Commentary

Article

Pursuit of Effective Agents Continues in Multiple Types of Sarcomas

Author(s):

Research has continued to focus on developing novel therapies and bringing new treatments to the sarcoma treatment paradigm.

Robert Maki, MD, PhD

Robert Maki, MD, PhD

Although there are still several areas of unmet need for the treatment of patients with various types of sarcomas, positive findings from multiple clinical trials have led to optimism among clinicians in the field and are inspiring them to expedite the development of more effective agents for these patients, according to a presentation given by Robert Maki, MD, PhD, during the 41st Annual CFS®.1

“Sarcomas represent less than 1% of all cancers that occur in adults and [approximately] 10% to 12% of the cancers that occur in children,” Maki, a sarcoma oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center and a professor of medicine at Weill -Cornell Medical College, both in New York, New York, said during the presentation. “The problem is the complexity. There are approximately 70 different subtypes of sarcoma, separate from each other histologically, not to mention the genetic entities. Now we have over 400 mutations and translocations that are associated with variations of these tumors.”

Gastrointestinal Stromal Tumors

Maki began his presentation with a discussion of gastrointestinal stromal tumors (GIST), which he identified as probably the most common type of sarcoma. Approximately 3500 diagnoses of GIST occur in the Unites States each year, he said. However, he noted that there is a well-defined treatment strategy for this class that usually follows the order of imatinib (Gleevec), sunitinib (Sutent), and regorafenib (Stivarga); however, there is still a need for additional options for patients who do not derive benefit from these approaches.

The phase 3 INVICTUS trial (NCT0335375) enrolled adult patients with advanced GIST who experienced disease progression on at least imatinib, sunitinib, and regorafenib, or had documented intolerance to any of these treatments. Patients were randomly assigned in a 2:1 manner to receive the TKI ripretinib (Qinlock; n = 85) or placebo (n = 44). The primary end point was progression-free survival (PFS) by blinded independent central review (BICR) and they secondary end point was objective response rate (ORR) by BICR.2

At a median follow-up of 6.3 months (interquartile range [IQR], 3.2-8.2), the median PFS was 6.3 months (95% CI, 4.6-6.9) in the ripretinib arm compared with 1.0 months (95% CI, 0.9-1.7) in the placebo arm (HR, 0.15; 95% CI, 0.09-0.25; P < .0001). The ORR was 9.4% (95% CI, 4.2%-17.7%) vs 0%, respectively. The median overall survival (OS) was 15.1 months (95% CI, 12.3-15.1) compared with 6.6 months (95% CI, 4.1-11.6), respectively (HR, 0.36; 95% CI, 0.21-0.62; P = .004), although Maki noted that this was dependent upon the response end point.

In terms of safety, the most common grade 1./2 treatment-related adverse effects (TRAEs) in the investigational arm included alopecia (49%), myalgia (27%), and nausea (25%). In the placebo arm (n = 43), these events occurred at rates of 2%, 9%, and 2%, respectively.

Maki highlighted that in the phase 1 NAVIGATOR trial (NCT02508532), investigators examined another TKI, avapritinib (Ayvakit), for the treatment of patients with unresectable PDGFRA D842V–mutant GIST that progressed on imatinib and at least 1 TKI. The primary end point was the maximum tolerated dose and secondary end points included ORR and safety.3

Preliminary efficacy findings showed that 98% of patients who received avapritinib (n = 36) in the dose-expansion portion of the study experienced tumor size reduction. In the safety population, patients treated at all dose levels (n = 231) did not experience any grade 5 treatment-emergent adverse effects (TEAEs), and only 9% of patients discontinued treatment due to TEAEs. The most common any-grade AEs consisted of nausea (61%), fatigue (55%), and anemia (46%); Maki noted that most AEs were grade 1 or 2.

“It takes a large effort to find this group of patients with metastatic disease, but when you do find them, the drug is active and [FDA] approved,” Maki said. “There will be some memory impairment in people who are on this compound, which is a little bit scary and something you have to watch for. This medication also can be used for mast cell tumors, if you have any patients with that diagnosis.”

