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Clinical

In season 4, episode 1 of Targeted Talks, Benjamin L. Schlechter, MD, senior physician at Dana-Farber Cancer Institute and instructor in Medicine at Harvard Medical School, discuses new studies in the  gastrointestinal cancers space. Schlechter explains how these studies can inform future research.

First, in a phase 1a/1b study (NCT03860272) of botensilimab (AGEN1181) plus balstilimab (AGEN2034), promising clinical activity and durable responses were shown in patients with metastatic heavily pretreated patients with microsatellite stable (MSS) colorectal cancer (CRC). The findings were presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI). Schlecter explains that botensilimab is a first-in-class drug targeting the CTLA-4 protein receptor, and therefore offers something different than the anti-CTLA-4 therapies that are currently available.

“I don't think anyone expected things like this to work, because there have been so many failures in this space. I think it emphasizes that this is not just a CTLA-4 inhibitor, and not just a checkpoint inhibitor. There’s something fundamentally different about how this agent behaves. We see that in the efficacy profile and the toxicity profile. And I think it's easy to put this in the same basket as tremelimumab [Imjudo], or ipilimumab [Yervoy], and I don't think that's fair assessment. It's a next class of drug, and it really is its own thing,” Schlechter says.

In another early-phase study (TACTIC-02; NCT04727151), investigators are exploring the use of autologous T cells expressing T-cell antigen couple (TAC) that target HER2 in patients with solid tumors. Schlechter says that T-cell therapy is difficult in solid tumors, but if this study is successful, it will create opportunities for other targeted therapy studies in the future.

Schlechter says: “I think this is a really important beginning. If we can target HER2 safely and successfully, this really opens the door for a number of targets that right now are off limits. There are so many cancers right now that we know there's a target for, but we can't go after that target because there's so much targeting normal tissue that it will be dangerous to do so. This is both an important innovation in T-cell therapy and HER2. But this is also important innovation for cellular therapy in oncology because products like this would allow us to target far more things than we currently can with existing technology.”

Schlechter also discusses later-phase trials that appear to be practice-changing. The SUNLIGHT study (NCT04737187), for example, may have global implications for adding 

bevacizumab (Avastin) to the combination of trifluridine/tipiracil (Lonsurf)

 for the treatment of metastatic CRC. This strategy is already standard in the United States. In addition, adding liposomal irinotecan to 5-fluorouracil with leucovorin plus oxaliplatin (NALIRIFOX) may achieve better efficacy compared with standard treatment, as shown in the 

 in patients with pancreatic ductal adenocarcinoma.

1. El-Khoueiry AB, Fakih M, Gordon MS, et al. Results from a phase 1a/1b study of botensilimab (BOT), a novel innate/adaptive immune activator, plus balstilimab (BAL; anti-PD-1 antibody) in metastatic heavily pretreated microsatellite stable colorectal cancer (MSS CRC). 

. 2023; 41(suppl 4): LBA8. doi: 10.1200/JCO.2023.41.3_suppl.LBA8

2. Schlechter BL, Olson D, Sailbil S, et al. A phase I/II trial investigating the safety and efficacy of autologous TAC T cells targeting HER2 in relapsed or refractory solid tumors. 

. 2023;41(suppl 4): TPS816. doi: 10.1200/JCO.2023.41.4_suppl

In season 4, episode 1 of Targeted Talks, Benjamin L. Schlechter, MD, discuses new studies in the gastrointestinal cancers space.

Unpacking the Latest Research in Gastrointestinal Cancers

In season 2, episode 2 of Targeted Talks, Cathy Eng, MD, the David H. Johnson Chair in Surgical and Medical Oncology; professor of medicine, hematology and oncology; co-director, GI Oncology at Vanderbilt-Ingram Cancer Center, speaks with Benjamin Weinberg, MD, associate professor of medicine, Division of Hematology and Oncology, in the Lombardi Comprehensive Cancer Center at Georgetown University, about the gut microbiome, and how the presence of certain microbiota impact the onset and intensity of disease as well as the potential response to certain treatments.

