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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

A regular review of an FDA approval application is underway for the combination of pembrolizumab and standard chemotherapy for the treatment of advanced biliary tract cancer. 

FDA May Soon Approve Pembrolizumab Plus Standard Chemotherapy for Advanced BTC

ACTION-1 is investigating RYZ101 versus standard-of-care therapy in patients with SSTR-positive gastroenteropancreatic neuroendocrine tumors after 177Lu-SSA therapy.

ACTION-1: Study Initiates Treatment With RYZ101 in SSTR+ Gastroenteropancreatic NETs

The claudin 18.2 antibody-drug conjugate ATG-022 is being investigated in a phase 1 study as a potential treatment for advanced or metastatic solid tumors. 

ATG-022 Granted Orphan Drug Status by FDA for 2 Types of GI Cancer

Mitazalimab has received an orphan drug designation from the FDA and is currently being investigated in the OPTIMIZE-1 trial in combination with modified FOLFIRINOX for the treatment of patients with pancreatic cancer.

FDA Grants Orphan Drug Designation to Mitazalimab for Pancreatic Cancer

According to interim phase 2 results, GEN-001 in combination with avelumab has a significant objective response rate in patients with gastric and gastroesophageal junction adenocarcinoma.

GEN-001/Avelumab Combination Induces Antitumor Activity in Gastric and GEJ Cancer

Ken Kato, MD, PhD, chief of the department of head and neck, and esophageal medical oncology and gastrointestinal medical oncology at the National Cancer Center Hospital in Tokyo, Japan, discusses the traits clinicians should look out for when seeing if a patient with esophageal squamous cell carcinoma (ESCC) is a candidate for the combination of nivolumab (Opdivo) and ipilimumab (Yervoy).

Based on updated findings of the phase 3 CheckMate 648 trial (NCT03143153) that were presented at the 

2023 ASCO Gastrointestinal Cancers Symposium

, at a median follow-up of 28.8 months, the median overall survival (OS) for patients on nivolumab and chemotherapy (n = 321) was 12.8 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-12.1) for patients on chemotherapy alone (n = 324). The 24-month OS rate also favored the combination vs chemotherapy alone at 29% vs 19%, respectively. For patients with a PD-L1 expression of 1% or higher, the median OS still favored the nivolumab combination arm at 15 months compared with 9.1 months in the chemotherapy arm (HR, 0.59; 95% CI, 0.46-0.76).

OS was significantly longer for patients with a PD-L1 expression of 1% or greater on ipilimumab/nivolumab compared with those on chemotherapy alone at a median of 13.7 vs 9.1 months, respectively (HR 0.64; 98.6% CI, 0.46-0.90; 

 = .001). Moreover, this result was also seen in the overall population of patients on ipilimumab/nivolumab compared with patients on chemotherapy alone at 12.7 vs. 10.7 months (HR, 0.78; 98.2% CI, 0.62 to 0.98; 

 = .01). These results were based on a preliminary analysis of the CheckMate 648 trial that Kato presented at last year’s ASCO GI Symposium, but according to Kato, they have continued to hold true in real world data.

Here, Kato discusses which patient profiles fit the best for use of the immunotherapy combination over chemotherapy alone in patients with an acceptable ECOG performance score and a strong PD-L1 positivity score. 

We found the better response with [ipilimumab and nivolumab] and with longer follow-up, compared with the chemotherapy/nivolumab. We should focus on the patient who achieved a long-term efficacy [result] with ipilimumab and nivolumab.

Last year, [we] presented [that for the] patient, [there is] already a benefit with ipilimumab/nivolumab. I think that the patient with a less aggressive disease with a small tumor burden, a good performance status, and good nutritional status, can be a good candidate for the ipilimumab/nivolumab treatment. Of course, the PD-L1 positivity is good and the predictive marker for the ipilimumab/nivolumab treatment, which we already [have seen] in the real-world data with ipilimumab/nivolumab and the patient background in the further evaluation.

Videos

Ken Kato, MD, PhD, discusses which patient characteristics to look out for when looking to put a patient on the combination of ipilimumab and nivolumab.

News

Discussing Patient Characteristics in ESCC On Ipilimumab/Nivolumab

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.

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

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.

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


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