Experts Spotlight Ongoing Efforts Evaluating Immunotherapy in Sarcoma

Roman Groisberg, MD

Despite encouraging data shown in some subtypes, there is still a lot of work that still needs to be done with regard to determining the optimal use for immunotherapy in patients with sarcoma, a population that has historically been difficult to treat.

“When assessing the data presented during the 2020 ASCO Virtual Scientific Program, it’s tough to miss the elephant in the room: Many patients do not respond to dual checkpoint inhibitor therapy,” said Roman Groisberg, MD. “Since some patients demonstrated 100% growth in tumor size, additional research is of critical importance.”

In a special episode of OncLive^® On Air, Shiraj Sen, MD, PhD, associate director of Drug Development at Sarah Cannon Research Institute, and Groisberg, a medical oncologist at Rutgers Cancer Institute, highlighted ongoing research efforts evaluating the use of immunotherapy in the rapidly-evolving sarcoma treatment paradigm that were presented during the medical meeting.

Neoadjuvant Checkpoint Blockade Proves Safe, Well Tolerated in DDLPS and UPS

Neoadjuvant nivolumab (Opdivo) or nivolumab plus ipilimumab (Yervoy) with or without radiation therapy appeared to be safe and well tolerated in patients with surgically resectable undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS), according to preliminary results of a phase 2 study (NCT03307616) presented during the meeting.¹

In the randomized phase 2 study, investigators sought to evaluate the pathologic response of neoadjuvant single-agent nivolumab and nivolumab plus ipilimumab with and without radiation therapy in treatment-naïve patients with UPS or locally recurrent DDLPS. The key secondary end points of the trial included objective response rate (ORR) per RECIST v1.1 criteria, 12- and 24-month recurrence-free survival, safety in the neoadjuvant setting, and patient-reported outcomes.

“The study design is neat because it provides insight on how these drugs are working,” said Groisberg. “Ultimately, it’s assessing the activity on a tumor level rather than a radiographic level, which is typically done in these types of studies.”

A total of 24 patients were included in the analysis. Of these patients, 14 with surgically resectable DDLPS were randomized 1:1 to receive 3 mg/kg of nivolumab every 2 weeks for 3 cycles (n = 7; cohort A) or 1 mg/kg of ipilimumab plus 3 mg/kg of nivolumab for 1 cycle followed by 3 mg/kg of nivolumab every 2 weeks for 2 cycles (n = 7; cohort B). A total of 9 patients with surgically resectable UPS were randomized 1:1 to receive 3 mg/kg of nivolumab for 1 cycle followed by 50Gy of radiation therapy plus 3 mg/kg of nivolumab once every 2 weeks for 3 cycles (n = 5; cohort C) or 1 mg/kg of ipilimumab plus 3 mg/kg of nivolumab for 1 cycle followed by 50 Gy of radiation therapy plus 3 mg/kg of nivolumab once every 2 weeks for a total of 6 cycles (n = 4; cohort D).

Results showed significant clinical activity in patients with UPS who received nivolumab plus radiation and ipilimumab/nivolumab plus radiation, with a median hyalinization rate of 93%; these data compare favorably with the 5% to 10% median hyalinization rate seen with historical controls. However, limited responses were observed in the DDLPS cohorts, with a median hyalinization rate of just 8.75%.

“These are interesting data because, along with [findings from] other studies, they showed the impact of radiation on hyalinization in sarcoma subtypes,” Sen noted.

With regard to safety, between both cohorts, 8 patients experienced grade 3 adverse effects (AEs): 1 patient in cohort A, 3 in cohort B, 2 in cohort C and 2 in cohort D. Moreover, 1 patient developed metastasis while receiving neoadjuvant treatment. Unique grade 3 AEs included renal failure (1 patient in cohort A), colitis (2 cohort B, 2 cohort C, 2 cohort D), hyperbilirubinemia (1 cohort B), and leukocytosis (1 cohort B).