In recent years, the increasing number of 

young adults developing colorectal cancer

 has been believed to be closely linked with the gut microbiome. Several studies have examined this onset of disease and suggested that diet and obesity may play a role. Still, there is little known about how the gut microbiome may impact average-aged patients and the older patient population.

Other ongoing questions in the space include how to utilize information obtained from 

gut microbiome research in colorectal cancer

 to diagnose, treat, and monitor disease.

In season 2, episode 2 of Targeted Talks, Cathy Eng, MD, speaks with Benjamin Weinberg, MD, about the gut microbiome, and how the presence of certain microbiota impact the onset and intensity of disease as well as the potential response to certain treatments.

The Impact of the Gut Microbiome in Young Patients With Colorectal Cancer

During a Targeted Oncology™ Case-Based Roundtable™ event, Jaffer A. Ajani, MD, discussed the trials investigating the use of immune checkpoint inhibitors in patients with upper gastrointestinal cancers. 

Ajani Discusses Immune Checkpoint Inhibition in HER2-Negative Upper GI Cancer

A phase 1 study is investigating anti-TIGIT therapy combined with immune checkpoint inhibition for the patients with metastatic microsatellite stable colorectal cancer.

Study Investigates Anti-TIGIT Therapy Plus Pembrolizumab in Metastatic MSS CRC 

Patrick Wagner, MD, director of complex general surgical oncology at AHN Cancer Institute, discussed the current state of important developments in treatment of gallbladder cancer. 

Gallbladder Cancer Awareness Month: Steady Progress in Optimizing Patient Care

A phase 1 dose-escalation and -expansion clinical trial will evaluate BA3182, a potential anticancer therapy, for patients with advanced adenocarcinoma based on the clearance of an investigational new drug application from the FDA.

FDA Okays IND Application of BA3182 for Advanced Adenocarcinoma

A read out from the phase 3 KEYNOTE-859 at the February ESMO Virtual Plenary hints pembrolizumab/chemotherapy is a new treatment choice for locally advanced or metastatic, HER2-negative gastric or gastroesophageal junction adenocarcinoma.

Pembrolizumab Plus Chemo Emerges as New Option for Advanced, HER2–Negative Gastric/GEJ Cancer

Jashodeep Datta, MD, a surgical oncologist at Sylvester Comprehensive Cancer Center and assistant professor of Clinical at the University of Miami Miller School of Medicine, explains 

 co-alteration in patients with pancreatic cancer.

, explains Datta. The reason for these co-alterations is unknown, and oncologists also do not have a clear picture of how this effects the disease. These questions were explored preclinically and warrant further study.

 We are very interested in understanding the chasm that exists between the genotype of pancreas cancer and the virulent phenotype of pancreas cancer. What makes it so hostile for patients? To do that we approach this from the genome of the pancreatic cancer cell, which is really the incipient event in pancreatic tumorigenesis. And what's very interesting about pancreas cancer is compared with all of the cancers, if you look across the Cancer Genome Atlas, pancreatic cancer is the number one cancer that has cooperated mutations of 

 We really want to understand if there is a biologic basis for that, and what are the downstream repercussions of that. The was really the basis of this study. The most important finding that really paved the way for the remainder of our study was our finding, using a cohort of 250 patients from the University of Miami, as well as validation in two independent datasets, one from the Cancer Genome Atlas, as well as one from an international molecularly annotated data set the ICGC, where we showed that patients who had quadrate mutations in 

 had worse survival and worse prognosis compared with patients who had mutations in either the carrier s gene alone. And they had may have other mutations, but not 

. So, this really paved the foundation for the remainder of the study.

Videos

Jashodeep Datta, MD, explains KRAS and TP53 co-alterations in patients with pancreatic cancer.

News

Investigating KRAS/TP53 Co-Alterations in Pancreatic Cancer

Zev A. Wainberg, MD, a professor of medicine at University of California, Los Angeles, and co-director of the UCLA GI Oncology Program, discusses the recent findings from NAPOLI 3 (NCT04083235) which were presented at the 2023 Gastrointestinal Cancers Symposium.

