A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma

Our plain-English summary of A Phase 1 Safety Study of Avelumab Plus Stereotactic Body Radiation Therapy in Malignant Pleural Mesothelioma, by A. Rimner, P.S. Adusumilli, M.D. Offin, et al (JTO Clinical and Research Reports, 2023).

The study

• Authors: A. Rimner, P.S. Adusumilli, M.D. Offin, S.B. Solomon, E. Ziv, S.A. Hayes, M.S. Ginsberg, J.L. Sauter, D.Y. Gelblum, A.F. Shepherd, D.M. Guttmann, J.E. Eichholz, Z. Zhang, E. Ritter, P. Wong, A.N. Iqbal, R.M. Daly, A. Namakydoust, H. Li, M. McCune, E.H. Gelb, N.K. Taunk, D. von Reibnitz, N. Tyagi, E.D. Yorke, V.W. Rusch, M.G. Zauderer
• Journal: JTO Clinical and Research Reports
• Published: 2023;4(1):100440
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Single-agent monoclonal antibody therapy against programmed death-ligand 1 (PD-L1) has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the antitumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. We present the results of a phase 1 trial to evaluate the safety of the anti-PD-L1 antibody avelumab plus SBRT in patients with malignant pleural mesothelioma.

Methods: This was a single-arm, investigator-initiated trial in patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to one lesion in three to five fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary end point of the study was safety on the basis of grade 3+ nonhematologic adverse events (AEs) within 3 months of SBRT.

Results: Thirteen assessable patients received a median of seven cycles (range: 2-26 cycles) of avelumab. There were 27 grade 1, 17 grade 2, four grade 3, and no grade 4 or 5 avelumab-related AEs. The most common were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade 1, four grade 2, one grade 3, and no grade 4 or 5 SBRT-related AEs. The most common were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2).

Conclusions: Combination avelumab plus SBRT seems tolerable on the basis of the prespecified toxicity end points of the first stage of this Simon two-stage design phase 1 study.

© 2022 The Authors.

In plain English

This phase 1 trial at Memorial Sloan Kettering Cancer Center in New York tested the safety of combining the immunotherapy avelumab with focused radiation (stereotactic body radiation therapy, SBRT) to one tumor lesion. Fifteen people with malignant pleural mesothelioma that had progressed after chemotherapy enrolled between January 2018 and September 2019. Thirteen were assessable; 6 of these self-reported occupational asbestos exposure. Two of the 13 patients had a total of four grade 3 (severe) treatment-related side effects: an infusion-related allergic reaction, chest wall pain, muscle pain and loss of appetite. No avelumab-related or SBRT-related grade 4 or 5 side effects were observed. The safety goal was met, but the study stopped after its first stage because limited effectiveness was seen. Of nine patients assessed by scans, the irradiated lesion had a partial response in one and was stable in eight. Non-irradiated lesions were stable in five and progressed in four. For all 13 assessable patients, median progression-free survival was 3.7 months and median overall survival 12.1 months. The authors concluded the combination was feasible and tolerable, noting the small sample size.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Single-arm, investigator-initiated phase 1 trial with a two-stage design; only the first stage (13 patients) was carried out
• Who was studied: 15 patients with pathologically confirmed malignant pleural mesothelioma enrolled at Memorial Sloan Kettering Cancer Center, New York, between January 2018 and September 2019. All had at least one prior line of chemotherapy and no plan for surgery. 13 were assessable: median age 71 (range 51–82), 11 male and 2 female; 9 epithelioid, 2 biphasic, 2 sarcomatoid.
• Exposure: Treatment studied: avelumab (anti-PD-L1 antibody) 10 mg/kg every other week. After two priming doses, SBRT was given to one lesion in three to five fractions (minimum 30 Gy), and avelumab continued for up to 24 months or until disease progression. Asbestos exposure was recorded only as a patient characteristic, not studied.
• Main results:
  • Among the 13 assessable patients, 6 (46%) reported asbestos exposure, defined as self-reported classic occupational exposure; 4 (31%) reported none and 3 (23%) were unknown.
  • Patients received a median of seven (range 2–26) cycles of avelumab over a median of 3.5 months.
  • The median SBRT dose was 30 Gy in three fractions (range 24–35 Gy in three to five fractions).
  • Two of 13 patients had a total of four grade 3 nonhematologic treatment-related adverse events: an infusion-related allergic reaction, chest wall pain, myalgia and anorexia.
  • No avelumab-related grade 4 or 5 adverse events were observed.
  • The most common avelumab-related grade 2 or higher adverse events were infusion-related allergic reactions (6 patients), followed by anorexia or dehydration (3 patients) and fatigue or hypothyroidism (2 patients each).
  • The only grade 3 SBRT-related adverse event was noncardiac chest pain in one patient, likely a pain flare after SBRT. Three patients had grade 2 events possibly related to SBRT. There were no SBRT-related grade 4 or 5 events.
  • The first-stage primary safety end point was met, but because limited efficacy was observed, the study did not continue to stage 2.
  • Of the 9 patients available for RECIST assessment, the irradiated lesion showed a partial response in 1 patient and stable disease in 8. All irradiated lesions were locally controlled at the end of follow-up.
  • Among the same 9 patients, the non-irradiated lesion showed stable disease in 5 and disease progression in 4, with no partial or complete responses.
  • In all 13 assessable patients, median progression-free survival was 3.7 months and median overall survival was 12.1 months.
  • There was no clear correlation of clinical response with PD-L1 expression; 8 patients had 0% PD-L1 expression. There was also no clear association between tumor mutation burden and progression-free survival.
• The authors' conclusion: The authors concluded that SBRT combined with avelumab is feasible and tolerable with an acceptable rate of adverse events. They found the effect seemed additive rather than synergistic and said further research is needed.
• Limitations the authors state:
  • The sample size was small because the study stopped after the first planned stage, so a larger study would be needed for a more robust toxicity assessment.
  • The small sample size limited assessment of the anticancer effects of avelumab plus SBRT.
  • Correlative (biomarker) analyses were limited because only one patient responded to avelumab.

Topics

Medical terms in this study, explained in our Lexicon: Stereotactic Body Radiation Therapy (SBRT), Pleural Mesothelioma, Monoclonal Antibody, PD-L1, Immunotherapy, Chemotherapy, Disease Progression, Dyspnea.

Related studies

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• Managing oligoprogressive malignant pleural mesothelioma with stereotactic body radiation therapy — A.R. Barsky, N. Yegya-Raman, et al. (2021)
• A reply to "managing oligoprogressive malignant pleural mesothelioma with stereotactic body radiation therapy" — G.L. Ceresoli, P. Ghirardelli, et al. (2021)
• Expansion Phase 1 Study of Pegargiminase Plus Pemetrexed and Cisplatin in Patients With Argininosuccinate Synthetase 1-Deficient Mesothelioma: Safety, Efficacy, and Resistance Mechanisms — P.W. Szlosarek, M.M. Phillips, et al. (2020)
• Phase II trial of neoadjuvant pemetrexed plus cisplatin followed by surgery and radiation in the treatment of pleural mesothelioma — R. Federico, F. Adolfo, et al. (2013)
• A Novel Prospective Study Assessing the Combination of Photodynamic Therapy and Proton Radiation Therapy: Safety and Outcomes When Treating Malignant Pleural Mesothelioma — S.R. Rice, Y.R. Li, et al. (2019)

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