A Next-Generation BRAF Inhibitor Overcomes Resistance to BRAF Inhibition in Patients with BRAF-Mutant Cancers Using Pharmacokinetics-Informed Dose Escalation.

RAF inhibitors have transformed treatment for patients with BRAFV600-mutant cancers, but clinical benefit is limited by adaptive induction of ERK signaling, genetic alterations that induce BRAFV600 dimerization, and poor brain penetration. Next-generation pan-RAF dimer inhibitors are limited by a narrow therapeutic index. PF-07799933 (ARRY-440) is a brain-penetrant, selective, pan-mutant BRAF inhibitor. PF-07799933 inhibited signaling in vitro, disrupted endogenous mutant-BRAF:wild-type-CRAF dimers, and spared wild-type ERK signaling. PF-07799933 ± binimetinib inhibited growth of mouse xenograft tumors driven by mutant BRAF that functions as dimers and by BRAFV600E with acquired resistance to current RAF inhibitors. We treated patients with treatment-refractory BRAF-mutant solid tumors in a first-in-human clinical trial (NCT05355701) that utilized a novel, flexible, pharmacokinetics-informed dose escalation design that allowed rapid achievement of PF-07799933 efficacious concentrations. PF-07799933 ± binimetinib was well-tolerated and resulted in multiple confirmed responses, systemically and in the brain, in patients with BRAF-mutant cancer who were refractory to approved RAF inhibitors. Significance: PF-07799933 treatment was associated with antitumor activity against BRAFV600- and non-V600-mutant cancers preclinically and in treatment-refractory patients, and PF-07799933 could be safely combined with a MEK inhibitor. The novel, rapid pharmacokinetics (PK)-informed dose escalation design provides a new paradigm for accelerating the testing of next-generation targeted therapies early in clinical development.

First-in-human Phase I Trial of TPST-1120, an Inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors.

PURPOSE: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). RESULTS: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. CONCLUSIONS: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. SIGNIFICANCE: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.

Multidisciplinary treatment strategies in high-risk resectable melanoma: Role of adjuvant and neoadjuvant therapy.

Stage III melanoma encompasses a range of disease burdens, including microscopic foci of metastatic melanoma in a sentinel lymph node; bulky, clinically detected lymphadenopathy; and in-transit dermal metastases. After initial surgical management, patients with stage III melanoma at highest risk for recurrence are most likely to benefit from adjuvant therapy. Novel therapies that have improved the disease response rates and long-term survival of patients with advanced or metastatic melanoma have now been evaluated in the adjuvant setting, with the goal of eliminating residual microscopic disease to improve relapse-free and overall survival. Alternatively, implementing systemic therapies in the neoadjuvant setting for bulky, clinically detected disease can potentially limit surgical morbidity and improve understanding of an individual's response to applied therapy. With multiple therapeutic approaches currently under evaluation for adjuvant and neoadjuvant treatment of high-risk melanoma, establishing optimal treatment regimens, appropriate clinical endpoints, and treatment risk-benefit profiles has become increasingly challenging. There is also a critical need to identify and validate biomarkers predictive of melanoma patient outcomes or treatment efficacy. This article provides an overview of current clinical evidence and ongoing trials of targeted therapy and immunotherapy in this rapidly evolving area of oncology.

Challenges and Opportunities of Neoadjuvant Treatment in Locally Advanced Melanoma.

Locally advanced and metastatic melanoma have historically had poor survival outcomes. Long-term follow-up of both targeted therapies and immune checkpoint inhibitors has confirmed the survival benefit of these agents in stage IV melanoma, and recent studies have now demonstrated relapse-free survival benefits from these targeted and immunotherapeutic agents in the adjuvant setting. Neoadjuvant treatment of locally advanced melanoma, including in-transit disease, is now under investigation. Clinical trials have shown early promising results using either combination targeted therapy or immune checkpoint inhibitors. Neoadjuvant treatment may improve surgical morbidity, but balancing treatment efficacy and toxicity has already been challenging in the use of combination immune checkpoint inhibitors preoperatively. While improvement in relapse-free survival has been noted, additional follow-up of patients receiving neoadjuvant treatment will be necessary to report on long-term outcomes. Neoadjuvant treatment also provides additional translational research opportunities to determine predictive biomarkers for targeted therapy and immune checkpoint inhibitors. Evidence of early resistance to treatment may also lead to novel combination therapies to explore in future clinical trials. While neoadjuvant treatment in locally advanced melanoma has exciting potential, more investigation is necessary to determine efficacious regimens with manageable toxicities.