ASCO Presentations Indicate Bright Future For Immunotherapy Combinations in Soft Tissue Sarcoma

Jonathan C. Trent, MD, PhD, a professor and associate director for Clinical Research at the Sylvester Comprehensive Cancer Center, University of Miami Health Syste

Jonathan C. Trent, MD, PhD

Research in the field of soft tissue sarcoma has increasingly supported the use of immunotherapy combinations as a potential new standard of care (SOC), according to Jonathan C. Trent, MD, PhD, as evidenced by several investigations of CTLA-4 and PD-1 inhibitors presented at the 2023 ASCO Annual Meeting.

Among these was a single-arm phase 2 trial (NCT04028063), which demonstrated that the addition of the CTLA-4 inhibitor zalifrelimab (AGEN1884) and PD-L1 inhibitor balstilimab to standard-of-care doxorubicin resulted in a 6-month progression-free survival (PFS) rate of 46.4% (95% CI, 28%-65%) in patients with difficult-to-treat soft tissue sarcoma subtypes. The median PFS with the combination was 24.4 weeks (range, 23.4-72.9). The historical median PFS observed with doxorubicin monotherapy has ranged from 4.1 to 6.8 months.¹

Additionally, data from a phase 2 trial (NCT04551430) showed that the combination of cabozantinib (Cabometyx), nivolumab (Opdivo), and ipilimumab (Yervoy) led to improved PFS and disease control rates (DCR) vs cabozantinib alone in patients with metastatic soft tissue sarcoma. The median PFS was 5.4 months with the combination vs 3.8 months with the monotherapy (P = .016). The DCRs were 80% and 42%, respectively (P =.0004). Notably, the combination improved activity despite crossover allowed from the monotherapy arm at the time of progression.²

“These combinations with immunotherapy and other agents seem to enhance efficacy with tolerable safety and are going to be the way of the future,” said Trent in an interview with OncLive® News Network: On Location at the meeting. “[Overall, it was] a very exciting [meeting, with data] that will lead to new therapies for our patients with sarcoma.”

In the interview, Trent discussed data from these phase 2 trials of immunotherapy in soft tissue sarcoma, as well as their clinical significance. He also highlighted 2 studies investigating biomarkers for treatment selection in gastrointestinal stromal tumor (GIST), including findings from an analysis of outcomes in patients without detectable circulating tumor DNA (ctDNA) enrolled in the phase 3 INTRIGUE study (NCT03673501).³

Trent is a professor at the University of Miami Miller School of Medicine and associate director for clinical research at the Sylvester Comprehensive Cancer Center, Miami, Florida.

OncLive: Doxorubicin is the SOC for patients with unresectable soft tissue sarcoma. How did the results of a phase 2 trial of doxorubicin plus zalifrelimab and balstilimab measure up to the hypothesis supporting the trial’s inception?

Trent: This is a great trial performed by Breelyn Wilky, MD, and her group [at the University of Colorado Cancer Center]. This trial looked at the activity of doxorubicin in combination with 2 novel immunotherapies: 1 PD-1 inhibitor and 1 CTLA-4 inhibitor. These new agents provide immunotherapy in combination with chemotherapy. Now, the choice of [using] doxorubicin as a single agent is somewhat controversial. At some centers, the SOC for metastatic high-grade soft tissue sarcoma is the combination of doxorubicin plus ifosfamide. Whether this new promising combination is better than doxorubicin plus ifosfamide [has yet to be answered]. Nonetheless, that combination did provide some promising results in this study. For instance, it provided a response rate in certain patients as high as 50% and did produce a PFS at 6 months that was better than expected.

Acknowledging the flaws of cross-trial comparisons, how might these data be incorporated in your practice at Sylvester Comprehensive Cancer Center?

Our question at Sylvester Comprehensive Cancer Center, and many other sarcoma centers around the world, is whether the combination of doxorubicin plus targeting CTLA-4 and PD-1 is better than doxorubicin plus ifosfamide. In some publications, doxorubicin plus ifosfamide [produced] response rates as high as 65%. We can’t do cross-trial comparisons, and we will not know the answer unless a prospective study is done comparing these 2 approaches. But it is good to see this single-arm study showing the safety and tolerability of this novel combination of chemotherapy and immunotherapy.

The combination of cabozantinib, nivolumab, and ipilimumab seems to have taken off in several tumor types. What can we conclude from looking at the results of the phase 2 trial of this combination in metastatic soft tissue sarcoma?

Cabozantinib is being explored not only in soft tissue sarcomas, but [in other tumor types like] bone tumors. [Data on] its [use in GIST] have already been published. This agent seems to have a lot of activity across many different soft tissue sarcoma histologies. [As] there’s 175 different sarcoma subtypes, that’s a meaningful agent. I was delighted to see this agent used in combination with immunotherapy.

