Pembrolizumab Prolongs PFS in Rare Sarcoma Subtypes

Data from the sarcoma cohort of the phase 2 AcSé basket study presented during the 2020 ESMO Virtual Congress showed that pembrolizumab (Keytruda) monotherapy prolonged progression-free survival (PFS) in selected rare sarcoma subtypes, supporting the immune checkpoint inhibitor’s (ICI’s) ability to improve outcomes across histotypes.¹

Jean-Yves Blay, MD, Phd, general director of the Centre Léon Bérard in Lyon, France, shared results from thesarcoma cohort, which enrolled 81 patients with rare sarcomas (incidence < 0.2/100,000/year) between September 4, 2017, and May 26, 2020. The AcSé study enrolled 24 patients with chodorma, 14 with alveolar soft-part sarcoma (ASPS), 5 with desmoplastic small round cell tumors (DSRCT), 6 with smarca4-malignant rhabdoid tumor (SMBT), and 32 with other histotypes, including epithelioid sarcoma, angiosarcoma, and chondrosarcoma, among others.¹

At a median follow-up of 228 days, the median PFS was 7.9 months. The median overall survival was 19.7 months, with 33 deaths. The PFS advantage differed by sarcoma subtype and was “superior in patients with alveolar soft part sarcoma, chordoma, and also in patients with desmoplastic small round cell tumors” compared with other histotypes, including SMBT, Blay said (P = .013). At the data cut-off in May 2020, the median PFS had not been reached in the chordoma and ASPS subsets. In the OS analysis, survival was also longer with chordoma and ASPS versus SMBT, DSCRT, and other subtypes (P = .081).¹

ASPS, chordoma, DSCRT, and SMBT are not consistently associated with TLS, PD-L1 expression, high tumor mutational burden, or cell infiltrates, which could be evaluated to select patients likely to respond to immunotherapeutic approaches.¹ “[These data suggest] that sarcoma can be responsive to immunotherapy using anti–PD-L1 in selected rare histological subtypes, and additional work is needed to better define the [role] of this treatment in the future for these rare subsets,” Blay said.

Confirmed objective response rate, the primary end point of the study, was partial response in 12 patients, translating to a PR rate of 15%. At 84 days and at the data cut-off date, March 17, 2020, there were no complete responses, but the disease control rate increased from 48% to 52% and the progressive disease rate decreased from 35% to 32%. Treatment benefit was most pronounced in patients with ASPS, SMBT, and epithelioid sarcoma, where 35.7% (5 of 14), 33.3% (2 of 6), and 20% (1 of 5) achieved a PR, respectively.¹

Patients received 200 mg of pembrolizumab every 21 days until progression, unacceptable toxicity, or patient or physician decision to halt therapy, for a maximum of 2 years. The median number of treatment cycles was 6 (interquartile range, 4-11). A total of 76% of patients prematurely discontinued pembrolizumab after a median of 4 cycles. Thirty-three patients died after a median of 3 cycles; 27 deaths were to cancer.¹

There were 88 toxicities recorded in 28 patients, 13 and 51 of which were related to pembrolizumab and disease progression, respectively. Six of the former toxicities were grade 3 in nature and included 1 cognitive disorder, 1 case of bullous pemphigoids, 1 instance of febrile aplasia, and 1 report of erysiplas. There was also 1 grade 4 case of lipasemia, which represented the sole grade 4 treatment related toxicity. Of the 7 grade 3 or 4 serious adverse events (AEs), 4 resulted in treatment withdrawals and 2, treatment interruption. AEs attributed to disease progression entailed 26, 5, and 1, grade 3, 4, and 5 events, respectively.¹

The AcSé Study

The nonrandomized, parallel arm, open-label AcSé trial (NCT03012620), launched by the French National Cancer Institute and sponsored by the French network of comprehensive cancer centers (Unicancer), is testing the safety and efficacy of pembrolizumab in patients with metastatic or refractory rare tumor types^.1 Specifically, the study is enrolling patients with unresectable locally advanced or metastatic disease that is resistant or refractory to standard therapy or for which no standard therapy exists or is contraindicated, and for which no other experimental treatment options are available.² Patients must not have received a diagnosis for any other malignancy within the past 5 years to be eligible to participate.¹

AcSé will enroll a maximum of 350 patients 15 years or older who have not received prior treatment with anti–PD1 or anti–PD-L1 across 7 cohorts: sarcoma, ovarian cancer, primary central nervous system lymphomas, thyroid cancer, malignant neuroendocrine cancer, germ-cell cancer, and natural killer/T-cell lymphoma.² Each cohort, excluding the sarcoma group, will accrue 20 to 50 patients. The 2-stage Bayseian enrichment trial design has a different objective for each stage. In the first stage, investigators will identify any “possibly sensitive indications” of efficacy; in the second, they will compare outcomes among subsets of patients in the identified cohorts to distinguish between subpopulations of patients who may benefit from pembrolizumab and patients for whom there is no evidence of efficacy. Use of pembrolizumab in this investigational context is supported by a nationwide exploratory program that has allowed access to anti–PD-L1 therapies outside of their existing indications.¹

Refining Checkpoint Blockade in Sarcoma

The rationale for evaluating pembrolizumab in the AcSé basket study is based on limited but observed activity with ICIs in unselected sarcoma populations, whether as single agents or combined with PD-1– or CTLA4–directed drugs. When co-administered with antiangiogenic agents, immunotherapy prolonged PFS in selected subtypes, including ASPS, Blay said. Immunologic monotherapy has also demonstrated anti-cancer capacities in rare subtypes such as chordoma and rhabdoid tumors.¹

Elucidating predictive biomarkers will help refine the role of immunotherapy in the treatment of sarcoma, but identifying these indicators is challenging because there are more than 150 “different types or molecular subtypes of disease,” Blay explained.¹ However, a paper published by Helmink et al in Nature in January 2020 specified B cells and tertiary lymphoid structures (TLS) as potential indicators of response to immune checkpoint blockade, providing a direction for biomarker-focused research in this space.³

“Additional translational research is foreseen to understand the determinants of response in these sarcoma histotypes,” Blay concluded.

References

1. Blay JV, Ray-Coquard I, Penel N, et al. High clinical benefit rates of single agent pembrolizumab in selected rare sarcoma histotypes: first results of the AcSé pembrolizumab study. Presented at: 2020 European Society for Medical Oncology Virtual Congress; September 19-21, 2020. Abstract 1619O.
2. Secured access to pembrolizumab for patients with selected rare cancer types. (AcSé). ClinicalTrials.gov. Updated November 1, 2019. Accessed September 21, 2020. https://clinicaltrials.gov/ct2/show/NCT03012620​
3. Helmink BA, Reddy SM, Gao J, et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature. 2020;577(7791):549-555. doi:10.1038/s41586-019-1922-8