Top NY GI Oncologists Spotlight Groundbreaking Research Efforts

During the 2020 OncLive^® State of State of the Science Summit^™ on Gastrointestinal Malignancies, experts from Memorial Sloan Kettering Cancer Center and NYU Langone Health’s Perlmutter Cancer Center highlighted some of the exciting research efforts being conducted at their respective institutions.

Evan Ya-Wen Yu, MD, a professor in the Department of Medical Oncology, University of Washington School of Medicine, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

Yelena Y. Janjigian, MD

Yelena Y. Janjigian, MD: Chief, Gastrointestinal Oncology Service, and Medical Oncologist, Memorial Sloan Kettering Cancer Center

“My research focus is in gastric cancer—identifying subsets of the disease that we can really target and potentially cure. We know that [in patients with] stage IV gastric cancer [we see] very varied outcomes. However, in HER2-positive disease, we have really been able to raise the bar, particularly in [those whose] tumors are strongly HER2-positive; these patients tend to do better.

A biomarker analysis performed by my group [has demonstrated that patients with esophageal cancer] who have HER2 amplification detected in their circulating tumor DNA, particularly those with a high level of ERBB2 amplification in their blood, [will] benefit from HER2-directed therapy quite a bit more than those who [do not have] ERBB2 amplification. [The former will also] have significant improvements in progression-free survival and overall response rates (ORRs) with HER2-directed therapies.

[We’re using this information] to help us understand why some patients benefit quite a bit from HER2-directed therapies while others progress on frontline [treatment with these therapies], as if their tumors are not even HER2-driven. This is an important area of research, particularly now that we’re doing first-line studies in the space to further improve on outcomes [with these targeted therapies]. As you know, trastuzumab (Herceptin) is FDA approved and it has been in our clinics for over a decade now. However, beyond trastuzumab, we have not really been successful at improving outcomes [with] HER2-directed agents. Many drugs on the market that were approved for use in breast cancer have actually been failing in gastric cancer.

Our strategy has been to combine a tumor-targeting anti-HER2 antibody with an anti—PD-1 agent that helps augment the immune response that we see from the patient’s own immune system. [With this approach, we want to] build on [that immune response] and attack the cancer through multiple pathways. [One of our] phase II trials examined the combination of pembrolizumab (Keytruda) plus trastuzumab and we saw quite promising preliminary data [from that research]. Pembrolizumab is an PD-1 inhibitor that, in our experience, has really augmented the response that we see with anti-HER2 [therapies].

Preliminary data [from that trial showed that] 100% of the patients [experienced] a reduction in their tumor burden [with the pembrolizumab combination] and a confirmed ORR of 89%. These findings compare favorably with the 47% ORR that we see in this population with trastuzumab plus chemotherapy alone. This strategy is now [being examined in the] phase III KEYNOTE-811 trial, which is randomizing patients to receive either first-line chemotherapy plus trastuzumab/placebo or chemotherapy plus trastuzumab/pembrolizumab.

In the second-line setting and beyond, the HER2-positive space has [historically] been quite vacant; however, some of the drugs that are on the market right now are really quite exciting. I’m particularly excited about fam-trastuzumab deruxtecan-nxki (DS-8201; Enhertu); this is a HER2-directed agent linked with a topoisomerase 1 inhibitor [that has] cytotoxic activity similar to [that of] irinotecan, which is also a very active drug in gastrointestinal cancers. We’re developing this drug now in gastric cancer and bringing it to our patients. We’ll look out for [more data on] that [agent] at the 2020 ASCO Annual Meeting. [In the future, DS-8201] is probably going to be among our most prominent strategies.

Evan Ya-Wen Yu, MD, a professor in the Department of Medical Oncology, University of Washington School of Medicine, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

Neil H. Segal, MD, PhD

Neil H. Segal, MD, PhD: Medical Oncologist, Memorial Sloan Kettering Cancer Center

“I’m currently working on clinical trials in microsatellite instability—high (MSI-H) colorectal cancer (CRC). [These clinical trials are enrolling] untreated patients, [those who received] 1 line of prior therapy, [and those who received] more than 1 line of prior therapy. Depending on how many prior lines of treatment they received, patients will be randomized to receive either standard chemotherapy, PD-1 blockade with nivolumab (Opdivo), or a combination of a CTLA-4 [inhibitor] and a PD-1 [inhibitor]. Our intention is to define what the benefit is of 1 immunotherapy [agent] versus combination immunotherapy in these patients.

