Breakthrough Clinical Results
Verastem Oncology announced positive updated results from the RAMP 205 Phase 1/2 trial evaluating the combination of avutometinib and defactinib with standard chemotherapy in frontline metastatic pancreatic ductal adenocarcinoma (PDAC). In the recommended Phase 2 dose (RP2D) cohort, an overall response rate (ORR) of 83% (10/12 patients) was observed. The company plans a registrational Phase 3 study in frontline metastatic PDAC. Additionally, updated data on VS-7375, an oral KRAS G12D inhibitor, will be presented at ASCO. Avutometinib and defactinib are already FDA-approved for KRAS-mutated recurrent low-grade serous ovarian cancer.
Key Highlights
- 83% overall response rate (ORR) in the recommended Phase 2 dose cohort of the RAMP 205 trial for frontline metastatic pancreatic cancer.
- Plans for a registrational Phase 3 study in frontline metastatic pancreatic cancer are underway.
- Updated data on VS-7375 (KRAS G12D inhibitor) to be presented at ASCO.
- Avutometinib and defactinib combination already FDA-approved for a different indication.
Drug used in other indications
The context provided does not contain any information about clinical trials of Avutometinib and Defactinib for pancreatic ductal adenocarcinoma or any other indications. The context also does not provide any information about intervention models for trials involving these medications.
Incidence and Prevalence
Global Incidence and Prevalence of Pancreatic Ductal Adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) represents a significant global health concern as one of the leading causes of cancer-related deaths worldwide. This aggressive malignancy is characterized by its extreme difficulty to detect and treat, making it one of the most lethal cancers in Europe and the United States.
Prevalence and Classification
PDAC is the most common form of pancreatic malignant tumor, accounting for more than 85% of all pancreatic cancers. In the United States specifically, PDAC represents approximately 3% of all cancers but is responsible for about 7% of all cancer deaths, highlighting its disproportionate impact on mortality.
Survival Rates
The prognosis for PDAC patients remains poor, with a 5-year survival rate post-diagnosis of less than 5% according to some sources, while more recent data indicates rates of less than 10% or up to 12%. This dismal survival rate can be attributed to various factors, including the high degree of intra- and interindividual tumor heterogeneity that characterizes this cancer.
Genetic Characteristics
From a molecular perspective, PDAC has distinct genetic features, with the tumor suppressor TP53 gene being mutated in approximately 75% of PDAC cases.
Risk Factors
Several conditions significantly increase the risk of developing PDAC:
-
Diabetes mellitus (DM) is a notable risk factor with an overall summary-combined relative risk of 1.97 (95% CI 1.78-2.18).
-
The risk of PDAC is highest early after a diabetes diagnosis but remains elevated long-term, with individual-level relative risk ranging from 6.69 at less than 1 year to 1.36 at 10 years post-diabetes diagnosis.
-
Chronic pancreatitis (CP) presents an even more substantial risk, with affected individuals being 20-fold more likely to develop PDAC.
PDAC continues to pose significant challenges for early detection and effective treatment, contributing to its position as one of the most lethal forms of cancer globally.