The randomized, open-label, pivotal phase 3 NAPOLI 3 trials is evaluating the combination of irinotecan liposome injection (Onivyde), 5-fluorouracil (5-FU), oxaliplatin, and leucovorin (NALIRIFOX) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Patients enrolled in the study were required to be diagnosed 6 or less weeks prior to screening, have at least 1 metastatic lesion measurable by MRI or CT scan per RECIST v1.1 criteria, and have an ECOG performance status of 0 or 1.

Recent findings revealed that treatment with NALIRIFOX improved overall survival and progression-free survival compared with nab-paclitaxel plus gemcitabine in this patient population of previously untreated patients with mPDAC.

 We presented the top-line results, which included the overall survival, which was statistically significantly improved in the group of patients who've got NALIRIFOX over nab-paclitaxel plus gemcitabine by about 2 months. The median improvement was about 2 months, the hazard ratio is .83, and the 

 value is .04. The statistics also showed that this progression-free survival was superior with NALIRIFOX over nab-paclitaxel plus gemcitabine. There was no statistically significant difference in response rate, although the response rate was numerically higher with NALIRIFOX, but it did not make statistical significance.

 The safety of the regimens essentially is a tradeoff, in my opinion, of toxicity between 1 regimen that causes more of the GI toxicity that have been influenced at higher rates of diarrhea and nausea, as opposed to higher rates of cytopenias, which are neutropenia, anemia and thrombocytopenia. Those were seen more commonly in the nab-paclitaxel plus gemcitabine arm. It is a tradeoff of toxicity profiles when one talks to their patients.

Zev A. Wainberg, MD, discusses recent findings from the NAPOLI 3 trial which were presented at the 2023 Gastrointestinal Cancers Symposium.


NALIRIFOX Improves Survival vs Nab-Paclitaxel/Gemcitabine in mPDAC 

Samuel Klempner, MD, gastrointestinal medical oncologist, Oncology, Massachusetts General Hospital and faculty, Medicine, Harvard Medical School, explains the rationale for the phase 3 SPOTLIGHT study (NCT03504397) of zolbetuximab administered with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) versus with placebo plus mFOLFOX6.

Klempner presented results from the study were presented during the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium (ASCO GI). In the study, 

zolbetuximab achieved a significant improvement in progression-free survival

 (median 10.61) compared with mFOLFOX and placebo (median 8.67). Zolbetuximab also showed an overall survival advantage. Toxicity was not significantly increased by adding zolbetuximab to mFOLFOX vs placebo.

The whole field of stomach and esophageal cancers is moving towards biomarker selection strategies, and this is great for patients. It helps us match patients to drugs that are ideally suited to have the greatest chance of benefit. That's the idea behind it. The SPOTLIGHT trial, which was presented at ASCO GI 2023, is the latest addition to the biomarker world of gastric and GEJ adenocarcinomas.

There were some earlier clues about the activity of this approach in prior work. CLDN18.2 is overexpressed to varying levels in a large portion of patients with stomach and esophageal cancer. It’s seen in roughly around 40% of patients, depending on what cut off you use. There was a prior trial using monoclonal antibody against CLDN18.2 in combination with an anthracycline-based chemotherapy. It showed that the patients who got the zolbetuximab precursor in this case, IMAB362, added to chemotherapy had an improved survival. It was a phase 2 trial called the FAST study [NCT01630083]. It suggested that this strategy of targeting CLDN-high patients for treatment with a CLDN-directed antibody was something that had a lot of potential. That was the background and rationale for the phase 3 SPOTLIGHT trial presented at ASCO GI 2023.

Samuel Klempner, MD, explains the rationale for the phase 3 SPOTLIGHT study.

Zolbetuximab Plus mFOLFOX for CLDN18.2+/HER2- Advanced Gastric/GEJ Cancers

Samuel Klempner, MD, gastrointestinal medical oncologist, Oncology, Massachusetts General Hospital and faculty, Medicine, Harvard Medical School, discusses zolbetuximab for patients with claudin 18.2 (CLDN18.2)-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer.

 The landscape of stomach and esophagus cancer is rapidly evolving, and that's a good thing for patients. Even in the past couple of years, we've had approvals for new HER2 agents like trastuzumab deruxtecan [Enhertu]. We've had immunotherapy added to the frontline. We've had neoadjuvant immunotherapy for MSI-high patients where these are all great things for patients.

