A personalized approach to selecting antibody therapy for patients with newly diagnosed stage IV gastroesophageal adenocarcinoma resulted in a 1-year overall survival rate of 66% and a median overall survival of 16.4 months in the PANGEA study (see Table 1).1 The study used a novel clinical “expansion platform type II” trial design that matched a patient’s molecular profile to a targeted antibody.
“PANGEA was feasible and met its primary efficacy objective. The results of this pilot study support a randomized study to test a personalized treatment strategy as compared with best control, to overcome the hurdles that have hindered implementation of targeted and immuno-oncologic therapies into routine care,” said Daniel V.T. Catenacci, MD, of the University of Chicago. Dr. Catenacci presented these findings at the 2020 Gastrointestinal Cancers Symposium.1
The phase IIa study of a personalized treatment strategy enrolled 80 patients with newly diagnosed stage IV gastroesophageal adenocarcinoma in order to identify and treat 68 patients per protocol. Patients received up to three lines of cytotoxic chemotherapy and an antibody that was selected based on biomarker data (molecular profile) and using a predefined treatment algorithm to address the instances when a patient’s tumor fit into more than one biologic category—a common occurrence. Baseline biomarker profiling was mandated on primary and metastatic tumors and at two progressive disease time points.
Study Aim: To Improve Upon Conventional Treatment
Targeted therapies have had limited benefit due to molecular heterogeneity of this cancer, including the infrequent incidence of some biomarker groups. In addition, survival rates have been disappointing with conventional therapy: 1-year survival is about 40% for HER2-negative and 55% for HER2-positive advanced disease.
Daniel V.T. Catenacci, MD
“We hypothesized that a personalized treatment strategy, applied at the first diagnosis of advanced disease and then serially over three treatment lines using monoclonal antibodies in combination with optimally sequenced chemotherapy, could contend with these hurdles,” he said. Based on historical data, he said the expected 1-year overall survival rate would be 50%, and the rate of 63% achieved in this study would correspond to a 33% improvement (hazard ratio = 0.67) and meet the study’s endpoint. “If we randomly selected 68 patients, including 15% to 20% of them with HER2-positive cancer, and treated them with standard of care, we would expect the median survival to be less than 1 year.”
PANGEA Study Design and Antibodies
The study was designed so that at first diagnosis of metastatic disease, patients were initiated on standard first-line FOLFOX (leucovorin, fluorouracil [5-FU], oxaliplatin) chemotherapy while molecular profiling of the primary and metastatic lesions was underway. When this was completed, an initial antibody was added to therapy based on the baseline biomarker profile.
“This was and still is a unique way to approach first-line biomarker-selecting studies. Most studies require the patient to wait to determine trial eligibility and start therapy until the biomarker profiling is completed, which can often be 3 to 5 weeks without standard palliative therapy after a patient is first diagnosed. Many patients cannot wait for this, and therefore those studies do not reflect many or most of the patients we encounter by enriching for a group of patients who can wait this long and who have a relatively better prognosis,” Dr. Catenacci explained.
Notably, if there was biomarker assignment discordance within a patient between their primary tumor biopsy and metastatic biopsy, then the metastatic biomarker profile would take priority—this discordance occurred in 35% of patients. “We reasoned that metastatic disease is what is ultimately the problem, and therefore this would take priority,” Dr. Catenacci said.
On first disease progression, patients were assigned second-line FOLFIRI (leucovorin, 5-FU, irinotecan) chemotherapy plus an antibody based on their biomarker profile at that time. Patients changed antibodies only if their molecular profile changed; the same occurred upon the second disease progression to taxane-based third-line therapy. If a predefined targetable amplification or mutation was not identified at baseline or at any progressive time point, then patients received an anti-VEGFR2 antibody (ramucirumab) as a “relegation” arm.
Therefore, all patients screened and enrolled were intended to be eligible and participate in this all-inclusive study and assigned what was thought to be the best targeted therapy for them at each time point in the study. However, in two predefined molecular subgroups, the investigators were unable to secure pharmaceutical collaboration and access to anti-MET and anti-FGFR2 therapeutic antibodies. These patients (12 of 80) received chemotherapy alone (the standard of care) in order to follow and document the natural history of the disease for these subgroups. Fortuitously, two patients with FGFR2 amplification were able to be treated with anti-FGFR2 antibody (bemarituzmab) per protocol (one in first line, and one who evolved to FGFR2 amplification in second line) and these patients were included in the intention-to-treat group. The primary endpoint was 1-year overall survival for the collective group treated per protocol (n = 68), compared with historical controls.
Dr. Catenacci noted that the PANGEA trial differs from other basket studies, which he referred to as “expansion platform type I” studies and ultimately still require a number of patients in each basket to identify effective targeted treatments. “It’s nearly impossible to study subgroups at a very low incidence [of molecular aberrations]. We haven’t been able to do those traditional phase III studies because tens of thousands of patients are required to screen to find these individuals. For a biomarker with an incidence of 50%, a study will accrue quickly, but for one with a 5% incidence, you must screen thousands of patients. Many basket studies don’t accrue patients to all the molecular subgroups due to this.
