Cabozantinib/Atezolizumab Combo Provides Durable Benefit in Non–clear Cell RCC, Across Histological Subtypes

Cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) showcased durable clinical activity in patients with non–clear cell renal cell carcinoma (RCC), with some responses lasting for more than 18 months and continued disease control observed, according to extended 3-year follow-up data from the phase 1b/2 COSMIC-021 trial (NCT03170960).1 The findings underscore the potential utilization of immuno-oncology (IO) and TKI combinations across varying histological subtypes of the disease, according to Bradley A. McGregor, MD.

Prior data from the dose-escalation portion of the trial demonstrated that, at a median follow-up of 13.3 months, the doublet elicited an objective response rate (ORR) of 31% (80% CI, 20%-44%) in those with non–clear cell RCC (n = 32), with a disease control rate (DCR) of 94% and a median progression-free survival (PFS) of 9.5 months (95% CI, 6.4-18.3).²

Extended follow-up findings from cohort 10 presented at the 2023 Genitourinary Cancers Symposium showed that at a median follow-up of 37.2 months, cabozantinib plus atezolizumab still had an ORR of 31% (95% CI, 16.1%-50.0%) with a DCR of 94% (95% CI, 79.2%-99.2%).1 Notably, responses were observed across histological subtypes, with ORRs of 47% and 11% in those with papillary and chromophobe disease, respectively.

The median PFS by investigator assessment and RECIST v1.1 criteria was 9.3 months (95% CI, 5.5-12.3). In those with papillary disease, the median PFS was 8.1 months; it was 10.8 months in those with chromophobe histology. The median OS had not yet been reached.

“It’s a very exciting time…and we’re getting a lot of data [on] different combinations [under exploration]. We’re starting to appreciate that histology-directed therapy, which we used to think was impossible, may be the way [forward],” McGregor, lead study author, as well as a senior physician and the clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts, told OncLive^®. “Hopefully we can do genomic analysis [as we have done with] trials such as [COSMIC-021] to figure out the difference between these histologies and how to improve care for these patients.”

In the interview, McGregor, who is also an instructor of medicine at Harvard Medical School, discussed the clinical significance of the updated COSMIC-021 data, how these findings support the continued investigation of IO/TKI combinations in non–clear cell RCC, and other efforts underway to better care for patients with varying histological subtypes of the disease.

OncLive^®: Could you provide some background on the COSMIC-021 trial of cabozantinib and atezolizumab in non–clear cell RCC, and expand on the patient population in cohort 10?

McGregor: COSMIC-021 was a large, multi-institutional, multi-cohort study looking at the combination of cabozantinib and atezolizumab in solid tumors. This included cohorts across a variety of genitourinary tumors, as well as other malignancies. This abstract looked at updated results [from] the cohort of [patients with] non-clear cell RCC. We previously presented results [from] this trial over a year ago, [which had] a median follow-up of 1 year. Now, we have over 3 years of follow-up.

This cohort [included] patients with varying histologies, [including] papillary, chromophobe [or other]. Patients [received] 40 mg of cabozantinib [daily] with 1200 mg of intravenous atezolizumab every 3 weeks. Patients were kept on therapy until unacceptable toxicity or clinical progression [was observed]. Notably, patients who had radiographic progression but who were deriving clinical benefit could [continue] therapy. Just over half of patients [had] papillary [disease], and the [remaining patients had a] variety of other tumor types.

What efficacy and safety data from cohort 10 were reported at the 2023 Genitourinary Cancers Symposium? What are the clinical implications of these results?

Overall, the updated ORR was comparable to what we’ve seen before. What’s impressive [about] this 3-year follow-up is that there were no new toxicity signals. At this point in time, 5 patients remain on therapy. Some of these patients had maintained radiographic progression, and then developed radiographic regression again. This really does highlight that beyond the ORR we have seen in the past, there seems to be some patients who derive durable benefit. I think that’s really important [to note].

We’ve had a lot of trials looking at different IO/TKI combinations in varying [histologies of] RCC, [such as] cabozantinib and nivolumab [Opdivo] or lenvatinib [Lenvima] plus pembrolizumab [Keytruda]. Both had an ORR of close to 50%, but the median duration of follow-up has been short. [Although] the PFS and ORR didn’t [significantly] change with this prolonged follow-up, [we saw that] some patients derived a prolonged benefit. It will be interesting to see whether this [benefit] holds up with the other IO/TKI combinations.

[Additionally,] no new safety signals [were reported. This doublet] remains a well-tolerated regimen with toxicity that [was as] expected. Of note, the dose of cabozantinib in this cohort was 40 mg daily—[not] the 60-mg daily [dose] that is being studied in the ongoing CONTACT-03 trial [NCT04338269].