Nivolumab/Ipilimumab Shows Encouraging Responses in DDLS and UPS

In the open-label multicenter phase 2 ALLIANCE A091401 trial (NCT02500797), nivolumab monotherapy and nivolumab plus ipilimumab demonstrated response rates of 5% and 16%, respectively, in patients with advanced sarcoma. Notably, these responses were observed in those with UPS, myxofibrosarcoma, leiomyosarcoma, sarcoma not otherwise specified, and alveolar soft part sarcoma (ASPS).² Efficacy results from 3 expansion cohorts—gastrointestinal stromal tumor (GIST), UPS, and DDLPS—were reported during the meeting.

Results showed that in the DDLPS and UPS expansion cohorts, the primary end point of 6-month response rate was met with the combination of nivolumab plus ipilimumab, but not with single-agent nivolumab.³

In the randomized phase 2 analysis, investigators sought to determine the efficacy of nivolumab and nivolumab plus ipilimumab in patients with GIST, UPS, and DDLS, who were refractory to at least 1 regimen.

“For a while now, there has been talk in the sarcoma community that a single-agent PD-1 inhibitor may not yield any benefit in terms of efficacy, but that the combination may be worth exploring,” said Groisberg.

Across the 3 expansion cohorts, a total of 79 patients were randomized to receive either 3 mg/kg of nivolumab every 2 weeks or 3 mg/kg of nivolumab every 3 weeks for 4 cycles then given every 2 weeks plus 3 mg/kg of ipilimumab every 3 weeks for 4 cycles.

Results showed that the ORR with nivolumab/ipilimumab was 28.6% in patients with UPS and 14.3% in patients with DDLS versus 7.7% and 6.7% with nivolumab alone, respectively. In the GIST cohort, neither the combination nor nivolumab led to a confirmed response.

“I’m having a tough time determining whether the combination, with an ORR of 28.6%, is going to be any better than a single-agent checkpoint inhibitor,” Sen said. “Although, this abstract certainly does argue that dual checkpoint inhibitor therapy in UPS appears to show better response. Looking at spider plots can help us better determine how durable these responses are.”

Additionally, in the DDLS cohort, the median progression-free survival (PFS) was 4.6 months with nivolumab alone versus 5.5 months with the combination, while the median OS was 8.1 months with nivolumab monotherapy versus 13.1 months with nivolumab/ipilimumab. In the UPS expansion cohort, the median PFS was 1.5 months versus 2.7 months with nivolumab and nivolumab/ipilimumab, respectively, while the median OS was 6.6 months with nivolumab monotherapy and had not estimable with the combination. In the GIST cohort, the median PFS was 1.5 months with nivolumab alone versus 2.9 months with the combination, while the median OS was 9.1 months and 12.2 months, respectively.

Durvalumab and Tremelimumab Elicits Encouraging Response Rates in Advanced/Metastatic Sarcoma

In addition to histology, a higher tumor-infiltrating lymphocyte immune score can help predict clinical benefit, according to results from a phase 3 trial (NCT02815995) assessing durvalumab (Imfinzi) and tremelimumab in patients with advanced or metastatic sarcoma.⁴

In the single-center, open-label phase 2 trial, investigators sought to assess the efficacy of the combination of durvalumab and tremelimumab in specific sarcoma subtypes, including liposarcoma (n = 6), ASPS (n = 10), chordoma (n = 5), osteosarcoma (n = 5), UPS (n = 5), synovial sarcoma (n = 5), vascular tumors (n = 10), and other (n = 11). The primary end point of the trial was to determine the PFS rate at 12 weeks, as defined by RECIST criteria. Key secondary end points included tumor response, PFS and OS, as well as safety and tolerability.

In the analysis, patients 12 years of age or older with advanced/metastatic sarcoma were separated into subtype-specific cohorts. Patients received 1500 mg of durvalumab every 4 weeks plus 75 mg of tremelimumab every 4 weeks for 4 cycles followed by durvalumab alone every 4 weeks for up to 12 months or until intolerable toxicity or disease progression.