 The area that's the most complex is that in patients that have expression of multiple biomarkers, how we're going to manage or choose which is approach. Let's say a patient walks into your clinic 9 months from now, and they're PD-L1 positive and they're  CLDN18.2-positive, how do we decide between giving them chemotherapy with immunotherapy or chemotherapy with zolbetuximab. Right now, we don't have head-to-head comparison to pick that. So, we have to look at the patient factors, we have to look at the side effects of the drugs we have to have shared decision-making and discussions with the patients. And then we need to look at the relative benefit in the areas that we do have data. For example, someone who is PD-L1-low, but claudin and that's someone that I envision using a claudin antibody in the front-line setting. For someone who's had very high PD-L1 expression, perhaps you might use immunotherapy, or you could do both, but you could choose immunotherapy plus zolbetuximab plus chemotherapy. There are some ongoing trials to test that to see if it's safe and active.

So, someday, we may be using triplet combinations of targeted plus immunotherapy plus chemotherapy. But right now, we’re really trying to tease apart the data and decide what we think is best for our patients.

Samuel Klempner, MD, discusses zolbetuximab for patients with claudin 18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer.

Fitting Zolbetuximab into the Gastric/GEJ Cancer Treatment Paradigm

Michael Chuong, MD, medical director of proton therapy and photon therapy, radiation, Baptist Health South Florida, discusses the study design of a trial evaluating radiation therapy in patients with locally advanced pancreatic cancer.

The use of radiation therapy in this space is not a standard. However, a non-ablative dose can show promising efficacy with little adverse events.

According to Chuong, ablative radiation therapy in 5 fractions guided by MRIdian Linac online adaptive replanning or 15-25 fractions delivered with CT guidance can be viable options for this patient population.

 The study design is essentially a single-arm phase 2 trial in which all patients would have initially received chemotherapy before enrollment. Then if there was no evidence of distant progression, they would be considered for study participation.

 In the trial, all patients received 5 fractions or essentially 5 days of radiation therapy delivered on the meridian device, with the intent being to deliver an ablative, or very high dose to the tumor. This is a dose that is not routine or standard on regular radiation machines, just simply because the safety of that would be where it would not be safe to do.

Michael Chuong, MD, discusses the study design of a trial evaluating radiation therapy in patients with locally advanced pancreatic cancer.


Study Evaluates Use of Radiation Therapy in Pancreatic Cancer

Allan Pickens, MD, thoracic surgeon at Emory University, program director for cardiothoracic surgery residencies and the director of Medical Oncology, discusses the current treatment landscape for esophageal cancer.

In the past decade, there has not been much of a change in regard to new procedures and drugs to help treat patients with esophageal cancer.

However, Pickens notes that 1 big advancement has been made in the early detection for esophageal cancer. This includes aggressive screening programs, having better screening programs and opportunities to treat patients with porousness.


Esophageal cancer has devastating effects on patients in terms of it being a very lethal tumor. The treatments that we have available for esophageal cancer have not made significant leaps and bounds over the past 10-20 years in the sense that we have not had a lot of new drugs on the market and not a lot of new procedures to combat it. The 1 advancement we have made is in early detection of esophageal cancer, including much more aggressive screening programs for Barrett's dysplasia, and other forms of premalignant lesions that lead to esophageal cancer.


 In the earlier diagnosis of esophageal cancer, we have better opportunities to treat porousness. If we find something that's contained to the surface or mucosal layer of the esophagus, we can use some of the ablative techniques to take care of it. There's something called endoscopic mucosal resection, where we actually take away a portion of the lining of the esophagus with the tumor contained in it. Those don't interfere with the traditional surgical procedures that we have available. If those fail, we can then do a surgical resection to completely remove a early-stage esophageal cancer. The problem lies when we don't make the diagnosis early and these tumors have grown through the wall of the esophagus into our surrounding structures. This leads to a much worse outcome when it goes to lymph nodes and things that are outside of the esophagus.

Allan Pickens, MD, discusses the current treatment landscape for esophageal cancer.


