By Jennifer Lubell

The American Society of Clinical Oncology’s 2021 Gastrointestinal Cancers Symposium underscored the merits of combining therapies to prolong life and using molecular technology, such as circulating tumor DNA (ctDNA), to detect cancer months before it is visible on a CT scan.

Treating patients with gastrointestinal cancer “is not a one-size-fits all or a one-molecule-fits all,” Marcia Cruz-Correa, MD, PhD, executive director at the University of Puerto Rico Comprehensive Cancer Center and GI Symposium chair, told OBR. “More and more data show that tumors are not homogeneous; they’re very much heterogeneous.”

Systemic therapy, which combines therapy with multiple targets, including classic cytotoxic therapy is helping oncologists manage metastatic disease — and changing the way they are practicing medicine.

“This is a result of the heterogeneity of cancers and the way we obtain cancer biopsies for next-generation sequencing testing,” Dr. Cruz-Correa said. “Even when you have a driver mutation, you still have to consider combining therapy.”

M. Shaalan Beg, MD, a GI medical oncologist and member of ASCO’s communications committee, agreed that combinations of novel agents or other established drugs are the wave of the future.

“When it comes to immune therapy, we seem to be moving away from just the targeted monotherapy and immune therapies for many cancers. While those are moving the needle, we need to come up with rational combinations of immune therapy, chemotherapy, or other molecularly targeted agents. And that’s where we’re going to see bigger gains,” said Dr. Beg, an associate professor and director for GI medical oncology at UT Southwestern Medical Center.

Combination Therapies

Several presentations advanced the conversation on combined therapies. An update on the IMbrave150 trial’s overall survival (OS) data (Abstract 267) demonstrated the longest survival seen in a front-line Phase 3 study for advanced unresectable hepatocellular carcinoma (HCC). Oncologists for a long time had only one agent to manage advanced HCC, and the clinical benefit was limited, Dr. Cruz-Correa said.

In this study, investigators tested two agents in combination: atezolizumab and bevacizumab. In total, 501 patients were randomized 2-to-1 to receive either the combination treatment every 3 weeks, or single-agent sorafenib. Richard S. Finn, MD, and colleagues, collected data up to August 31, 2020 and followed patients over a median of 15.6 months. Patients on the combination treatment had a median overall survival (OS) of 19.2 months, compared with 13.4 months on sorafenib (Hazard Ratio [HR], 0.66; 95% CI 0.52-0.85; P=0.0009).

IMbrave “had pretty compelling results,” Dr. Beg said. The survival rates in the combination group “were twice of what we’d normally see in clinical trials in this disease population.”

The confirmed overall response rate for atezolizumab plus bevacizumab was 30%, versus 11% with sorafenib. “This new combination provides a significant clinical benefit over sorafenib monotherapy,” Dr. Cruz-Correa said, noting that it changes the current paradigm for HCC patients.

“Data on diverse populations and comorbidities will be valuable and should be followed up in real world data clinical trials to determine if the study observations are similar across racial/ethnic and comorbid populations,” she said.

Dr. Rachna Shroff discusses the IMbrave150 and FIGHT trials, and data on FGFR-targeted treatments from ASCO GI 2021:

The CheckMate 040 study (Abstract 269) “was another exciting study in HCC,” Dr. Beg said. Investigators examined different immunotherapy dosings of the combination regimen nivolumab plus ipilimumab, randomizing 148 HCC patients into three cohorts. The overall survival rates at 36 months were 42%, 26%, and 30% across the three dosing cohorts. The investigators concluded that the survival and “manageable” safety profile support the second-line use of nivolumab plus ipilimumab for patients with advanced HCC who previously received sorafenib.

“When you fast forward a year or so, if you ask practicing physicians which combination treatment we’ll offer our patients, I think the next competitor will be a combination of immune therapy agents or a combination of immune therapy with drugs targeting the vasculature,” Dr. Beg said.

Other reports from the CheckMate study (Abstract 478) showed higher median progression-free survival rates in a triplet regimen – nivolumab, ipilimumab, and cabozantinib — compared with a doublet regimen of nivolumab plus cabozantinib. However, it also had higher treatment-related adverse events (71%) than the nivolumab plus cabozantinib arm (42%).

Focus on FGFR-Targeted Treatments

The growing influence of FGFR-targeted therapies in the GI cancer space was demonstrated by two studies presented at the GI Symposium. “I’ve always felt that GI cancers are a few years behind lung and genitourinary cancers in terms of immunotherapy and targeted treatments, so there’s great enthusiasm in the field about FGFR,” Dr. Beg said.

The FIGHT trial, which examined first-line treatment of advanced gastric/gastroesophageal junction adenocarcinoma (Abstract 160), “demonstrated that adding that antibody therapy directed at FGFR2b improved clinical outcomes with gastric cancer,” Dr. Cruz-Correa said. The trial, the first to target overexpression of this protein in any cancer, randomized 155 patients to receive either bemarituzumab plus modified FOLFOX6 or placebo plus modified FOLFOX6.

The bemarituzumab plus FOLFOX6 combination improved progression free survival from 7.4 months to 9.5 months (Hazard Ratio [HR], 0.68; 95% CI 0.44-1.04; P=0.07). Investigators also reported improved overall survival and overall response rates in these patients. The approach, however, was associated with an increase in corneal adverse events and stomatitis. “This abstract again highlights combination therapy, and is very promising,” Dr. Cruz-Correa said.

