On August 4, 2021 CytomX Therapeutics, Inc. (Nasdaq: CTMX), a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational conditionally activated therapeutics based on its Probody technology platform, reported the publication of three articles in peer-reviewed journals on pacmilimab (CX-072), the Company’s wholly-owned conditionally activated antibody directed against PD-L1 currently being developed in combination with praluzatamab ravtansine (CX-2009) for the treatment of triple-negative breast cancer (TNBC) (Press release, CytomX Therapeutics, AUG 4, 2021, View Source [SID1234585799]).
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"My colleagues and I are delighted to see our ground-breaking work on the CytomX Probody therapeutic platform being published in high quality journals as we continue to lead this emerging and important field," said Sean McCarthy, D.Phil., president, chief executive officer and chairman of CytomX Therapeutics. "These comprehensive first-in-human results with the first ever Probody therapeutic candidate evaluated in clinical studies provide robust evidence that Probodies function as designed, eliciting potent anti-tumor activity in the context of enhanced systemic tolerability. Our technology is enabling a wide range of potentially first-in-class therapies against previously undruggable targets and also new combination therapies, opening up different ways of thinking about cancer treatment."
Constructed using CytomX’s industry-leading conditional activation Probody platform, each Probody therapeutic has a unique built-in mask that limits target binding in healthy tissues, while localizing its activation in the tumor microenvironment. This conditional activation is achieved by enabling mask removal by specific enzymes called proteases, which are activated in the tumor microenvironment, but tightly controlled in healthy tissues. Upon removal of the mask in the tumor microenvironment, Probody therapeutics engage their targets and destroy the cancer cells they were ultimately activated by.
While immune checkpoint inhibitor (ICI) therapies have transformed the landscape of cancer treatment, the limited response rates observed for cancer patients treated with single-agent PD-1/PD-L1 or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) blocking antibodies leave significant room for improvement. Conventional anti-PD-1/PD-L1 therapies can be impaired by immune-related adverse events (irAEs), which have been reported in as many as 30% of patients in Phase 3 studies, and particulary in combination settings.1
Pacmilimab (CX-072) is a Probody therapeutic directed against PD-L1 designed and developed by CytomX. Pacmilimab is engineered to be conditionally activated in the tumor microenvironment by tumor-associated proteases and to remain predominantly masked in the circulation. In preclinical studies, pacmilimab induced anti-tumor responses comparable to those of the parental anti-PD-L1 antibody and demonstrated reduced toxicity. Pacmilimab is wholly owned by CytomX.
First-in-human PET Imaging Study of Pacmilimab Biodistribution Published in Clinical Cancer Research
To evaluate the effect of Probody modifications on biodistribution and pharmacokinetics, we, in collaboration with Elisabeth G.E. de Vries, MD, PhD., Professor of Medical Oncology at the University Medical Centre Groningen, Groningen, the Netherlands, studied the biodistribution of pacmilimab labeled with the positron emission tomography (PET) isotope, zirconium-89 (89Zr), in patients with locally advanced or metastatic malignancies.
89Zr-labeled pacmilimab was found to be intact in the blood for up to 7 days and predominantly in its masked form in circulation, consistent with Probody design. All patients showed uptake of radioactivity into tumor lesions. Tumor-to-blood ratio of radioactivity increased over time, indicating that tumor uptake of pacmilimab is specific and retained in the tumor.
"This is the first human imaging report of a Probody therapeutic candidate that is conditionally activated in the tumor microenvironment," stated Marcia P. Belvin, Ph.D., senior vice president and head of research of CytomX Therapeutics. "The findings of intact pacmilimab in the circulation, modest uptake in normal lymphoid organs, and accumulation in the tumor, all support mechanistic performance of the Probody therapeutic platform, with target engagement in the tumor and reduced target engagement in normal tissues."
First-in-human Study of Pacmilimab in Patients with Advanced Solid Tumors Published in the Journal for ImmunoTherapy of Cancer
Patients with advanced solid tumors who were naïve to ICI therapies were eligible for this Phase 1/2 multicenter study. After the dose escalation (n=53) was complete and a recommended dose for future study defined, an additional 98 patients were enrolled into the dose expansion phase of the study, with pacmilimab administered intravenously at 10 mg/kg, the recommended Phase 2 dose (RP2D), every two weeks until confirmed disease progression or unacceptable toxicity. The tumor types evaluated included TNBC, anal squamous cell carcinoma (aSCC), cutaneous SCC (cSCC), undifferentiated pleomorphic sarcoma (UPS), small bowel adenocarcinoma (SBA), thymic epithelial tumor (TET), and high tumor mutational burden tumor (hTMB).
