Endometrial Carcinoma

Phase 1 analysis from the PYNNACLE Phase 1/2 study showed promising efficacy of rezatapopt (PC14586) in heavily pre-treated patients with advanced ovarian cancer harboring a TP53 Y220C mutation featured in a late-breaking oral presentation at 2024 SGO Annual MeetingOf the 15 patients in the efficacy evaluable population, seven patients achieved a confirmed partial response with a seven-month median duration of response and a favorable safety profileRezatapopt is a first-in-class precision oncology investigational therapy in patients with advanced solid tumors with a TP53 Y220C mutation and KRAS wild-type which is being evaluated in a registrational Phase 2 study PRINCETON, N.J., March 18, 2024 (GLOBE NEWSWIRE) -- PMV Pharmaceuticals, Inc. (Nasdaq: PMVP), a precision oncology company pioneering the discovery and development of small molecule, tumor-agnostic therapies targeting p53, today announced that a Phase 1 analysis reported promising anti-tumor activity of rezatapopt (PC14586) in heavily pre-treated patients with advanced ovarian cancer harboring a TP53 Y220C mutation. Rezatapopt is a first-in-class precision oncology small molecule investigational therapy that selectively targets the TP53 Y220C mutation in solid tumors. These data were featured today in a late-breaking oral presentation at the 2024 Society for Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer being held March 16-18, 2024 in San Diego, CA. The presentation entitled, “Phase 1 Analysis from the PYNNACLE Phase 1/2 Study PC14586 in the Subgroup of Patients with Advanced Ovarian Cancer Harboring a TP53 Y220C Mutation,” was delivered by Alison M. Schram, M.D., Medical Oncologist, Memorial Sloan Kettering Cancer Center. “In this Phase 1 study, we observed promising efficacy of rezatapopt in heavily pre-treated patients with advanced ovarian cancer harboring a TP53 Y220C mutation. In addition, rezatapopt showed a favorable safety profile,” said Dr. Schram. “These data are encouraging given the significant unmet medical need for patients with advanced solid tumors, particularly in patients with ovarian cancer who are platinum resistant. Further study of rezatapopt as monotherapy in ovarian cancer is warranted.” Deepika Jalota, Pharm.D., Chief Development Officer of PMV Pharma added, “These Phase 1 PYNNACLE data presented at the SGO meeting showed that rezatapopt, a first-in-class precision oncology investigational therapy, continues to demonstrate clinical benefit in a patient population of high unmet need. Our registrational, tumor-agnostic PYNNACLE Phase 2 trial, which includes an ovarian cancer cohort, remains on track to initiate in the first quarter of this year. The trial will assess rezatapopt as monotherapy at the recommended Phase 2 dose of 2000 mg daily in patients with TP53 Y220C and KRAS wild-type advanced solid tumors.” Results of Phase 1 Analysis of PYNNACLE in Advanced Ovarian Cancer Phase 1 data from the PYNNACLE trial (NCT04585750) demonstrated that rezatapopt has a favorable safety profile and induced responses in heavily pre-treated patients across multiple tumor types. This subgroup analysis investigated the efficacy of rezatapopt in patients with advanced ovarian cancer treated across the efficacious dose range (1150 mg daily to 1500 mg twice daily). Patient Characteristics As of September 5, 2023, the median age of patients with ovarian cancer (N=22) was 66 years (range 49 – 81 years)At baseline, 20 patients had high-grade serous ovarian cancer and two had endometrioid cancer Nineteen patients were platinum resistant and one was platinum refractoryTwo patients had a BRCA2 mutationSix patients were homologous recombination deficiency positiveAll patients were KRAS wild-typeMedian number of prior lines of systemic therapy was four (range 1 – 9) Efficacy The efficacy evaluable population consisted of 15 patients with measurable disease at baseline and ≥1 post-baseline tumor assessment. Seven patients achieved a confirmed partial response (PR), seven had stable disease (SD), and one had progressive diseaseMedian duration of response was seven monthsOf the 15 patients with measurable serum CA-125 at baseline, six had a CA-125 response. Among these, five patients achieved radiographic PR and one had SD Safety In the overall population of 67 patients assessed in the efficacious dose range (≥1150mg daily), including this subset of patients with ovarian cancer, treatment-related adverse events (TRAEs) were mostly grade 1 and 2. Most frequent TRAEs were nausea (51%), vomiting (43%), and increased blood creatinine (27%)Frequency and severity of TRAEs were similar in the ovarian cancer population compared with the overall populationRezatapopt administration with food led to an improvement in nausea and vomiting About Rezatapopt Rezatapopt (PC14586) is a first-in-class, small molecule, p53 reactivator designed to selectively bind to the pocket in the p53 Y220C mutant protein, restoring the wild-type, or normal, p53 protein structure and tumor-suppressing function. The U.S. Food and Drug Administration (FDA) granted Fast Track designation to rezatapopt for the treatment of patients with locally advanced or metastatic solid tumors with a p53 Y220C mutation. About the PYNNACLE Clinical Trial The ongoing Phase 1/2 PYNNACLE study is evaluating rezatapopt