Another FGFR inhibitor, infigratinib (BGJ398), was evaluated in patients with advanced cholangiocarcinoma (Abstract 265). The open-label, phase 2 study included 108 cholangiocarcinoma patients in their 50s with FGFR fusions or rearrangements. Investigators reported an overall response rate of 23.1%, a median progression free survival of 7.3 months, and a mean duration of response of 5 months by blinded independent central review.

“This really demonstrated the depth of response we have with FGFR treatments, in altering cholangiocarcinoma,” Dr. Beg said.

Dr. Zev Wainberg talks about the FIGHT trial data from ASCO GI 2021:

ctDNA as Prognosticator

Using ctDNA analysis to modify treatment plans for patients with colorectal cancers is a ground-breaking area of research, Dr. Cruz-Correa said. Several studies at the GI Symposium looked at integrating this technology into the management of patients.

A prospective, multicenter study evaluated ctDNA analysis as a way to detect minimal residual disease (MRD) and identify patients at high risk of recurrence, assess the efficacy of adjuvant therapy, and detect relapse earlier among patients with stage I-III colorectal cancer (CRC) (Abstract 11).

One of the reasons to use ctDNA analysis for MRD detection “is it tells us whose disease is likely to recur,” Dr. Beg said. “If you’ve had surgery and we still see cancer DNA in the blood, the chances that you’ll have a recurrence is very high. This study quantitates what that risk is like.”

Investigators used this test to evaluate ctDNA in 260 patients prior to and after surgery, repeating samples every 3 months. They assessed whether changes in ctDNA were associated with recurrent disease. For 80% of patients with positive ctDNA, they were able to identify MRD 8 months before it was discoverable by CT scan.

“Lo and behold, they saw that when CRC patients went from not having detectable to detectable ctDNA, this predicted who was going to develop colorectal cancer,” Dr. Cruz-Correa said.

This is a test that has prognostic value, she added. “As a medical gastrointestinal oncologist, I wonder if we’re treating people more than we need to, or if we’re not treating enough.” By tracking MRD through ctDNA rather than what is in the pathology report, clinicians can potentially avoid unnecessary treatments, she added.

Multiple studies in the United States and Europe are looking into integrating ctDNA in randomized clinical trials to guide which patients need chemotherapy after surgery. “The next few years should yield robust data,” Dr. Cruz-Correa said.

New Paradigm for Rectal Cancer

The phase 3 OPERA trial (Abstract 12) builds on evidence supporting non-surgical management for specific types of rectal cancer patients. “For several years now, there’s been a desire to minimize morbidity and mortality associated with surgery of rectal cancer patients. The question is whether or not every patient requires total mesorectal excision (TME),” Dr. Cruz-Correa said.

The trial evaluated standard management for rectal cancer (radiation, chemotherapy, and TME) in 71 patients, compared with dose escalation (contact X-ray brachytherapy to improve rectum preservation) in 73 patients.

Investigators concluded that non-TME surgical treatment for cT2 and cT3a/b rectal cancer was feasible in those who were fit and wanted to avoid surgery, the key thinking behind “watch and wait,” said Dr. Cruz-Correa. Those who fail and need surgery can be offered salvage surgery immediately for local residual disease or for local regrowth at a later date. The study showed that organ preservation was achieved in 80.5% of all patients. TME-free survival overall was 76% at 18 months.

“This data adds to the growing body of evidence supporting non-surgical management for specific rectal cancer patients in the last 12 centimeters for the rectum, improving quality of life and not adversely affecting the overall survival,” Dr. Cruz-Correa said.

Microbiome Research

More than 20 presentations at the Symposium addressed the topic of microbiome research. “We know there’s an interaction with the immune system and our gut flora. How that modulates the body’s immune system and how we make it do what we want it to do, is a hot area of research,” Dr. Beg said.

One observational-translational study (Abstract 161) evaluated patients with gastric cancer who received treatment with nivolumab to evaluate the relationship between the gut microbiome and the response to immunotherapy. The study included more than 400 patients (180 in the training cohort and 257 in validation cohort), most of whom had intestinal-type gastric cancer. Microbiome diversity was higher in patients who were responders to nivolumab, compared to non-responders. Microbiome specifically involved in the epithelial cell pathway were also more commonly present among gastric cancer patients with progressive disease.

The study highlights the interaction between the gut microbiome and the response to immunotherapy, suggesting that a new microbiome-based biomarker could help predict response to immunotherapy, according to Dr. Cruz-Correa.

It is also a first step in understanding what potential diet or supplementation formulations should look like, Dr. Beg said.

The Specter of COVID-19

The conference also addressed COVID-19 and its impact on treating GI cancer patients. “A significant number of patients didn’t get cancer screening because of COVID,” Dr. Cruz-Correa said. New diagnoses of colon, breast, and lung cancer in 2020 also dropped to lower-than-expected numbers, she added, suggesting the limited availability of screenings.

There is now a significant backlog of people needing cancer screenings, which will likely result in higher numbers of cancer and advanced cancer diagnoses over the next few years, she predicted. “We really need to increase capacity to be able to identify those people who missed screenings and hopefully start catching up,” Dr. Cruz-Correa said.

During the Symposium, Peter Jay Hotez, MD, PhD, Baylor University’s dean for the National School of Tropical Medicine, led a discussion about the various COVID-19 vaccines. It is anticipated that immunocompromised patients will be able to tolerate mRNA-based vaccines. At this point, no data supports withholding vaccination for these types of patients, including cancer patients or those receiving immunotherapy, Dr. Cruz-Correa said.

“We need data on antibody development and rates of infections post-vaccine among immunocompromised patients. Hopefully, this will be coming soon as more cancer patients receive the vaccine,” she said.

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