Combining all patients treated at 10 mg/kg, the overall objective response rate (ORR) in 114 evaluable patients who had at least one post-baseline disease assessment was 12 percent, with a disease control rate of 42 percent. Best responses per RECIST 1.1 in each tumor type are summarized in the table below:
TNBC
(n=15) aSCC (n=15) cSCC
(n=14) UPS
(n=20) SBA
(n=14) TET
(n=10) hTMB
(n=14) Others (n=12) Total (N=114)
ORR, % 7 13 36 5 0 0 29 8 12
CR, n (%) 0 0 1 (7) 0 0 0 1 (7) 0 2 (2)
PR, n (%) 1 (7) 2 (13) 4 (29) 1 (5) 0 0 3 (21) 1 (8) 12 (11)
SD, n (%) 7 (47) 6 (40) 5 (36) 4 (20) 2 (14) 5 (50) 2 (14) 3 (25) 34 (30)
DCR, n (%) 8 (53) 8 (53) 10 (71) 5 (25) 2 (14) 5 (50) 6 (43) 4 (33) 48 (42)
ORR, objective response rate; CR, complete response; PR, partial response; SD, stable disease; DCR, disease control rate (defined as CR, PR or SD of at least 8 weeks duration)
"These early results are very encouraging when compared with historical data from conventional ICIs," remarked Amy C. Peterson, M.D., executive vice president and chief development officer of CytomX Therapeutics. "The activities in TNBC and aSCC are particularly noteworthy given that single-agent atezolizumab had a 6% ORR in second or higher-line metastatic TNBC and the ORR for single-agent pembrolizumab in recurrent, PD-L1-positive aSCC was 17%, both of which are similar to our findings with pacmilimab in patients with more advanced disease," added Dr. Peterson.
At the RP2D of 10 mg/kg, pacmilimab displayed a favorable tolerability profile. Grade 3 or higher treatment-related adverse events (TRAEs) were reported in 10 patients (9%) and serious TRAEs in six patients (5%). The discontinuation rate due to TRAEs was a low 2%. Grade 3 or higher irAEs occurred in two patients, one each for rash and myocarditis. Additionally, pneumonitis and colitis, irAEs commonly seen in patients receiving conventional anti-PD-1/PD-L1 agents (2.2% and 0.7%, respectively),2 were reported only once for pneumonitis (0.7%) and there were no reports of colitis (0%). Collectively, these adverse event data indicate that pacmilimab is an attractive candidate for combination therapy.
First-in-human Study of Pacmilimab in Combination with Ipilimumab in Advanced Solid Tumors Published in the Journal for ImmunoTherapy of Cancer
To maximize the benefits of immunotherapy for patients, the field has moved aggressively toward combination therapy. While many of these combinations have been shown to elicit improved response rates compared with monotherapy, their adverse event profiles are often worse. A notable example is the combination of nivolumab (anti-PD-1) at a dose of 1 mg per kilogram of body weight and 3 mg per kilogram of ipilimumab (anti-CTLA-4) every three weeks, which produced a 58% ORR in a cohort of 314 patients with previously untreated advanced melanoma. However, this improved efficacy came at the cost of safety and tolerability, with grade 3 or 4 TRAEs occurring in 59% of patients.3
The goal of this first-in-human dose-finding study was to evaluate the tolerability and preliminary antitumor activity of pacmilimab combined with ipilimumab in patients with advanced, unresectable solid tumors. Twenty-seven patients who had not been previously treated with an ICI were enrolled. Dose-escalation 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 ORR was 19%, including one patient with anal squamous cell carcinoma having a complete response and four partial responses in patients with leiomyosarcoma, mesothelioma, testicular cancer, and cancer of unknown primary. Moreover, these responses appeared durable, with four of five responses lasting for more than 1 year as of data cutoff on August 28, 2020, including the patient with a complete response maintaining for more than 24 months. Pacmilimab-related grade 3-4 AEs and grade 3-4 irAEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment due to AEs. There were no treatment-related deaths and no new safety signals were identified. Based on these findings, the MTD and recommended Phase 2 dose was pacmilimab 10 mg/kg in combination with ipilimumab 3 mg/kg administered every 3 weeks.
Pacmilimab is currently being evaluated in combination with praluzatamab ravtansine (CX-2009), the Company’s wholly-owned conditionally activated antibody-drug conjugate targeting CD166, in a Phase 2 study in patients with TNBC. To learn more about this study, please go to www.ClinicalTrials.gov using the identifier: NCT04596150.