Alveolar Soft Part Sarcomas

Maki transitioned his presentation to briefly discussing recent updates in the alveolar soft part sarcoma space. The phase 2 Study ML39345 (NCT03141684) examined the TKI atezolizumab (Tecentriq) in adult and pediatric patients with advanced metastatic alveolar soft part sarcoma. The primary end point was ORR and secondary end points included PFS and duration of response (DOR).4

At the July 31, 2022, data cutoff, the ORR was 37% (95% CI, 24%-51%) among efficacy-evaluable patients (n = 52), including 1 patient with a confirmed complete response. The median DOR was 24.7 months (95% CI, 4.1-55.8) and the median PFS was 20.8 months. Maki noted that PD-1/L1 expression was not a factor in terms of response and patients had a very low tumor mutational burden.

On December 9, 2022, the FDA approved atezolizumab for the treatment of adult and pediatric patients 2 years of age and older with unresectable or metastatic alveolar soft part sarcoma. The approval was supported by findings from Study ML39345.5

Maki also pointed out that other TKIs had previously shown some activity in patients with alveolar soft part sarcoma, presenting results from the phase 2 CASPS trial (NCT01337401). The study evaluated cediranib (Recentin) in patients with metastatic alveolar soft part sarcoma that had progressed in the previous 6 months. The primary end point was the percentage change in the sum of target lesion diameters between baseline and week 24 or progression, if sooner.6

At a median follow-up of 34.3 months (IQR, 23.7-55.6), patients who received cediranib (n = 32) experienced an ORR of 19%, all of which were partial responses (PRs), compared with 0% for placebo (n = 16). However, the median PFS was 10.1 months (IQR, 5.3-19.0) compared with 4.9 months (IQR, 1.9-20.0) for patients in the cediranib and placebo arms, respectively (HR, 0.82; 95% CI, 0.47-1.43; P = .28). Moreover, the median OS was 27.8 months (IQR, 18.8-63.2) vs 47.3 months (IQR, 7.8–not reached [NR]), respectively (one-sided log-rank P = .48).

“[There was] a similar response rate [compared with atezolizumab] with the use of cediranib,” Maki said. “But if you take a look at the PFS, it's only approximately 10 months compared with 25 months for responders with atezolizumab. So clearly, there's a durability of the response that really was meaningful. [In atezolizumab] we now have that standard of care.”

Well-Differentiated and Dedifferentiated Liposarcomas

Maki opened the section of his presentation concerning well-differentiated and dedifferentiated liposarcomas by explaining that CDK4 inhibitors have shown minor activity in dedifferentiated liposarcomas. He also noted that the agents have relatively low toxicity and an adequate PFS rate. However, these agents have low response rates, underscoring the need for additional therapies in the space, he said.

In a phase 1, first-in-human study (NCT01877382) of the MDM2 inhibitor milademetan (RAIN-32) enrolled patients with advanced solid tumors or lymphomas. Patients with dedifferentiated liposarcomas (n = 53) experienced a median PFS of 7.2 months (95% CI, 3.8-10.1); those with dedifferentiated liposarcomas who received the agent via an extended/continuous dosing schedule (n = 30) and an intermittent dosing schedule (n = 23) achieved a median PFS of 6.3 months (95% CI, 3.8-10.0) and 7.4 months (95% CI, 2.7-14.6), respectively. Investigators concluded that the agent had notable activity as a monotherapy in patients with dedifferentiated liposarcomas, prompting the initiation of a phase 3 trial.7

However, on May 22, 2023, Rain Oncology, the manufacturer of milademetan, announced that the phase 3 MANTRA trial (NCT04979442), which evaluated milademetan vs trabectedin (Yondelis) in patients with unresectable and/or metastatic dedifferentiated liposarcomas who had received at least 1 prior systemic therapy, did not meet its primary end point. The median PFS in the investigational arm was 3.6 months vs 2.2 months in the control arm, resulting in just an 11% relative reduction in the risk of progression or death (HR, 0.89; 95% CI, 0.61-1.29; P = .53).8

“The idea that was different with this agent was that [it is administered] via intermittent scheduling, with patients getting treatment 3 days out of every 14, not with a continuous dosing as has been done in the past,” Maki said. “There was a decent, not great, median PFS [in the phase 1 trial], but it did not hold up in the randomized phase 3 trial. As a result, this was [deemed] a negative study and the drug has been pulled by-and-large, unless there's some idea to further change the schedule, maybe with more intensive therapy and less frequency.”

