PD-1 Inhibitors Gain Momentum in Soft Tissue Sarcomas

Breelyn Wilky, MD

Among immunotherapies, PD-1 inhibitors are gaining the most attention for the treatment of patients with sarcoma, said Breelyn Wilky, MD. Many current studies have honed in on the possible effectiveness of this strategy, though additional research is needed to discover additional checkpoint inhibitors and indications of possible response in subgroups of sarcoma.

“We know that sarcoma patients, even with the same histology, can demonstrate dramatically different responses to chemotherapy or targeted therapy, and I’d argue it’s also the case for immunotherapy. Thus the bulk of our efforts needs to be focused on establishing effective biomarkers of response to checkpoint inhibitors,” Wilky said.

Progress and possibilities in the field of immunotherapy in soft tissue and bone sarcomas were presented by Wilky, associate professor of medicine, Sylvester Comprehensive Cancer Care, University of Miami Health System, during the 2016 ASCO Annual Meeting.

Overall, more responses were seen in the soft tissue sarcomas than in the bone sarcomas. There were also a few strong responses among sarcoma subtypes that require further investigation.

The SARC028 phase II trial testing pembrolizumab (Keytruda) in advanced soft tissue and bone sarcomas showed that treatment was the most promising in undifferentiated pleomorphic sarcoma, dedifferentiated liposarcoma, and synovial sarcoma.¹

Bone sarcomas showed fewer responses, with only 2 patients expressing partial responses for an objective response rate (ORR) of 5%. However, patients with chondrosarcoma showed a median progression-free survival of 14 weeks.

Bone tumors, especially Ewing sarcomas, may grow too rapidly for the immune system to be able to catch up and respond, Wilky said. However, the possibility was raised that RECIST, the usual method for judging responses, may not be an accurate method of assessment for bone sarcomas.

The ORR for soft tissue sarcomas was 19% and an additional 40% of patients had a best response of stable disease. Eleven of 37 patients showed tumor regression. The median follow-up was 7.5 months with a 4-month progression-free survival (PFS) rate of 44% (95% CI, 22%-66%), which was a significant improvement on the historical PFS control rate of 20%.

There was a lack of response for leiomyosarcoma in this trial as well as in the phase II trial of PD-1 inhibitor nivolumab (Opdivo) in metastatic uterine leiomyosarcoma, which was found to be ineffective, with no objective responses observed. In this study, 12 women were treated with nivolumab monotherapy, but each of the patients had progressive disease as of 3 months.²

A study of nivolumab in patients with relapsed metastatic sarcomas revealed a response in 20 soft tissue sarcoma patients who received at least 4 doses of nivolumab either with or without combination pazopanib (Votrient), a tyrosine kinase inhibitor (TKI).³One patient with dedifferentiated chondrosarcoma showed an excellent partial response and was still continuing treatment as of 9 months.

Further expansion trials in histology-based cohorts, particularly for sensitive histologies, have been recommended to continue to test the efficacy of the drug. However, Wilky said, we will miss those rare responders in other subtypes. Wilky provided the example of a dedifferentiated chondrosarcoma patient which registered a response during the third month, demonstrating the delayed benefit of immunotherapy treatments.

“It’s important to remember that immunotherapy works slowly and it may impart delayed overall survival benefits even after initial progression, so it’s critical that we continue to follow patients treated in this manner for overall survival as well as any overall response to subsequent therapies,” Wilky said.

PD-1 inhibitor agents showed an overall survival (OS) benefit in patients who had progressed on prior treatments, and an improved response for subsequent therapies was also suggested, but a longer follow-up is needed for confirmation.

Understanding more of the biomarkers for response would potentially increase the effectiveness of checkpoint inhibitor therapies, and help discover which patient populations would have the best response to the treatment.

PD-L1 is an important predictive biomarker of response in other tumor types. Most tumors with high PD-L1 expression will respond better to PD-1 directed therapies. However, PD-L1 is also effective in PD-L1-negative tumors. About 20% of sarcomas positively express PD-L1 (≥1%), but its expression may not be a requirement for response to PD-1 therapies.

Other possible predictive biomarkers for checkpoint blockade are currently under investigation after showing progress in other tumor types. IDO1 and KYN, which are both highly expressed in sarcomas, show potential as predictive biomarkers. According to a study of PD-L1, IDO, and KYN in soft tissue sarcomas, approximately 42% of sarcomas positively express IDO1 (≥5%) and 59% express KYN (≥1%). KYN+ tumors showed an improved OS compared to KYN- tumors.⁴

“This suggests that an altered immunologic milieu within a sarcoma may be potentially predictive for a response to therapy. And I would argue that these markers should be included in our future correlative analysis for any patients treated on checkpoint inhibitors as potentially they may emerge to be predictive biomarkers for immunotherapy,” Wilky urged.

Most sarcomas appear to not be immunogenic. In other tumor types the use of chemotherapy, radiation, TKIs, and more can induce an immunogenic response, but this has not been seen yet in sarcomas.

“Perhaps we’re using checkpoint inhibitor therapy too late in our treatment of sarcomas and we might see better results moving it earlier in treatment to take advantage of neoantigen release from traditional treatments,” said Wilky.

Earlier immunotherapy treatments or treatment in combination with other agents, which has been shown to benefit other tumor types, may help to boost the body’s immune response over time.

References:

1. Tawbi HA, Burgess MA, Crowley J, et al. Safety and efficacy of PD-1 blockade using pembrolizumab in patients with advanced soft tissue (STS) and bone sarcomas (BS): Results of SARC028—A multicenter phase II study.J Clin Oncol34, 2016 (suppl; abstr 11006).
2. George S, Barysauskas CM, Solomon S, et al. Phase 2 study of nivolumab in metastatic leiomyosarcoma of the uterus.J Clin Oncol34, 2016 (suppl; abstr 11007).
3. Paoluzzi L, Ghesani MV, Cacavio A, et al. Anti-PD1 therapy with nivolumab in sarcoma.J Clin Oncol34, 2016 (suppl; abstr 11047).
4. Toulmonde M, Adam J, Bessede A, et al. Integrative assessment of expression and prognostic value of PDL1, IDO, and kynurenine in 371 primary soft tissue sarcomas with genomic complexity.J Clin Oncol34, 2016 (suppl; abstr 11008).