Study Design Parameters
Key Clinical Trials for Pancreatic Ductal Adenocarcinoma: Study Design and Endpoints
ESPAC-3 Trial
- Design: Open-label, phase 3, randomized controlled trial
- Setting: 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada
- Participants: 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection
- Randomization period: July 2000 to January 2007
- Follow-up: At least 2 years
- Interventions: Fluorouracil plus folinic acid (n=551) vs. gemcitabine (n=537) for 6 months
- Primary outcome: Overall survival
- Secondary outcomes: Toxicity, progression-free survival, quality of life
- Results: Median survival was 23.0 months for fluorouracil plus folinic acid and 23.6 months for gemcitabine
- Adverse events: 14% of fluorouracil plus folinic acid patients had treatment-related serious adverse events vs. 7.5% of gemcitabine patients
Gemcitabine + Hydroxychloroquine Trial
- Design: Open-label, phase 2 randomized clinical trial
- Time period: March 18, 2013, to November 16, 2017
- Setting: University of Pennsylvania, HonorHealth, and The Johns Hopkins University
- Participants: 112 patients with previously untreated metastatic or advanced pancreatic ductal adenocarcinoma
- Eligibility: Eastern Cooperative Oncology Group performance status of 0 or 1, adequate marrow and organ function
- Interventions: Gemcitabine hydrochloride and nab-paclitaxel (GA) with or without hydroxychloroquine sulfate (HCQ)
- Primary outcome: Overall survival at 1 year
- Results: Overall survival at 12 months was 41% in the HCQ group and 49% in the non-HCQ group
- Response rates: 38.2% in the HCQ group vs. 21.1% in the non-HCQ group (p=0.047)
Dutch Stepped-Wedge Trial
- Design: Multicenter, stepped-wedge cluster randomized trial
- Time period: May 22, 2018, through July 9, 2020
- Setting: 17 Dutch networks for pancreatic cancer care
- Participants: 5887 patients with pathologically or clinically diagnosed pancreatic ductal adenocarcinoma
- Intervention: Implementation of 5 best practices including optimal use of perioperative chemotherapy, palliative chemotherapy, pancreatic enzyme replacement therapy, referral to a dietician, and use of metal stents
- Primary outcome: 1-year survival
- Secondary outcomes: Adherence to best practices and quality of life
Cetuximab + Gemcitabine Trial
- Design: Prospective, open-label, multicenter, nonrandomized phase II study
- Sample size: 76 patients with R0- or R1-resected ductal adenocarcinoma
- Inclusion period: October 2006 to November 2008
- Treatment: Gemcitabine and cetuximab administered for 24 weeks
- Primary endpoint: Disease-free survival (DFS) at 18 months
- Secondary endpoints: Overall survival (OS) and toxicity
- Results: 73 patients received cetuximab; median DFS was 10.0 months; DFS rate at 18 months was 27.1%; median OS was 22.4 months
Gemcitabine + Capecitabine vs. Gemcitabine Trial
- Design: Phase 3, two-group, open-label, multicenter, randomized clinical trial
- Setting: 92 hospitals across six European countries
- Sample size: 732 patients enrolled, 730 included in final analysis
- Inclusion criteria: Patients aged 18+ years with complete macroscopic resection for ductal adenocarcinoma (R0 or R1)
- Treatment: Randomized 1:1 within 12 weeks of surgery to receive six cycles of either gemcitabine alone or gemcitabine with capecitabine
- Primary endpoint: Overall survival
- Results: Median OS for gemcitabine plus capecitabine was 28.0 months vs. 25.5 months for gemcitabine alone
DocOx Trial
- Design: Prospective, multi-center, single arm, phase II trial
- Sample size: 44 patients with chemorefractory pancreatic cancer
- Enrollment period: 2008-2012 at five German institutions
- Treatment: Docetaxel (75 mg/m²) and oxaliplatin (80 mg/m²) in 21-day cycles for up to 8 cycles
- Primary endpoint: Tumor response according to RECIST 1.0
- Secondary endpoints: Progression-free survival, overall survival, safety/toxicity, quality of life, clinical benefit
- Results: 15.9% achieved primary endpoint (7 partial remissions); median PFS was 1.82 months; median OS was 10.1 months
Necuparanib Trial
- Design: Randomized multicenter phase II trial
- Sample size: 110 patients (62 necuparanib arm, 58 placebo arm)
- Inclusion criteria: Age 18+, histologically confirmed metastatic PDAC, measurable disease, ECOG 0-1
- Treatment: Necuparanib (5 mg/kg daily) or placebo plus gemcitabine/nab-paclitaxel
- Primary endpoint: Median overall survival
- Results: Median OS was 10.71 months for necuparanib arm vs. 9.99 months for placebo arm; trial terminated early for futility