On September 18, 2020 Phosplatin Therapeutics, a clinical stage pharmaceutical company focused on oncology therapeutics, reported that data from a Phase 1b dose escalation study (NCT 03409458) of lead candidate PT-112, an immunogenic cell death inducer, used in combination with avelumab, a PD-L1 immune checkpoint inhibitor, in patients with progressing solid tumors who previously exhausted all available treatment options (Press release, Phosplatin, SEP 18, 2020, View Source [SID1234565370]). Data were pre-released under the Mini Oral presentation format (session 1026MO) in the Investigational Immunotherapy category at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020, taking place September 19-21. Avelumab is co-developed and co-commercialized by Merck KGaA, Darmstadt, Germany and Pfizer Inc.
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The combination of PT-112 and avelumab was found to be safe and well tolerated in 36 heavily pre-treated solid tumor patients who have exhausted standard therapy options, the majority of whom had received prior immunotherapy. Common treatment-related adverse events (TRAEs) were nausea (47%), fatigue (31%), thrombocytopenia (28%), and decreased appetite (28%); 44% of patients had grade 3-4 TRAEs (most frequent was thrombocytopenia: 17%). Clinical benefit was observed in patients treated with PT-112 doses ranging from 150 to 360mg/m2. Sixty percent of patients with RECIST-evaluable disease achieved stable disease or better, including a durable RECIST response, PSA response and improvement in bone scan and bone pain in a patient with metastatic castration-resistant prostate cancer (mCRPC) with 8 prior therapies and no signature of likely response to immune checkpoint inhibition. Further activity signals were observed in patients with mCRPC, with 4 of 14 patients achieving a >50% PSA reduction, and consistent reduction in alkaline phosphatase (ALP) levels associated with bone metastatic site of disease.
"These results demonstrate that the PT-112 and avelumab combination is safe and well tolerated in heavily pre-treated patients. As in any advanced cancer population treated with numerous prior therapies, appropriate dose modifications are important. We are encouraged by activity observed thus far, and we look forward to confirming the combination dose in future studies as we seek treatment options for these patients who effectively have no other therapeutic alternatives remaining," said Daniel D. Karp, MD, Professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center.
No dose-limiting toxicities occurred during the study. The study enrolled 36 patients with progressing solid tumors across a range of tumor types, including 15 patients with mCRPC who were enrolled in a supplemental cohort. Phase 2 studies are planned to confirm the recommended dose, and to implement correlative immune-profiling assays.
"The results of this first combination study, including the evidence of activity among patients with prostate cancer, are indeed encouraging," said Robert Fallon, co-founder and Chief Executive Officer, Phosplatin Therapeutics. "Based upon these data, our immunotherapy combination appears feasible and active. These results add to the emerging body of evidence around the potential of PT-112, as an immunogenic cell death (ICD) inducer, to provide benefit to patients with advanced solid tumors, and to offer a potential treatment to patients who do not respond to current immunotherapy options."
The study was conducted under a collaboration agreement between Phosplatin Therapeutics, Pfizer Inc. and Merck KGaA, Darmstadt, Germany (EMD Serono in the US and Canada). Under the terms of the collaboration, Phosplatin Therapeutics is the Sponsor of Phase 1b/2a clinical trials in several indications. Pfizer and Merck KGaA, Darmstadt, Germany supply avelumab for the trials.
The ESMO (Free ESMO Whitepaper) presentation is available on-demand for the duration of the conference to registered attendees, and the underlying abstract is publicly available.
About PT-112
PT-112 is the first small molecule conjugate of pyrophosphate developed in oncology therapeutics. PT-112 promotes immunogenic cell death (ICD), or the release of damage associated molecular patterns (DAMPs), that lead to downstream immune effector cell recruitment in the tumor microenvironment. PT-112 represents a potential best-in-class small molecule inducer of this immunological form of cancer cell death and is under Phase II development. The first in-human study of PT-112 demonstrated an attractive safety profile and evidence of long-lasting responses among heavily pre-treated patients and won "Best Poster" within the Developmental Therapeutics category at the ESMO (Free ESMO Whitepaper) 2018 Annual Congress. The novelty of its pyrophosphate moiety also results in osteotropism, or the propensity of the drug to reach the mineralized bone. This property is of interest in cancer types that originate in bone or frequently lead to metastatic bone involvement, such as metastatic castrate-resistant prostate cancer (mCRPC). The first human clinical results in mCRPC were presented at the 2020 Genitourinary Cancers Symposium.
Avelumab Approved Indications
Avelumab (BAVENCIO) is indicated in the US for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. BAVENCIO is also indicated for the treatment of patients with locally advanced or metastatic UC who have disease progression during or following platinum-containing chemotherapy, or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Avelumab in combination with axitinib is approved in the US for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
In the US, the FDA granted accelerated approval for BAVENCIO for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.
Avelumab Important Safety Information from the US FDA-Approved Label
The warnings and precautions for avelumab (BAVENCIO) include immune-mediated adverse reactions (such as pneumonitis and hepatitis [including fatal cases], colitis, endocrinopathies, nephritis, and other immune-mediated adverse reactions as a single agent or in combination with axitinib [which can be severe and have included fatal cases]), infusion-related reactions, hepatotoxicity in combination with axitinib, major adverse cardiovascular events (MACE) in combination with axitinib [which can be severe and have included fatal cases], and embryo-fetal toxicity.
Common adverse reactions (reported in at least 20% of patients) in patients treated with BAVENCIO monotherapy include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction peripheral edema, decreased appetite, urinary tract infection and rash. Common adverse reactions (reported in at least 20% of patients) in patients receiving BAVENCIO in combination with axitinib include diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain and headache. Grade 3-4 hematology laboratory value abnormalities reported in at least 10% of patients with Merkel cell carcinoma treated with BAVENCIO monotherapy include lymphopenia; in patients receiving BAVENCIO in combination with axitinib, grade 3-4 clinical chemistry abnormalities include blood triglyceride increased and lipase increased.