Advancements Needed in the Esophageal Cancer Space

Charles J. Schneider, MD, FACP, clinical professor of Medicine at the Abramson Cancer Center at Perelman Center for Advanced Medicine, discusses some of the ongoing research examining patients with anal cell carcinoma.

Currently, immunotherapy and targeted therapy are used when treating patients with anal carcinoma. The 2 PD-1 inhibitors, nivolumab (Opdivo) and pembrolizumab (Keytruda), have become the standard of care for patients with advanced disease who are resistant to chemotherapy.

According to Schneider, studies are investigating new agents that will hopefully add to the treatment paradigm for early-stage disease. Experts hope these new additions will improve survival and outcomes for these patients.

We have a lot of research ongoing. For instance, we just completed accruing nationally to a trial through the Eastern Cooperative Oncology Group that assigned patients after receiving potentially curative and intensive chemotherapy radiation for early disease, assigning them to either observation, which is our standard of care vs 6 months of immunotherapy using the drug nivolumab. That's an exciting trial that's been completed, and we're just waiting for results. We are hoping that adding immunotherapy to the treatment paradigm for early-stage disease will improve survival in that group even higher.

Second is localized disease. There's an ongoing trial that's looking at lowering the amount of radiation given which would reduce toxicity from radiation to the area to the pelvis, while still hopefully maintaining high cure rates. In advanced disease, there are many trials that are looking at different immunotherapy drugs, and also adding immunotherapy to chemotherapy, which would be the logical next step.

Charles J. Schneider, MD, FACP, discusses some of the ongoing research examining patients with anal cell carcinoma.

 Next Steps in Anal Carcinoma Research

Allan Pickens, MD, director of Thoracic Oncology Emory Healthcare, and professor, Department of Surgery, Emory University School of Medicine, discusses disparities occurring in patients with esophageal cancers.

 The work that we've done in terms of racial disparity has been more from the surgical side of things. How we can affect the surgical treatment of esophageal cancer in underrepresented minorities. What we've found in looking at the data is that it tends to have a more devastating effect in the minority population. There is a poor survival for esophageal cancer in minorities.

 We are looking at the multifactorial causes of that, 1 being access to early diagnosis and treatment. The fact that many minorities are often offered the non-surgical options for treatment, they are more likely to proceed with definitive chemoradiation as opposed to surgical procedures. Has that mostly been related to [having] access to surgeons or qualified surgeons to do their procedures at smaller hospitals and smaller, underrepresented communities? Perhaps there are not dedicated esophageal cancer surgeons that can take care of it. And if they're required to travel hours away to a center of excellence that has those physicians, they perhaps don't have the resources to do that in some instances. So, how do we help in those situations? How do we make it available for virtual visits with physicians in other locations so that they only have to make one visit for the preop and perhaps the actual operation. Then they go back to their community and get their follow-up care with physicians that they are in contact with. So, looking at that disparity and how it affects the survival of soft tissue cancer is truly important.

According to Allan Pickens, MD, surgery outcomes differ in minority patients and oncology surgeons are researching the issue.

Oncology Surgery Disparities Among Patients With Esophageal Cancer

Cristian Tomasetti, PhD, associate professor at the John Hopkins University School of Medicine, discusses the role of circulating tumor-DNA (ctDNA) after surgery in patients with stage II colon cancer.

(ACTRN12615000381583), using a ctDNA approach in this patient population leads to a reduction in the use of adjuvant chemotherapy. This result was achieved without compromising recurrence-free survival.

Further, the use of ctDNA after surgery can help determine which patients may relapse and who may need adjuvant chemotherapy or not.

It's been known now for some time that normal cells as well as cancer cells shed some of their DNA into the bloodstream. By measuring the levels of cell-free DNA, we may be able to detect some of these DNA fragments that don't come from regular healthy cells but come from cancer cells.

The idea in this specific setting with colon cancer is that if the surgery was a success, and the cancer was fully removed, then after a few weeks, in theory, we shouldn't find any cell-free DNA coming from cancer cells, because the cancer has been fully removed, in theory.

Cristian Tomasetti, discusses the role of circulating tumor-DNA after surgery in patients with stage II colon cancer.