“Moreover, most studies do not continue to follow patients after a given line of therapy and miss the opportunity to ‘keep up with the tumor’,” he stated. “For our study, we set our number around the intent-to-treat analysis of the personalized therapy. We needed to have 68 patients total, and whatever profile they happened to be, they fit into a category in an ‘all-inclusive’ and real-world manner.”
The investigators chose eight molecular subgroups that are important in this cancer and identified corresponding treatments, which included immunotherapy (anti–programmed cell death protein 1 [PD-1]) and antibodies targeting HER2, MET, FGFR2, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor 2 (VEGFR2). Patients without targetable abnormalities (21% of primary tumors and 11% of metastatic tumors) received the VEGFR2 antibody ramucirumab.
“Baseline heterogeneity between primary site and metastatic site biopsies led to biologic group assignment changes in 35% of patients,” noted Dr. Catenacci. Since having this information is important, he said, his own practice considers biopsy of both sites.
The study is also evaluating the role of circulating tumor DNA (ctDNA). In interim assessment, they have found its results to be 90% concordant with tissue biopsies of the metastatic tumor.2 Full analyses of ctDNA utility to address intrapatient molecular heterogeneity is underway and will be presented at a future meeting. “In the future, we will likely be able to just do a blood test,” Dr. Catenacci predicted.
Improvement in Overall Survival Rates
Of 68 patients treated according to the design, the 1-year overall survival rate was 66% (P < .001), and the median overall survival was 16.4 months (95% confidence interval = 13.8–20.8 months). The outcomes achieved in the various molecular subgroups are shown in Table 1 (data cut as of October 1, 2019).
Survival was based on all patients treated with a personalized strategy across all lines. All patients enrolled received first-line therapy, and of the intent-to-treat population, 86.7% of those in whom first-line therapy failed received second-line treatment and 35% of those in whom first- and second-line therapy failed went on to third-line treatment. However, some PANGEA patients are still in first line (9), second line (5), or third line (3) to date, and so, these rates of later-line therapy may change. “The best results and majority of benefit were derived from the personalized strategy as first-line treatment, and these data (response rate and progression free survival in each line of therapy) will be reported at an upcoming meeting,” said Dr. Catenacci.
“All 80 patients who were screened were able to get some form of targeted treatment, with the exception of two arms in which drug access was a problem,” he added. “Those patients received the standard of care and did poorly, with a 1-year survival of about 30%, as compared with 66% for the others treated per the PANGEA protocol.
“Our median overall survival from the time of diagnosis of stage IV disease is nearly double that seen in many first-line studies, and it is better than we saw in the phase III RAINFALL trial of ramucirumab,” Dr. Catenacci noted. In RAINFALL, the median overall survival was 11.7 months for patients receiving chemotherapy plus ramucirumab and 10.7 months with chemotherapy alone.3
“For the HER2 subgroup specifically, the median survival was 25.8 months, again around double the survival time of 13.8 to 14.2 months observed in pivotal phase III studies evaluating trastuzumab and other agents. I think this is related to the attention to baseline molecular heterogeneity, the biomarker-profiling prioritization algorithm, and the personalized treatment beyond disease progression. For example, 5 (26.3%) of 19 patients with an aspect of HER2 positivity had a different treatment assignment at baseline, compared to what would have been done by standard approaches, as a consequence of baseline primary to metastasis discordance and/or the priority treatment algorithm. Of course, our observations need to be confirmed in a prospective and larger randomized study.” 4
DISCLOSURE: Dr. Catenacci has received honoraria from, consulted or advised for, or served on speakers bureaus of Amgen, Astellas Pharma, Bristol-Myers Squibb, Five Prime Therapeutics, Foundation Medicine, Genentech/Roche, Genmab, Gritstone Oncology, Guardant Health, Lilly, Merck, NantOmics, OncoPlex Diagnostics, Taiho Pharmaceutical, and Merck.
1. Catenacci DVT, Lomnicki S, Chase L, et al: Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): Primary efficacy analysis of the phase II platform trial (NCT02213289). 2020 Gastrointestinal Cancers Symposium. Abstract 356. Presented January 23, 2020.
2. Pectasides E, Stachler MD, Derks S, et al: Genomic heterogeneity as a barrier to precision medicine in gastroesophageal adenocarcinoma. Cancer Discov 8:37-48, 2018.
3. Fuchs CS, Shitara K, Di Bartolomeo M, et al: Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): A double-blind, randomised, placebo-controlled, phase III trial. Lancet Oncol 20:420-435, 2019.
4. Catenacci DVT: Expansion platform type II: Testing a treatment strategy. Lancet Oncol 16:1276-1278, 2015.
Marcia Cruz-Correa, MD, PhD
Marcia Cruz-Correa, MD, PhD, Professor of Medicine at the University of Puerto Rico and Adjunct Professor of Surgical Oncology at The University of Texas MD Anderson Cancer Center, congratulated the investigators on the conduct of the PANGEA trial and the outcomes...