How has this research inspired the continued investigation of IO/TKI combinations across varying histological subtypes of RCC?

This trial paved the way for the CONTACT-03 trial looking at cabozantinib and atezolizumab vs cabozantinib [alone] in patients who are refractory to IO-based therapies. Notably, this is one of the first trials to include [those with] clear cell and papillary RCC. We saw [in COSMIC-021] that [patients with] papillary disease had responses comparable to what we see with clear cell [RCC].

Ultimately, [these findings] show that we need to continue to do more for these patients with variant histology RCC. I alluded to multiple trials we have done with cabozantinib/nivolumab and lenvatinib/pembrolizumab [for this population]. We [also] have an investigator-initiated [phase 2] trial [NCT04413123] that [is being done at Dana-Farber Cancer Institute and is] looking at the combination of cabozantinib with nivolumab and ipilimumab [Yervoy] for those patients. We look forward to seeing those results.

Has this trial revealed any remaining unmet needs in RCC? If so, what can be done to address them?

What we have seen with these data, as well as [with] the other IO/TKI combinations, is that those patients with chromophobe RCC do not seem to respond as well to IO-based therapy. The response [rate] with these IO/TKI combinations [in this population] is generally less than 15%. That [represents] an unmet need [in this space]. We need to find new avenues [for research.] Data on lenvatinib and everolimus [Afinitor] showed that [some] patients with chromophobe [RCC] responded [to the regimen], which is exciting. We need to continue to look at new options for those patients, but it’s a very exciting time.

What key trials are on the horizon in non–clear cell RCC?

There [will] be [other] single-arm, phase 2 trials that are looking at different IO/TKI combinations [in addition to] our trial [of] cabozantinib, nivolumab, and ipilimumab.

We’re looking forward to some randomized trials like the [phase 2] SUNNIFORECAST trial [NCT03075423], which is looking at nivolumab and ipilimumab vs sunitinib [Sutent] in [non–clear cell] RCC. There is the [phase 2] PAPMET2 study [NCT05411081] of cabozantinib and atezolizumab vs cabozantinib, and there are other trials looking at TKI/IO combinations vs sunitinib. [We hope to] start seeing some data showing that this doublet, [which] looked impressive in phase 2, is better than a monotherapy in these randomized trials. At the same time, trying to find biomarkers of response and better understand the different tumor biologies is going to be critical [in] advancing care for these patients.

What data were you most excited to see presented at the 2023 Genitourinary Cancers Symposium, and what could they mean for the paradigm?

[Although] we didn’t have a large, phase 3 trial presented [at the meeting] this year in RCC, we’re seeing some updates on existing data [that are] intriguing. The benefit of IO monotherapy or IO/IO [in allowing patients to experience] a treatment-free interval is a great [advance]; learning more about [this benefit] will be critical

The extended follow-up of IO/TKI combinations [like] nivolumab and cabozantinib, [which showed] a marked improvement in the mean OS, is interesting and critical to our understanding of the potential [to achieve] durable responses with these different regimens.

Subset analysis of [the phase 3] KEYNOTE-564 [trial (NCT03142334)], highlighted that pembrolizumab not only benefits those with M1 or no evidence of disease, but seems to benefit [those with] intermediate- or high[-risk] patients that we see every day in the clinic. There’s not going to be major, practice-changing [data from these studies], but there will be a lot of practice-informing abstracts that will help us choose the best therapy as we talk with our patients in clinic.

Editor’s Note: Dr McGregor reports serving in a consultory or advisory role for Astellas Pharma, Bristol-Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Genentech/Roche, Merck, Pfizer, Seattle Genetics/Astellas, he received research funding from Bristol-Myers Squibb (Inst), Calithera Biosciences (Inst), Exelixis (Inst), Pfizer/EMD Serono (Inst), Seattle Genetics/Astellas (Inst).

References

1. McGregor B, Agarwal N, Suárez C, et al. Cabozantinib in combination with atezolizumab in non-clear cell renal cell carcinoma: extended follow-up results of cohort 10 of the COSMIC-021 study. J Clin Oncol. 2023:41(suppl 6):684. doi:10.1200/JCO.2023.41.6_suppl.684
2. Pal SK, McGregor B, Suárez C, et al. Cabozantinib in combination with atezolizumab for advanced renal cell carcinoma: results from the COSMIC-021 study. J Clin Oncol. 2021;39(33):3725-3736. doi:10.1200/JCO.21.00939