FGFR2 Mutant Neoplasms

Dive Brief:An experimental cancer drug developed by Revolution Medicines shrank pancreatic tumors in about one-quarter of participants who had been followed for at least five months after treatment in an early-stage study.The update, which Revolution Medicines shared with investors Monday, is the latest cut of data from the trial, which has tested the companys targeted therapy RMC-6236 in people with lung or pancreatic tumors that are driven to growth by mutations in a cancer gene known as RAS.Among study participants who previously received one or more prior drug regimens for their cancer and have a KRAS G12X mutation, treatment with RMC-6236 led to a median progression-free survival of 8.1 months. Revolution claims this is higher than typically seen with other regimens and is advancing its drug into a Phase 3 pancreatic cancer trial later this year.Dive Insight:Revolution Medicines is one of a handful of biotechnology and pharmaceutical firms looking to exploit drug research advances that have made RAS mutations easier to target. Mutations in the gene are frequently a trigger for cancers of the lungs, pancreas or colon.Pancreatic cancer, which is considered among the hardest tumor types to treat, is particularly dependent on RAS mutations, according to Revolution Medicines. Currently, however, standard treatment is chemotherapy-based regimens that have limited effectiveness.RMC-6236 is designed to inhibit RAS signaling by binding to the mutant protein in its on state. The companys first-in-human study, which has enrolled nearly 400 patients with RAS-driven solid tumors, has so far evaluated nine different doses of the drug. Results were last presented in October.Mondays data are from 127 study participants with pancreatic ductal carcinoma who received between 160 milligram and 300 milligram doses of RMC-6236. Nearly all experienced side effects, most commonly rash, diarrhea, mouth sores and vomiting. Those adverse events were considered severe or medically significant in 22% of participants and in 28% required dose modification.Median progression-free survival, a measure of how long treatment staves off disease progression or death, was a median of 8.1 months in people who specifically have the KRAS G12X mutation, and 7.6 months in those who broadly have RAS mutant tumors, including those with KRAS G12X changes. According to Revolution Medicines, the benchmark median progression-free survival for chemotherapy regimens in this setting ranges from 2 months to 3.5 months.Among participants who had at least three prior treatment regimens, the median progression-free survival was 4.2 months.Revolution Medicines said it plans to advance the 300 milligram dose of RMC-6236 into a Phase 3 study comparing it to investigators choice of standard chemo among previously treated people with pancreatic cancer. The company anticipates starting the study in the second half of the year, with progression-free survival data coming in the first half of 2026.Along with Revolution Medicines, a range of other companies are advancing RAS inhibitors in solid tumors, including BridgeBio Oncology Therapeutics, Frontier Medicines and Eli Lilly. Two drugs specifically targeted to KRAS mutations, Amgens Lumakras and Bristol Myers Squibbs Krazati, are currently approved for lung cancer.Revolution Medicines recently absorbed EQRx via an all-stock deal, swelling its cash balance to $1.7 billion as of March 31. Shares in the company fell in early Monday morning trading before bouncing back to trade up by more than 2%. '

Company expects to initiate dosing in the Phase 1 study of NST-628 in patients with advanced solid tumors harboring genetic alterations in the MAPK pathway in first half of 2024 CAMBRIDGE, Mass., March 28, 2024 /PRNewswire/ -- Nested Therapeutics, a biotechnology company pioneering a next-generation precision medicine platform to address hard-to-treat cancers, today announced that the U.S. Food and Drug Administration (FDA) cleared the investigational new drug (IND) application for NST-628 for the treatment of patients with advanced solid tumors harboring genetic alterations in the RAS-MAPK pathway. NST-628 is a mechanistically novel, fully brain penetrant non-degrading pan-RAF/MEK molecular glue that targets RAF and MEK nodes in the RAS-MAPK pathway. "The significant majority of KRAS-, NRAS-, and BRAF-mutant tumors are not addressable by currently approved therapies, creating a pressing need for new medicines that provide superior, durable efficacy and tolerability for people living with these hard-to-treat cancers," said Philip Komarnitsky, M.D., Ph.D., chief medical officer of Nested. "We believe that NST-628 has the potential to provide a differentiated clinical profile, including a superior therapeutic index and prevention of pathway reactivation, for patients with advanced solid tumors harboring RAS-MAPK pathway alterations. The IND clearance for NST-628 is an important step in the advancement of our first clinical-stage program, and with clinical trial sites already activated, we look forward to dosing the first patients in this trial in the first half of this year." The Phase 1 open-label, single-arm, two-part study (NCT06326411) is intended to investigate the safety, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary efficacy of single agent NST-628 in adult patients with RAS-MAPK pathway mutated/dependent advanced solid tumors who have exhausted standard treatment options. The study includes two parts: dose escalation (Part A) followed by dose expansion (Part B). The primary objectives for Part A are delineating NST-628's safety profile and establishing the recommended dose for Part B. For more information, visit clinicaltrials.gov. About NST-628 NST-628 is a fully brain-penetrant, mechanistically novel non-degrading molecular glue that targets multiple nodes in the RAS/MAPK pathway. NST-628 was developed based on Nested's proprietary structural insights of how signaling complexes form and function in cancer and addresses common pitfalls of other MAPK-targeted compounds, which remain unable to circumvent the risk of resistance via signaling pathway reactivation. Preclinical data evaluating all biomarkers relevant to RAS/MAPK-driven cell and patient-derived models collectively demonstrate superior anti-tumor activity, including in RAS and central nervous system-implanted tumor models, and tolerability of NST-628 compared to other MAPK-targeted compounds administered as either single agents or in combination. With a half-life and metabolic profile optimized to achieve a superior therapeutic index on a daily dosing schedule, as well as full intrinsic blood brain barrier penetrance, these data support NST-628's potential as a best-in-class treatment for RAS and RAF-driven cancers. About Nested Therapeutics Nested Therapeutics is a biotechnology company focused on discovering and developing novel, targeted, small molecule precision medicine therapies for patients with cancer by using mutation clusters to identify druggable pockets. With a platform that utilizes insights from genomics, computational chemistry, proteomics and AI, Nested is working to reach untapped mutations with the potential to improve outcomes for millions of patients. To learn more, visit and follow Nested Therapeutics on Twitter (@Nestedtx) and LinkedIn. SOURCE Nested Therapeutics Inc.

