with RCC who have experienced a long gap following prior immunotherapy exposure, the potential for combining VEGFR TKIs with HIF-2α inhibitors due to their non-overlapping toxicity profiles, and unmet needs for patients with RCC in later lines of treatment.

Hall is a physician and assistant professor in the Clinical Research Division at the Fred Hutchinson Cancer Center in Seattle, Washington, as well as an assistant professor at the University of Washington School of Medicine.

OncLive: Although data have shown that ICI continuation or rechallenge in the second-line setting shouldn’t be part of routine clinical practice for most patients with RCC, are there some patient populations that might benefit from this strategy?

Hall: The question of continuing PD-1 or PD-L1–directed antibody therapy in a patient who’s actively progressing on it has largely been sorted out. However, there’s nuance. If it’s been a few years since a patient had exposure to an immunotherapy agent that maybe they had a good initial benefit with, is rechallenge in that patient potentially useful? That wasn’t answered conclusively in either the [CONTACT-03 or TiNivo-2] studies. Then [there is] the question of: What about [rechallenge with] a different immunotherapy? Later-line use of ipilimumab plus nivolumab seems to benefit a small fraction of patients [if it is] not the same immunotherapy they have already progressed upon.

What patient characteristics and disease features inform your decision to use ipilimumab plus nivolumab in later-line settings?

[The RCC field has been] trying to decide that if we are going to give ipilimumab plus nivolumab in the second-line or beyond, who might that [ideal] patient be? I was thinking hard about that and trying to define that patient population, and I found it easier to define patients who I probably wouldn’t do that for. Patients who have high-volume or high-symptom disease, or those who’ve experienced bad immunotherapy toxicities already, would be patients who I would be worried about [giving this regimen to] because it’s not frequent that patients [in the later-line setting] have a treatment response.

Conversely, patients with limited-volume disease or those who have sarcomatoid features are patients who may generally be more responsive to immunotherapy. Many of those patients [receive immunotherapy] as a first-line treatment. However, if they haven’t for some reason, that could be considered [in later lines]. Additionally, in patients with a long treatment interval—who have received ipilimumab plus nivolumab [in the first-line setting], it worked well, and now it’s 4 or 5 years later—it does not seem reasonable to consider using that treatment again.

What available data could explain the potential synergistic mechanisms of action of VEGFR TKIs and HIF-2α inhibitors?

Large studies are being done [to answer this question]. There have been a couple attempts to combine drugs in the VEGFR TKI class with HIF inhibitor drugs. [These classes of agents] seem to at least cooperate on a toxicity basis. The toxicities of the 2 drug classes are not particularly overlapping, so [these combinations] seem tolerable.

Although [these agents are] not [directed at] the same targets, there is crosstalk between the hypoxia pathway and the VEGF pathway. We need to see a compelling signal that combination treatment [with these classes of agents] adds significant benefit. There may be true synergy, but we’re still in the learning stage for that. Encouragingly, though, it’s not like both drug classes [are associated with] terrible diarrhea [that becomes] intolerable when you give them together. The unique adverse effects [(AEs) associated with] each class seem to be complementary, so they seem to be relatively well tolerated in combination.

What novel immunotherapy combination regimens are under investigation in the second- and later-line RCC settings?

There’s always going to be the use of and interest in novel checkpoint inhibitor drugs. Different checkpoint inhibitor drugs have been explored and approved thus far. There’s always a cross-pollination [of drugs] between kidney cancer and other cancer types, but there are many immune checkpoints.

We have drugs that block PD-1, PD-L1, and CTLA-4. LAG-3 [inhibition] in kidney cancer hasn’t been incredibly promising thus far, although it’s been tested mainly in patients in later lines. There are many other ICIs in early-phase trials, and studying those to see whether there could be a signal in kidney cancer will be useful.

There are other immune approaches [as well]. Bispecific antibodies, which have made their way into other branches of cancer, are in clinical trials. [There are] different attempts to try to harness the power of hormones that stimulate immune cells, called cytokines, and to build upon what we know about cytokines like interleukin-2. Those are all variations of different types of immunotherapy that may eventually show promise and work their way into our treatment algorithm, but they are early in our study, so we’re still examining the safety and efficacy of many of those new approaches.

What unmet needs remain for patients with later-line RCC that future research may address?

One unmet need is a second chance at long-term disease control. We believe that for most patients, enduring disease control and the opportunity to even stop treatment for a period and not have the cancer regrow—which is called a treatment-free interval—is an immunotherapy phenomenon. TKIs can help keep some patients’ cancer in check during treatment, but we think that if they stop that therapy, the cancer usually starts to regrow. Having a second or third [treatment] attempt that can induce long-term remission and the ability to stop treatment in a fraction of patients would be great, because right now we have one immunotherapy-based attempt, and then we’re largely using non-immunotherapy agents.

We also need more drug targets that have different toxicity profiles. A lot of patients with kidney cancer are older. They have comorbidities like coronary artery disease, heart failure, [history of] stroke, or diabetes, and the drug classes we have in the later lines [are associated with] risks that interact with those comorbidities. It would be nice to have several more [treatment options] instead of just a few baskets of treatments to choose from so we could pick a treatment with a nice tolerability and safety profile for an individual patient based upon their comorbidities. Right now, most of our treatments fall into a few baskets, so sometimes we’re left with uncomfortable decisions about using drugs that may interact with the comorbidities of a patient, and patients may be at higher risk of AEs because of that. [Patients need] more options and [drugs with] different mechanisms, with the hope that perhaps we can find better fits for individual patients in the second- and third-line settings.

Disclosures: Hall reported receiving institutional research funding from NiKang Therapeutics, Bristol Myers Squibb, Neoleukin Therapeutics, Replimune, Checkmate Pharmaceuticals, Nektar Therapeutics, ImCheck Therapeutics, Pfizer, Gilead, Kezar Life Sciences, and Immunocore; as well as performing consulting roles with Eisai and Microbiotica.

References

1. Choueiri TK, Albiges L, Tomczak P, et al. Efficacy and safety of atezolizumab plus cabozantinib vs cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC): primary PFS analysis from the phase 3, randomized, open-label CONTACT-03 study. J Clin Oncol. 2023;41(suppl 17):LBA4500. doi:10.1200/JCO.2023.41.17_suppl.LBA4500
2. Choueiri TK, Motzer RJ, Beckermann K, et al. Tivozanib–nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma (RCC) following 1 or 2 prior therapies including an immune checkpoint inhibitor (ICI): results of the phase III TiNivo-2 study. Ann Oncol. 2024;35(suppl 1):S1261-S1262. doi:10.1016/j.annonc.2024.08.2316