Results showed that durvalumab/tremelimumab elicited a response rate of 14.3%. In the liposarcoma cohort, 50% of patients achieved stable disease (SD) with the combination and 50% experienced disease progression (PD). In the ASPS subgroup, 50% had a partial response (PR) to the treatment, 40% had SD, and 10% had PD. In those with chordoma, 20% achieved a PR with the combination, 60% had SD and 20% had PD.

Moreover, in those with osteosarcoma, 20% achieved SD while the majority, or 60%, had PD. In the UPS cohort, 20% had PR, 20% had SD, 40% had PD, and 20% had unconfirmed PD (uPD). In the synovial sarcoma cohort, 40% had SD, 20% had PD, and 40% had uPD with the treatment. Ten percent of those with vascular tumors had PR, while 10% had SD, 70% had PD, and 10% had uPD with the combination. In the “other” subgroup, 27% had SD, 45% had PD, and 27% had uPD.

“This is incredible because these patients have always been tough to treat. Now, several subtypes are showing response rates of at least 50%, most likely after progressing on other therapies," said Sen. “However, many patients do not respond, indicating that we still have a long way to go with this research.”

Additional results showed that the median 12-month OS with the durvalumab/tremelimumab combination was 65% for all patients, while the 24-month OS was 49%. The median PFS was 49% at 12 weeks, 28% at 12 months, and 15% at 24 months for all patients.

When broken down by cohort, the median PFS was 34.23 months in the ASPS cohort, 13.57 months in the chordoma cohort, 2 months in the LPS cohort, 2.43 months in the other cohort, 1.81 months in the osteosarcoma cohort, 7.46 months in the synovial sarcoma cohort, 1.81 months in the UPS cohort, and 1.81 months in the vascular-tumors cohort.

Moreover, the median OS was not reached (NR) in the ASPS subgroup, NR in the chordoma subgroup, 10.99 months in the LPS subgroup, 13.31 months in the other subgroup, 7.72 months in the osteosarcoma subgroup, 32.79 months in the synovial sarcoma subgroup, 4.99 months in the UPS subgroup, and 16.41 months in the vascular tumors subgroup.

With regard to safety, a total of 14 patients (24.6%) experienced grade 3 or higher treatment-related AEs; these included lung infection (1.75%), pneumonitis(5.25%), myocarditis (3.51%), thrush (1.75%), and colitis (5.26%), among others.

Reflections on Immunotherapy in Sarcoma

“We spoke about 3 abstracts in 2 different settings with similar agents. In my own practice, when it comes to certain subtypes such as UPS, I won’t offer these patients a checkpoint inhibitor clinical trial until they fail on at least 1 line of chemotherapy,” Groisberg concluded. “On the other hand, in subtypes such as synovial sarcoma, I will have them go through a few cycles of chemotherapy before I offer them a checkpoint inhibitor clinical trial.”

References

1. Roland CL, Keung EZ, Lazar AJ, et al. Preliminary results of a phase II study of neoadjuvant checkpoint blockade for surgically resectable undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma. J Clin Oncol. 2020;38(suppl 15):11505. doi:10.1200/JCO.2020.38.15_suppl.11505
2. D’Angelo SP, Mahoney MR, Van Tine BA, et al. Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): two open-label, non-comparative, randomised, phase 2 trials. Lancet Oncol. 2018;19(3):416-426. doi:10.1016/S1470-2045(18)30006-8
3. Chen JL, Mahoney MR, George S, et al. A multicenter phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401): results of expansion cohorts.J Clin Oncol. 2020;38(suppl 15):11511. doi:10.1200/JCO.2020.38.15_suppl.11511
4. Somaiah N, Conley AP, Lin HY, et al. A phase II multi-arm study of durvalumab and tremelimumab for advanced or metastatic sarcomas. J Clin Oncol. 2020;38(suppl 15):11509. doi:10.1200/JCO.2020.38.15_suppl.11509