CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study

Our plain-English summary of CX-072 (pacmilimab), a Probody PD-L1 inhibitor, in combination with ipilimumab in patients with advanced solid tumors (PROCLAIM-CX-072): a first-in-human, dose-finding study, by R.E. Sanborn, O. Hamid, E.G. de Vries, et al (Journal for Immunotherapy of Cancer, 2021).

The study

• Authors: R.E. Sanborn, O. Hamid, E.G. de Vries, P.A. Ott, J. Garcia-Corbacho, V. Boni, J. Bendell, K.A. Autio, D.C. Cho, R. Plummer, M. Stroh, L. Lu, F. Thistlethwaite
• Journal: Journal for Immunotherapy of Cancer
• Published: 2021;9(7)
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Probody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing 'off-tumor' toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.

Methods: Adults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).

Results: Twenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3-4 adverse events (AEs) and grade 3-4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.

Conclusions: The MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

In plain English

This was an early-stage, open-label drug trial for cancer patients. It was not a study of asbestos exposure, and the article does not mention asbestos. The authors tested an experimental drug, pacmilimab, given together with the approved drug ipilimumab, to find the highest dose combination patients could tolerate. A total of 27 adults with advanced solid tumors were enrolled between January 2017 and September 2019. One of them had mesothelioma; the article does not say whether it was pleural or peritoneal. Dose-limiting side effects occurred in three patients, and the maximum tolerated dose was set at 10 mg/kg pacmilimab plus 3 mg/kg ipilimumab. Treatment-related side effects of grade 3–4 on the trial's severity scale occurred in nine patients (33%), and three patients (11%) stopped pacmilimab because of side effects. Across all 27 patients the tumor response rate was 19% (95% CI 6.3% to 38.1%). This was one complete response and four partial responses, and one of the partial responses was in the patient with mesothelioma. The authors concluded that the combination was active and had a favorable tolerability profile. They noted that their conclusions are limited by 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: Phase 1/2, open-label, multicenter drug trial; this report covers the phase 1 dose-escalation part (standard 3+3 design) of pacmilimab combined with ipilimumab
• Who was studied: 27 adults with advanced or metastatic solid tumors of 21 different types who had not previously received PD-1/PD-L1 or CTLA-4 inhibitors, enrolled January 2017 to September 2019 at sites in six countries; one patient had mesothelioma
• Exposure: No asbestos exposure was studied. Patients received the drugs pacmilimab (0.3, 1, 3 or 10 mg/kg) and ipilimumab (3 or 6 mg/kg; one patient received 10 mg/kg) every 3 weeks for four doses, followed by pacmilimab alone every 2 weeks
• Main results:
  • Dose-limiting toxicities occurred in three of 27 patients: one at the 0.3+3 dose level (grade 3 dyspnea) and two at the 10+6 dose level
  • The maximum tolerated dose was 10 mg/kg pacmilimab plus 3 mg/kg ipilimumab
  • Among all 27 patients, treatment-related grade 3–4 adverse events occurred in nine (33%) and grade 3–4 immune-related adverse events in six (22%)
  • Three patients (11%) stopped pacmilimab because of adverse events; no grade 5 (fatal) toxicity was observed
  • Overall response rate among all 27 patients was 19% (95% CI 6.3% to 38.1%), with one complete response and four partial responses
  • One of the four partial responses was in the single patient with mesothelioma (site of the mesothelioma not stated)
  • Among the five responders, response duration ranged from 1.9 to 32.2 months; four kept a response for more than 1 year
• The authors' conclusion: The authors concluded that the maximum tolerated and recommended phase 2 dose (pacmilimab 10 mg/kg plus ipilimumab 3 mg/kg every 3 weeks) is active and has a favorable tolerability profile
• Limitations the authors state:
  • The conclusions that can be drawn are limited by the small sample size
  • The comparison of side-effect rates between ipilimumab doses was limited by the number of patients treated

Topics

Medical terms in this study, explained in our Lexicon: PD-L1, Ipilimumab (Yervoy), Tumor Microenvironment, checkpoint inhibitors, CTLA-4, Dyspnea, Pneumonitis, Squamous Cell Carcinoma.

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