in patients with advanced solid tumors harboring a TP53 Y220C mutation. The primary objective of the Phase 1 portion of the trial was to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of rezatapopt when administered orally to patients. Safety, tolerability, pharmacokinetics and effects on biomarkers will also be assessed. Phase 2 will be an expansion study with the primary objective of evaluating the efficacy of rezatapopt at the RP2D in patients with TP53 Y220C advanced solid tumors. For more information about the Phase 1/2 PYNNACLE clinical trial, refer to www.clinicaltrials.gov (NCT study identifier NCT04585750). About PMV Pharma PMV Pharma is a precision oncology company pioneering the discovery and development of small molecule, tumor-agnostic therapies targeting p53. p53 mutations are found in approximately half of all cancers. Our co-founder, Dr. Arnold Levine, established the field of p53 biology when he discovered the p53 protein in 1979. Bringing together leaders in the field to utilize over four decades of p53 biology, PMV Pharma combines unique biological understanding with a pharmaceutical development focus. PMV Pharma is headquartered in Princeton, New Jersey. For more information, please visit www.pmvpharma.com. Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the Company’s future plans or expectations for rezatapopt, including our ability to obtain approval on a tumor-agnostic basis, ongoing safety and response rate of participants in our clinical trials and expectations regarding timing and success of the Phase 2 portion of its current clinical trial for rezatapopt, including rezatapopt’s potential efficacy and safety profile in ovarian cancer patients. Any forward-looking statements in this statement are based on management’s current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include: the success, cost, and timing of the Company’s product candidate development activities and planned clinical trials, the Company’s ability to execute on its strategy and operate as a clinical stage company, the potential for clinical trials of rezatapopt or any future clinical trials of other product candidates to differ from preclinical, preliminary, interim or expected results, the Company’s ability to fund operations, and the impact that any current or future global pandemic or geopolitical emergency may have on the Company’s clinical trials, supply chain, and operations, as well as those risks and uncertainties set forth in the section entitled “Risk Factors” in the Company’s Annual Report on Form 10-K filed with the Securities and Exchange Commission (the “SEC”) on February 29, 2024, and its other filings filed with the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. Investors Contact:Tim SmithSenior Vice President, Head of Corporate Development and Investor Relationsinvestors@pmvpharma.com Media Contact:Kathy VincentGreig Communicationskathy@greigcommunications.com

AstraZeneca and GSK aim to bring their PD-1/L1 combinations to a broad front-line endometrial cancer population. After a quick FDA approval in a subset of endometrial cancer, GSK is back with more data for two Jemperli regimens in hopes of reaching a broader patient population. And AstraZeneca, utilizing a similar immunotherapy strategy, has also come up with a rivaling update as it awaits an FDA decision. For GSK, Jemperli plus chemotherapy showed a “clinically meaningful trend” in reducing the risk of death by 21% among patients with advanced endometrial cancer that’s mismatch repair proficient (pMMR) or microsatellite stable (MSS). Patients on the Jemperli regimen lived a median 34 months, compared with 27 months for those on chemo alone. The data, from an exploratory analysis of the first part of the phase 3 RUBY trial, were shared at the Society of Gynecologic Oncology (SGO) annual meeting. They come as part of a statistically significant overall survival win for the Jemperli-chemo combo in the overall trial group as it cut the risk of death by 31% in a broader endometrial cancer population that also includes patients with mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumors. With the updated analysis from RUBY Part 1, GSK said it expects the FDA will accept its submission to expand the PD-1 inhibitor Jemperli to the overall front-line endometrial cancer population in the first half of this year. The Jemperli-chemo combo was already greenlighted in July just for dMMR/MSI-H patients, who account for about 15% to 20% of new advanced endometrial cancer diagnoses in the U.S. Simultaneously, Part 2 of the RUBY trial found that a cocktail of Jemperli, chemo and GSK’s PARP inhibitor Zejula reduced the risk of progression or death by 37% in pMMR/MSS patients, according to data shared at SGO 2024. For the overall population, which also includes dMMR/MSI-H patients, the risk reduction was 40%. The Part 2 findings are particularly meaningful for patients with pMMR/MSS tumors as they further improved on the benefit observed for the Jemperli-chemo regimen in Part 1, Mansoor Raza Mirza, M.D., from the Copenhagen University Hospital and RUBY principal investigator, said in a statement Saturday. Previously, Jemperli and chemo cut the risk of progression or death by 24% versus chemo in the pMMR subgroup. However, the Part 2 data also raised the question of whether the further addition of Zejula is necessary for dMMR/MSI-H patients. Among that subset of patients, the Zejula-Jemperli-chemo combo showed a 52% advantage in progression-free survival over chemo alone, which was even smaller than the impressive 72% risk reduction Jemperli-chemo had posted without the PARP drug. Zejula appears to have brought extra toxicity. In Part 1, grade 3 or higher treatment-emergent adverse events were about 12% higher for Jemperli and chemo compared with control. In Part 2, the Zejula-containing regimen tripled that difference to about 36%. The potential longer-term detriment from PARP inhibitors have lately drawn attention at the FDA, leading to market withdrawal, restricted new approval or delayed application.  