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Pembrolizumab for Cutaneous Squamous Cell Carcinoma

The FDA approved pembrolizumab for patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

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Efficacy was investigated in KEYNOTE-629 (NCT03284424), a multicenter, multi-cohort, non-randomized, open-label trial. The study excluded patients who had previously received therapy with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody and those with autoimmune disease or a medical condition that required immunosuppression.


Patients received pembrolizumab 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months. Assessment of tumor status was performed every 6 weeks during the first year and every 9 weeks during the second year.


The major efficacy outcome measures were objective response rate (ORR) and response duration as assessed by blinded independent central review according to RECIST 1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ. The ORR was 34 percent (95% CI: 24, 44) and median response duration was not reached (range: 2.7, 13.1+ months).


Adverse reactions occurring in patients with cSCC enrolled in KEYNOTE-629 were similar to those occurring in patients who received pembrolizumab as a single agent in other clinical trials. The most common adverse reactions to pembrolizumab are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.


Efficacy and safety of pembrolizumab using a dosage of 400 mg every 6 weeks for cSCC was primarily based on the modeling of dose/exposure efficacy and safety relationships and observed pharmacokinetic data in patients with melanoma.


The recommended pembrolizumab doses for cSCC are 200 mg every 3 weeks or 400 mg every 6 weeks.


Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma

The FDA granted accelerated approval to brexucabtagene autoleucel, a CD19-directed, genetically modified, autologous T-cell immunotherapy for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL).


Approval was based on ZUMA-2 (NCT02601313), an open-label, multicenter, single-arm trial of 74 patients with relapsed or refractory MCL who had previously received anthracycline- or bendamustine-containing chemotherapy, an anti-CD20 antibody, and a Bruton tyrosine kinase inhibitor. Patients received a single infusion of brexucabtagene autoleucel following completion of lymphodepleting chemotherapy. The primary efficacy outcome measure was objective response rate (ORR) per Lugano [2014] criteria as assessed by an independent review committee.


Of the 60 patients evaluable for efficacy based on a minimum duration of follow-up for response of 6 months, the ORR was 87 percent (95% CI: 75, 94) with a complete remission (CR) rate of 62 percent (95% CI: 48, 74). The estimated median duration of response was not reached (range of 0+ to 29.2+ months) after a median follow-up time for duration of response of 8.6 months. Of all 74 leukapheresed patients, the ORR as assessed by independent review committee was 80 percent (95% CI: 69, 88) with a CR rate of 55 percent (95% CI: 43, 67).


The most common (>=10%) grade 3 or higher reactions were anemia, neutropenia, thrombocytopenia, hypotension, hypophosphatemia, encephalopathy, leukopenia, hypoxia, pyrexia, hyponatremia, hypertension, infection-pathogen unspecified, pneumonia, hypocalcemia, and lymphopenia. FDA approved brexucabtagene autoleucel with a Risk Evaluation and Mitigation Strategy because of the risk of cytokine release syndrome and neurologic toxicities.


The recommended dose of brexucabtagene autoleucel is a single intravenous infusion of 2 x 106 CAR-positive viable T cells per kg body weight (maximum 2 x 108 CAR-positive viable T cells), preceded by fludarabine and cyclophosphamide lymphodepleting chemotherapy.


BDTX-189 in EGFR/HER2-Mutant Solid Tumors

The FDA granted Fast Track designation to BDTX-189 for the treatment of adult patients with solid tumors harboring an allosteric human epidermal growth factor receptor 2 (HER2) mutation or an epidermal growth factor receptor (EGFR) or HER2 Exon 20 insertion mutation who have progressed following prior treatment and who have no satisfactory treatment options.


BDTX-189, an orally available, irreversible small molecule inhibitor, is designed to selectively inhibit the activity of a broad range of previously unaddressed oncogenic driver mutations of the ErbB kinases in EGFR and HER2.


The FDA's Fast Track designation provides the potential for an expedited review of new product candidates intended to treat serious or life-threatening conditions with high unmet need, allowing important new drugs to become available more quickly to patients suffering from these conditions. Benefits of Fast Track designation include enhanced interaction with the FDA, as well as potential eligibility to obtain accelerated approval and priority review at the time of a New Drug Application filing if relevant criteria are met.


MasterKey-01 (NCT04209465) is a combined phase I/II open-label, two-part, multicenter study to assess the safety, tolerability, pharmacokinetics, and anti-tumor activity of BDTX-189 in adult patients with advanced solid tumors who have no standard therapy available or for whom standard therapy is considered unsuitable or intolerable. Part A is a phase I, first-in-human, open-label, dose-escalation study comprised of initial single-patient, accelerated titration cohorts followed by multiple-patient cohorts utilizing a Bayesian design.


Part A is designed to determine the recommended phase II dose and schedule in up to 88 patients with allosteric HER2 or HER3 mutation, EGFR or HER2 exon 20 insertion mutation, HER2 amplified or overexpressing tumor, or EGFR exon 19 deletion or L858R mutation. Part B is a phase II, open-label, multicenter basket study designed to determine antitumor activity and safety in adult patients with solid tumors that have an allosteric HER2 mutation or EGFR or HER2 exon 20 insertion mutations using next-generation sequencing. This part will utilize a Simon 2-stage design and enroll up to 100 patients in four cohorts: 1) non-small cell lung cancer with EGFR or HER2 exon 20 insertion mutations; 2) breast cancer with an allosteric ErbB mutation; 3) solid tumors (except breast) with S310F/Y mutation; and 4) other tumors harboring allosteric ErbB mutations not included in cohorts 1-3.


BDTX-189 is an orally available, irreversible small molecule inhibitor that is designed to block the function of an undrugged family of oncogenic proteins defined by driver mutations across a range of tumor types, and which affect the EGFR and the tyrosine-protein kinase, ErbB-2, or HER2. These mutations include extracellular domain allosteric mutations of HER2, as well as EGFR and HER2 kinase domain exon 20 insertions, and additional activating oncogenic drivers of ErbB. The ErbB receptors are a group of receptor tyrosine kinases involved in key cellular functions, including cell growth and survival. BDTX-189 is also designed to spare normal, or wild-type EGFR, which is believed to have the potential to improve upon the toxicity profiles of current ErbB kinase inhibitors. Currently, there are no medicines approved by the FDA to target all of these oncogenic mutations with a single therapy.