The FDA full approval allows patients who’ve progressed on standard PD-1 treatment to get J&J's Balversa. When the FDA converts an accelerated approval into a full nod, it’s typically associated with a wider label for the drug at hand. But in the case of Johnson & Johnson’s Balversa, the FDA narrowed the use of the first-in-class bladder cancer drug in two ways and expanded it in another. A full FDA approval now allows Balversa (erdafitinib) to treat locally advanced or metastatic urothelial carcinoma in patients with susceptible FGFR3 genetic alterations following at least one line of prior therapy. In a Friday announcement about the drug’s updated label, the FDA specified that Balversa shouldn’t be used in patients who are eligible for and have not received a prior PD-1/L1 therapy. Compared with Balversa’s accelerated approval from 2019, the full nod is narrower on two fronts. Under the original go-ahead, Balversa was also able to reach patients with FGFR2 alterations, and it could target post-chemo patients regardless of their eligibility for PD-1/L1 therapy. In one positive label change for J&J, while the previous nod only allowed Balversa after prior treatment with platinum-based chemotherapy, the updated approval now covers second-line patients regardless of their prior systemic therapy. That means patients who’ve progressed on standard PD-1 treatment can also get Balversa. The way J&J approached the full approval—and the way the FDA ruled—tell a cautionary tale about the FDA's close attention to patient subgroup data and overall survival findings. For the full green light, J&J only pursued the approval of Balversa in patients with FGFR3 alterations, a company spokesperson told Fierce Pharma. To support a full approval, J&J conducted the phase 3 THOR study, also known as Study BLC3001. In cohort 1 of the trial, Balversa cut the risk of death by 36% compared with chemotherapy in previously treated patients, including those treated with a PD-1/L1 inhibitor. Those who got Balversa lived a median 12.1 months versus 7.8 months for the control group. The trial was designed to enroll patients with FGFR2 and FGFR3 alterations, but it eventually didn’t have any FGFR2 representation. The real-world frequency of this disease subtype is extremely low, the J&J spokesperson said. In a statement, Daniel Suzman, M.D., a deputy director at the FDA’s oncology division, said the approval was “limited to patients with FGFR3-altered tumors only because of a lack of data confirming clinical benefit in the extremely rare population of patients with FGFR2-altered tumors.” The developments come amid a growing trend at the FDA to exclude patient subgroups in approvals, either because of low representation in clinical trials or unconvincing efficacy data. In June 2023, the FDA left out patients with high-grade B-cell lymphoma in an approval for Roche’s large B-cell lymphoma therapy Columvi, citing a “limited number of patients” in a study. As for Balversa, cohort 1 was only a part of the THOR trial. For years, Merck & Co.’s Keytruda has had a second-line bladder cancer nod and a limited first-line approval. So in cohort 2 of THOR, J&J pitted Balversa directly against Keytruda in previously treated patients who had not received a PD-1/L1 drug. And the updated Balversa label suggests the FDA was not happy with the results. In cohort 2, Balversa failed to beat Keytruda in extending patients’ lives. In fact, the J&J drug was linked to an 18% increased risk of death. “Similar” overall survival was the word investigators used when presenting the data at the 2023 European Society of Medical Oncology annual congress in October. But a small improvement on progression-free survival and a negative overall survival showing have become a precarious combination at the FDA, and Balversa was clearly no exception. J&J is looking on the bright side, stressing that patients who are eligible to receive PD-1/L1s are increasingly receiving those treatments up front. The company seems to be positioning its medicine as an option for those who still need treatment after a PD-1/L1 inhibitor. After Balversa’s accelerated approval in 2019, Merck KGaA and its former partner Pfizer won an FDA nod for their PD-L1 therapy Bavencio as a first-line maintenance therapy in bladder cancer patients who’ve responded to an initial round of chemo. And the combination of Keytruda and Astellas and Pfizer’s Padcev just won approval as a first-line treatment for bladder cancer after showing a major overall survival benefit against chemo. “Due to emerging treatment landscape, anti-PD-1s are used more and more in the earlier line setting […] and therefore, there is an unmet need for patients after progressing on anti-PD-1,” the J&J spokesperson said.