[The study was] looking at targeting CTLA-4 and PD-1 [through] dual immunotherapy in combination with a multi-targeted kinase inhibitor in soft tissue sarcoma. It was a randomized study, which is not easy to perform in a rare disease. Sixty-nine patients received cabozantinib plus ipilimumab and nivolumab, and 36 received cabozantinib alone. The response rate with the combination was 11%, which is not great, but it shows some activity considering there will be patients who benefit in terms of stable disease with targeted immunotherapies. Single-agent cabozantinib [produced] a response rate of 6%. So, [the addition of ipilimumab and nivolumab] almost doubled the response rate. Although it’s a small amount, doubling the response rate [with] the combination is impressive, so we’re all excited about the promising activity. Interestingly, the combination also showed the ability to salvage patients who progressed on cabozantinib.

Due to the crossover design, patients with progression on cabozantinib crossed over to the combination of cabozantinib, ipilimumab, and nivolumab. Some of those patients had partial responses. It’s a useful combination either all together or perhaps sequentially. It was also reasonably well tolerated. The adverse effects with single-agent cabozantinib were very predictable [and in line] with what we’ve seen in other tumor types. The combination really reflected the addition of immune-oncology agents, with some hypothyroidism and some of the other toxicities we see with [this drug class. Subsequent biomarker analyses] were [conducted] by investigators that will be performing correlative studies. I believe we’ll learn a lot more about the activity of these agents in the future, and perhaps how to enhance them.

Several interesting approaches to treatment selection in GIST were presented at the meeting. Could you expand on some of those?

GIST is a sarcoma that’s driven by specific molecular aberrations, usually a mutation in the KIT or PDGFRA gene. There was a multiomic presentation at ASCO in the poster discussion. The multiomic analysis of almost 1000 patients with GIST showed that not only were there mutations in KIT or PDGFRA, but there were NF1, RAF, and NTRK mutations. Imatinib [Gleevec] is approved for gastrointestinal stromal tumors, but it wouldn’t make sense to treat a RAF-driven tumor, so we would use RAF inhibitors. In the case of NTRK, we would use larotrectinib [Vitrakvi] or entrectinib [Rozlytrek]. That was an exciting study.

Another [analysis] looked at ctDNA from the INTRIGUE study. INTRIGUE was a prospective clinical trial where patients with metastatic GIST were randomized to either sunitinib or ripretinib [Qinlock] in the second line. The overall study did not show any efficacy benefit. However, we’re now doing a subset analysis. There was [a past] presentation [that looked] at those exon 17–mutated patients. When you look at [those with] the exon 17 resistance mutation in GIST, they benefited substantially more from ripretinib than sunitinib in the study. That [result has] led to a prospective clinical trial that we’ll be opening soon to test the hypothesis of treatment based on ctDNA.

A second study of ctDNA looked at the subset from the same INTRIGUE study who didn’t have any ctDNA detected. [It might] sound odd [to be potentially] using that as a biomarker, but as it turns out, about one-fourth of patients with metastatic progressive GIST do not have detectable ctDNA in their blood. In this study, we looked at the subset of those patients who had ctDNA not detected [vs those] who had ctDNA detected.

There was a substantial superiority in PFS and overall survival [OS] if a patient had no detectable ctDNA, even if their tumors were progressive. The median OS wasn’t reached yet [in the] ctDNA-not-detected [population]. When you detect ctDNA, the median OS is about 28 months, which is fairly normal and predictable. [We may find] that not detecting ctDNA is a positive biomarker that we can share with our patients when we’re making decisions about therapy. The good news in the study was that whether ctDNA was detected or not, all the patients benefited equally from ripretinib and sunitinib.

What main message would you like to convey about this year’s meeting?

These are some exciting studies that we’ve discussed today. Combinations are the way to go [in sarcoma. This includes] the combinations presented [at this year’s meeting] and other combinations like axitinib [Inlyta] plus pembrolizumab [Keytruda].

There have been some great breakthroughs this year, all the way from [novel] biomarkers to prospective clinical trials, that are advancing the field of sarcoma. [This research indicates] a promising future for new, better tolerated, and more effective therapies.

References

1. Wilky BA, Maleddu A, Mailhot A, et al. A single-arm, open-label phase 2 trial of doxorubicin plus zalifrelimab, a CTLA-4 inhibitor, with balstilimab, a PD-1 inhibitor, in patients with advanced/metastatic soft tissue sarcomas. J Clin Oncol. 2023;41(suppl 16):11501. doi: 10.1200/JCO.2023.41.16_suppl.11501
2. Van Tine B, Eulo V, Toeniskoetter J, et. al. Randomized phase II trial of cabozantinib combined with PD-1 and CTLA-4 inhibition versus cabozantinib in metastatic soft tissue sarcoma. J Clin Oncol. 2023;41(suppl 17):LBA11504. doi:10.1200/JCO.2023.41.17_suppl.LBA11504
3. Trent J, Jones RL, George S, et al. Outcomes in patients with advanced gastrointestinal stromal tumor who did not have baseline ctDNA detected in the INTRIGUE study. J Clin Oncol. 2023;41(suppl 16):11536. doi: 10.1200/JCO.2023.41.16_suppl.11536