On the other hand, Maki noted that in a phase 1 trial (NCT03449381), another MDM2 inhibitor, BI 907828, showed activity in the realm of normally hard-to-treat well-differentiated liposarcoma. Patients with well-differentiated liposcarcoma who received the agent (n = 15) experienced a PR rate of 27% by RECIST v1.1 criteria. The dose-expansion phase of the study is ongoing.9

“I've never seen anything like this, this was quite remarkable,” Maki said. “The ORR [for patients with] well-differentiated liposarcoma to chemotherapy of any sort is zero, as far as the teaching that I have for our fellows. This is the first time I've seen any consistent change for the better of this diagnosis.”

Desmoid Tumors

Finally, Maki discussed an ongoing clinical trial in patients with desmoid tumors, the phase 3 DeFi study (NCT03785964). He noted that although few deaths are directly attributed to these tumors, there’s a high degree of morbidity from local invasion of normal tissues.

DeFi is examining the γ-secretase inhibitor nirogacestat in adult patients with progressing desmoid tumors. Patients were randomly assigned 1:1 to receive nirogacestat (n = 70) or placebo (n = 72). The 2-year PFS rates were 76% vs 44%, respectively (HR, 0.29; 95% CI, 0.15-0.55; P < .001). Study authors concluded that nirogacestat provided significant benefits over placebo regarding PFS, ORR, pain, symptom burden, and health-related quality of life, and that most AEs were low grade.10

“This was a positive phase 3 study, and this data will be going to the FDA,” Maki said in conclusion. “We hope to see more work in therapy for [sarcomas]. Not even mentioned are these cancers that occur more commonly in kids, osteosarcomas, where we have had no new therapy over the past 30 plus years. There is plenty of work to do in this area. We are going to be more aggressive about our tactics in studying these agents.”

Editor's Note: Clinicians referring a patient to MSK can do so by visiting msk.org/refer, emailing referapatient@mskcc.org, or by calling 833-315-2722.

References

  1. Maki R. Sarcoma and connective tissue tumor update. Presented at: 41st Annual CFS®; November 8-10, 2023; New York, NY.
  2. Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020;21(7):923-934. doi:10.1016/S1470-2045(20)30168-6
  3. Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020;21(7):935-946. doi:10.1016/S1470-2045(20)30269-2
  4. Chen AP, Sharon E, O'Sullivan-Coyne G, et al. Atezolizumab for advanced alveolar soft part sarcoma. N Engl J Med. 2023;389(10):911-921. doi:10.1056/NEJMoa2303383
  5. FDA grants approval to atezolizumab for alveolar soft part sarcoma. News release. FDA. December 9, 2022. Accessed November 9, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-approval-atezolizumab-alveolar-soft-part-sarcoma
  6. Judson I, Morden JP, Kilburn L, et al. Cediranib in patients with alveolar soft-part sarcoma (CASPS): a double-blind, placebo-controlled, randomised, phase 2 trial. Lancet Oncol. 2019;20(7):1023-1034. doi:10.1016/S1470-2045(19)30215-3
  7. Gounder MM, Bauer TM, Schwartz GK, et al. A First-in-human phase I study of milademetan, an MDM2 inhibitor, in patients with advanced liposarcoma, solid tumors, or lymphomas. J Clin Oncol. 2023;41(9):1714-1724. doi:10.1200/JCO.22.01285
  8. Rain oncology announces topline results from phase 3 MANTRA trial of milademetan for the treatment of dedifferentiated liposarcoma. News release. Rain Oncology Inc. May 22, 2023. Accessed November 9, 2023. https://www.rainoncology.com/news-press-releases/rain-oncology-announces-topline-results-from-phase-3-mantra-trial-of-milademetan-for-the-treatment-of-dedifferentiated-liposarcoma
  9. Schoeffski P, Yamamoto N, Bauer T, et al. A phase I dose-escalation and expansion study evaluating the safety and efficacy of the MDM2–p53 antagonist BI 907828 in patients (pts) with solid tumours. Ann Oncol. 2022;33(suppl 7):S743. doi:10.1016/j.annonc.2022.07.581
  10. Gounder M, Ratan R, Alcindor T, et al. Nirogacestat, a γ-secretase inhibitor for desmoid tumors. N Engl J Med. 2023;388(10):898-912. doi:10.1056/NEJMoa2210140
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