Personalized, Adaptable Treatment Strategies May Improve Survival in Metastatic Gastroesophageal Cancer

Daniel Catenacci, MD

Offering patients with metastatic gastroesophageal tumors a more personalized and adaptable treatment approach using monoclonal antibodies matched to genetic profiles in combination with chemotherapy may result in higher rates of survival compared with historic controls, according to the results from the phase 2 PANGEA study (NCT02213289).¹

A 1-year overall survival (OS) rate of 66% (95% CI, 54%-76%) was reported in the 68 patients who comprised the intent-to-treat population, meeting the primary efficacy end point of the trial (one-sided, P = .0024). The median OS was 15.7 months (95% CI, 13.4-17.7) in these patients; the median time to treatment failure (TTF) was 13.6 months (95% CI, 11.3-15.8). Moreover, the 2-year OS rate in this population was 29%, the 3-year rate was 14%, and the 5-year rate was 11%. The 1-year OS rate in the non-ITT population (n = 12) was 33.3%, with a 2-year rate of 8% and a median OS of 9.0 months (95% CI, 4.6-20.3).

“At first there was only chemotherapy for HER2-negative tumors in the first-line setting, but now other targeted therapies are coming out, including anti–PD-1, anti-FGFR2 and anti-claudin,” Daniel Catenacci, MD, an associate professor of medicine and director of the Gastrointestinal Oncology Program at the University of Chicago, as well as the assistant director of Translational Research in the Comprehensive Cancer Center, stated in a press release.² “How does a physician decide which treatment to prescribe when a patient might be eligible for multiple options given known overlap in a tumor of the predictive biomarkers for each of these therapies? This study shows that using an algorithm such as ours could help with that prioritization to direct optimal care and may potentially lead to better outcomes for patients.”

Although advances made in genetic testing have created opportunities to better inform treatment strategies, heterogeneity can cause difficulties in identifying the best targeted therapy for each individual patient. To address this unmet need, investigators developed a new treatment strategy for this patient population.

The goal of the study was to optimize survival in patients through the use of sequential doublet chemotherapy in combination with an individually matched monoclonal antibody at baseline diagnosis, then again serially over up to 3 lines of therapy.

To account for the potential of several therapeutic approaches because of concurrent molecular alterations in a given patient’s sample, a predefined prioritized biomarker and treatment assignment algorithm was applied at each line of therapy. Investigators hypothesized that the individualized treatment approach, which comprised 8 biological subsets with 6 matched monoclonal antibodies, could address formidable hurdles presented by molecular heterogeneity, resulted in improved outcomes over historical controls.

From June 2015 through May 2019, investigators enrolled 80 eligible patients. The median age of the study population was 61 years (range 28-81), the majority of whom were male (80%; n = 64). Of the 80 total patients enrolled to the study, 43% (n = 34) had esophageal tumors and 30% (n = 24) and gastroesophageal junction tumors. Seventy-four percent of patients (n = 59) had signet ring cells absent.

In the total patient population, baseline metastases were noted in the lymph nodes (63%; n = 50), peritoneum (38%; n = 30), liver (36%; n = 29), lung (8%; n = 6), bone (5%; n = 4), adrenal gland (4%; n = 3), or another location (1%; n = 1). Additionally, 40 patients (50%) had a performance status of 0, 33 (41%) had a status of 1, and 7 (9%) had a status of 2.

The biomarker prioritization and treatment assignment algorithm utilized by investigators placed patients in 1 or 8 treatment arms based on genetic testing results:

1. PD-L1 IHC combined positivity score of over 10, who were microsatellite instability–high, had a tumor mutation burden less than 15 mutations/mb, and/or Epstein–Barr virus–positive received anti-PD-1 nivolumab (Opdivo)
2. HER2-amplified received trastuzumab (Herceptin)
3. EGFR-amplified received ABT-806
4. FGFR2-amplified received bemarituzumab
5. MET-amplified received anti-MET (no agents available)
6. MAPK/PIK3CA aberrant received ramucirumab (Cyramza)
7. EGFR expressing received ABT-806
8. All negative received ramucirumab

In the ITT population, all patients received a first-line therapy, 87% (n = 53/61) went on to receive a second-line therapy, and 42% (n = 60) progressed and received a third-line therapy. Those who progressed on all 3 lines of therapy in the PANGEA study went on to receive a fourth line of therapy (12%; n = 8). No fifth-line or later therapies reported.

During the first cycle of treatment, 41.2% (n = 28) of patients in the ITT population received modified oxaliplatin, levofolinate, 5-fluorouracil (5-FU), and bevacizumab (Avastin; mFOLFOX7) without 5-FU bolus while the remainder were given leucovorin, 5-FU, and oxaliplatin (mFOLFOX6) with 5-FU bolus. Through the duration of their treatment, 20.6% of patients received palliative radiotherapy to the primary tumor, all of which were proximal esophagogastric junction tumors (28%; n = 14/50).

Additional findings indicated that 79% (n = 54) of patients in the ITT population and 83% (n = 10) of those in the non-ITT population had measurable disease. Four patients (7.4%) in the ITT population had a complete response (CR), 36 (66.7%) had a partial response (PR), 13 (24.1%) had stable disease, and 1 (1.9%) had progressive disease. No patients (0%) within the non-ITT population experienced a CR. However, 4 (40%) patients in the non-ITT population achieved a PR, 3 (30%) had stable disease, and 3 (30%) had progressive disease.

No diagnostic or treatment-related deaths were reported on the study, and only 1 patient required overnight monitoring due to abdominal pain following a baseline ultrasound-guided biopsy of a peritoneal nodule. The most frequent grade 3 or higher hematologic treatment-related adverse effects (TRAEs) reported across all lines of therapy included neutropenia (18%; n = 12), anemia (16%; n = 11), and white blood cell decrease (9%; n = 6). Other grade 3 or higher TRAEs included fatigue (13%; n = 9), as well as nausea and vomiting (9%; n = 6).

In the first-line setting, the most common high-grade hematologic toxicities included anemia (10%; n = 7), neutropenia (9%; n = 6), and thrombocytopenia (6%; n = 4), with other TRAEs including nausea and vomiting (6%; n = 4) and fatigue (4%; n = 3). Patients in the second-line setting experienced some neutropenia (8%; n = 4), fatigue (6%; n = 3) and diarrhea (6%; n = 3). Lastly, in the third-line setting, the most common TRAE was fatigue (16%; n = 4) with hematologic TRAEs including neutropenia (12%; n = 3), anemia (12%; n = 3), and thrombocytopenia (12%; n = 3).

“During the study, we learned that not only is it common to see genetic heterogeneity between the primary and metastatic tumor — about 40% of the time, the metastatic tumor differed substantially from the primary tumor — but also that about 45 or 50% of the time, patients had their therapies changed as the disease evolved,” Catenacci added. “By going after the metastatic site at the start of treatment, reassessing the tumor if and when there was clinical disease progression, and using the algorithm to prioritize therapy each time, the survival outcome was substantially higher than would be expected using standard therapies.”

References

1. Catenacci DVT, Moya S, Lommnicki S, et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): a phase II study evaluating an individualized treatment strategy for metastatic disease. Cancer Discov. Published online November 20, 2020. doi:10.1158/2159-8290.CD-20-1408
2. Dynamic, personalized treatment approach may improve outcomes in gastroesophageal cancers. News Release. University of Chicago Medicine. January 21, 2021. Accessed January 22, 2021. http://bit.ly/3o8XarI