A GSK spokesperson said the company was unable to provide additional details about its regulatory plans at this time. Meanwhile, AstraZeneca could face the same question of patient selection for its PD-L1 inhibitor Imfinzi and Merck-shared PARP drug Lynparza in first-line endometrial cancer. In an interim analysis of AZ’s phase 3 DUO-E trial shared at SGO 2024, a combination of Imfinzi, Lynparza and chemo cut the risk of death in dMMR/MSI-H endometrial cancer patients by 72% over chemo, a slight improvement from the 66% posted by the Imfinzi-chemo pairing. None of these numbers were mature or statistically significant. Previously, the trial found that the Lynparza-containing regimen reduced the risk of progression or death by 59% over chemo alone, whereas Imfinzi and chemo could already cut that risk by 58%, according to results announced in October. In the overall trial population that also includes pMMR patients, the Imfinzi-chemo pairing so far cut the risk of death by 23%, whereas the Lynparza-containing regimen delivered a 41% showing. Again, the data were immature as only 28% of deaths had happened across the three trial arms before a final overall survival analysis. The overall survival data are promising at this early stage of maturity, Andrea Mugan, AstraZeneca’s global franchise head of gynecological and genitourinary cancers, said in an interview with Fierce Pharma. As PARP inhibitor’s contribution in dMMR tumors comes into question, AZ also faces the question of whether Imfinzi could handle pMMR disease without Lynparza. During the current interim analysis, Imfinzi plus chemo only pared down the risk of death by 9% in pMMR patients, while adding Lynparza widened that to 31%. Imfinzi-chemo showed a progression-free survival benefit of 23% in this subgroup, versus 43% for the Lynparza regimen, according to data first released in October. “We do believe in the data we’re showing for the benefit of both regimens in the first-line endometrial cancer population,” Mugan said. But she acknowledged that Imfinzi showed the biggest benefit in the dMMR population, and that the “incremental benefit” for Lynparza was more pronounced in the pMMR subgroup. AZ’s filings for DUO-E have been accepted by the FDA, the European Medicines Agency and regulators in Japan, the company said. It’s not clear whether AZ is gunning for approvals for both regimens for both dMMR and pMMR cancers.

GSK said that a regimen of Jemperli (dostarlimab) plus standard chemotherapy reduced the risk of death by 31% versus chemotherapy alone in adults with primary advanced or recurrent endometrial cancer, boosting hopes of expanding the drug’s current label. The company also released new progression-free survival (PFS) data on the PD-1-blocking antibody in combination with the PARP inhibitor Zejula (niraparib).“The results we’ve seen to date comprise the growing body of evidence supporting the role of [Jemperli] as the backbone of our immuno-oncology development programme,” remarked Hesham Abdullah, GSK's global head of oncology R&D.Jemperli gained approval last year in the US and Europe for front-line treatment of advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) based on positive PFS data from Part 1 of the Phase III RUBY trial. The first part of the study also achieved its overall survival (OS) endpoint. Data unveiled on Saturday at the Society of Gynecologic Oncology (SGO) annual meeting on women’s cancer showed that median OS was 44.6 months for Jemperli plus chemotherapy, or 16.4 months longer than for chemotherapy alone. GSK added that in a subgroup of patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) tumours, Jemperli plus chemotherapy reduced the risk of death by 21%, with median OS in the two arms of 34 months and 27 months, respectively.Meanwhile, Part 2 of the RUBY trial - which is investigating Jemperli plus chemotherapy followed by Jemperli plus Zejula, versus chemotherapy plus placebo followed by placebo – also hit its PFS goal, according to results top-lined last December.Findings presented at the SGO conference showed that the Jemperli/Zejula arm had a 40% lower risk of disease progression or death, with median PFS of 14.5 months, or 6.2 months longer than the comparator group. In the MMRp/MSS population, the Jemperli/Zejula regimen reduced the risk of disease progression or death by 37%, with median PFS of 14.3 months, versus 8.3 months for chemotherapy alone.GSK gained Jemperli – which was developed as part of a collaboration with AnaptysBio - and Zejula via its $5.1-billion purchase of Tesaro in 2019.