Patients With Pretreated Sarcoma May Derive Benefit From Various Immunotherapy Combinations

Combination therapy strategies involving immune checkpoint inhibitors and a secondary agent have shown promise across sarcoma subtypes, according to analysis of clinical trial data that were presented at the European Society for Medical Oncology Sarcoma & GIST Symposium 2020, held in Milan, Italy.¹

“Combining strategies seems to be more effective than anti—PD-1 alone in sarcomas,” Javier Martin-Broto, MD, PhD, a medical oncologist at the University Hospital Virgen del Rocio in Seville, Spain, wrote in his presentation of the data. Martin-Broto compared sarcomas within the immune context of melanoma, a cancer which has experienced significant benefit with the integration of PD-1/PD-L1 inhibitors into treatment paradigms. In general, sarcomas have a much lower mutational burden than melanoma tumors and are less likely to be positive for PD-L1 expression.

Tumor mutational burden by subtype for angiosarcomas, undifferentiated pleomorphic sarcomas, and leiomyosarcomas is typically in the range of 2 to 3 mutations/ megabase versus <2 mutations/megabase that is observed with myxofibrosarcomas, liposarcoma, and synovial sarcoma. Even within certain subtypes, mutational burdens can range in value as demonstrated by the 13% of angiosarcomas with >20 mutations/megabase.

Martin-Broto began by exploring data &nbsp;related &nbsp;to the use of the PD-1/CTLA-4 inhibitor combination&nbsp;of nivolumab &nbsp;(Opdivo) &nbsp;plus &nbsp;ipilimumab &nbsp;(Yervoy) &nbsp;or nivolumab monotherapy in patients with advanced or unresectable sarcoma who had received at least 1 prior line of therapy. This patient cohort was heavily pretreated, with more than half of patients (61%) having received at least 3 prior lines &nbsp;of therapy.&nbsp;

Complete responses were observed in 5% of patients undergoing the combination therapy. Partial responses were observed in 5 patients (13%) treated with the combination and in 3 patients (8%) who received monotherapy. The corresponding confirmed objective response rates were 5% and 16% with clinical benefit rates of 18% and 29%, respectively.²

The investigators concluded that the combination cohort met the trial&rsquo;s primary end point, with responses observed &nbsp;in leiomyosarcomas, myxofibrosarcoma, undifferentiated pleomorphic sarcomas, and angiosarcoma, and the survival rate at 1 year for the combination cohort exceeded expectations for these patients. However, high rates of grade &nbsp;3/4 adverse events were observed with the combination (14% vs 7%).²

&ldquo;Targeting 2 checkpoints offers higher ORRs [objective response rates] and PFS [progression-free survival] and could be improved if treatment can be prolonged for both,&rdquo; &nbsp;Martin-Broto wrote.

Another potentially viable strategy being explored is the combination of PD-1 inhibitors with an antiangiogenic agent, which are&nbsp;thought to enhance the efficacy of immunebased cancer therapies. Angiogenic factors, such as vascular endothelial growth factor A, may have suppressive effects on the &nbsp;immune response and may induce expression of inhibitory molecules such as PD-1 (FIGURE).³

According to Martin-Broto, &ldquo;Antiangiogenic and anti—PD-1 seems to offer better disease control in selected sarcoma subtypes than monotherapy.&rdquo;

In a phase II trial, pembrolizumab (Keytruda) was combined with axitinib (Inlyta) for use in patients with previously treated advanced sarcoma, including those with alveolar soft-part sarcoma who accounted for 36% of the population. Thirty-six percent of patients had 2 or more prior lines of therapy, 51% had received prior tyrosine kinase inhibitors, and 61% had an ECOG performance status score of 0.4

Out of 32 total patients, 8 (25%) experienced a partial response and 9 (28%) had stable disease, for a clinical benefit rate of 53.1%. These results coupled with a manageable toxicity profile led investigators to conclude that this combination has activity in patients with advanced sarcomas, especially alveolar softpart sarcoma, and should be studied further.

In a phase II trial, patients with advanced soft tissue sarcoma were treated with the combination of sunitinib (Sutent) and nivolumab. The trial met its primary end point, with a 6-month PFS rate of 50% at 6 months. The overall survival rate at 6 months was 77%.⁵

Another phase I/II trial examined chemoimmunotherapy in patients with advanced sarcoma using doxorubicin with pembrolizumab. After the recommended dose for doxorubicin was determined in phase I, a 24-week PFS rate of 73% was observed in phase II. This compared favorably with the 30% PFS rate that was gleaned from data out of a retrospective cohort. The response rate was 22%.⁶

Other strategies that warrant further investigation include combining PD-1 inhibition with anti-LAG3 agents, radiotherapy, and IDO1 inhibitors, among other treatment strategies, Martin-Broto concluded.

References

1. Martin Broto J. Combination immunotherapy attempts. Presented at: European Society for Medical Oncology Sarcoma & GIST Symposium 2020; February 3-5, 2020; Milan, Italy. bit.ly/3dzJ0LQ.
2. D&rsquo;Angelo SP, Mahoney MR, Van Tine BA, et al. A multi-center phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401).J Clin Oncol. 2017;35(suppl 15; abstr 11007). doi: 10.1200/JCO.2017.35.15_suppl.11007
3. Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales.Nat Rev Immunol. 2011;11(10):702-711. doi:10.1038/nri3064
4. Wilky BA, Trucco MM, Subhawong TK, et al. Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: a single-centre, single-arm, phase 2 trial.Lancet Oncol. 2019;20(6):837-848. doi: 10.1016/S1470-2045(19)30153-6
5. Martin Broto J, Hindi N, Grignani GE, et al. IMMUNOSARC: a collaborative Spanish (GEIS) and Italian (ISG) sarcoma groups phase I/II trial of sunitinib plus nivolumab in advanced soft tissue and bone sarcomas: results of the phase II- soft-tissue sarcoma cohort.Ann Oncol. 2019;30(suppl 5; abstr 1669O). doi: 10.1093/annonc/mdz283.002
6. Pollack S, Redman MW, Wagner M, et al. A phase I/II study of pembrolizumab (Pem) and doxorubicin (Dox) in treating patients with metastatic/unresectable sarcoma.J Clin Oncol.2017;37(suppl 15; abstr 11009). doi: 10.1200/JCO.2019.37.15_suppl.11009