Other trials that I’m working on are [examining] bispecific antibodies in combination with anti—PD-L1 drugs to define the effectiveness of that strategy. We want to determine what the responses are [to that kind of approach]. Other [basket] trials are exploring various combination chemotherapies [with the goal of] identifying what the optimal therapy [are ongoing].”

Evan Ya-Wen Yu, MD, a professor in the Department of Medical Oncology, University of Washington School of Medicine, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

David H. Ilson, MD, PhD

David H. Ilson, MD, PhD: Medical Oncologist, Memorial Sloan Kettering Cancer Center

“Right now, we’re [doing research that is focused] in the HER2-positive breast cancer space. [For example], we’re involved in further evaluation of trastuzumab deruxtecan-nxki. Another [drug] that we’re looking at is another bispecific antibody that combines elements of trastuzumab with immune recruitment; that [agent is showing] some signal of activity.

We’re also interested in examining checkpoint inhibitors and combined modality therapy. To this end, we have a pilot study combining durvalumab (Imfinzi) with chemoradiation in esophageal and gastroesophageal junction cancers. In the adjuvant setting, [we have a] perioperative trial [examining the addition of] pembrolizumab to perioperative chemotherapy with 5-fluoruarcil and a platinum-based therapy.

That trial, if not already accrued, [should] be fully accrued fairly [soon]. I’m not that optimistic about PD-L1 inhibitors in the adjuvant setting because we know that the signal of benefit is only [seen] in a very small subset of patients. [The question of] whether or not [that signal is] going to translate into a benefit in a larger neoadjuvant or adjuvant setting remains to be established.”

Evan Ya-Wen Yu, MD, a professor in the Department of Medical Oncology, University of Washington School of Medicine, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

James J. Harding, M

James J. Harding, MD: Medical Oncologist, Memorial Sloan Kettering Cancer Center

“We have been very interested in any therapeutic that could improve outcomes for patients with liver cancer. Some of the programs that have been important for us have been looking at immunotherapy at earlier stages of disease and pairing that [approach] with regional therapies. To that end, we have led a trial of embolization with nivolumab for patients with liver-limited disease with the purpose of really defining the feasibility and safety of this approach. We presented some of those data in a poster at the 2020 Gastrointestinal Cancers Symposium, and preliminary [data] suggest that [this strategy] is safe. As part of this study, we have a number of correlates, both from the blood as well as from the tumor, [that will] hopefully help us understand how these drugs work and the differences [that exist] within the tumor and the microenvironment. [This research is] certainly very exciting to me.

Other programs at our institution are primed to examine [several pressing] questions, and so I believe [those research efforts] will be very significant. [For example], we need to understand why patients with liver cancer respond [to certain treatments]. As such, we continue to collect patient tissue on Institutional Review Board—approved protocols and we are working to understand what the immune environment [looks like] and how might that affect outcomes.

Another interesting question [has to do with] liquid biopsies in liver cancer. We hear a lot about these biopsies [being used in] other tumor types, and they are designed to look for key genomic drivers. In other diseases, such as lung cancer, melanoma, and even CRC, there may be therapeutic import to knowing the genomic driver and that, in turn, might lead to [better guided] treatment decisions. Liver cancer has not been a particularly targetable disease. But that said, having a liquid biopsy might help us to understand the rate of tumor growth, the potential response to treatment, and whether there is residual disease after surgery. These are all questions that are in their nascency, but we’re certainly collecting patient samples and analyzing them for [additional insight].

Finally, with regard to targeted therapy, one [area of research is focused in] patients with FGF19 genetic amplification, a genomic event that occurs in about 5% of patients with liver cancer, but it may be even higher if we look for it in the protein of liver cancers. A few programs are examining FGFR4 inhibitors in those patients, and we have one [trial] running now. Preliminary data suggest that there is activity [with this approach], and so we’re interested to [learn more about it] and we continue to enroll to those studies.”

Evan Ya-Wen Yu, MD, a professor in the Department of Medical Oncology, University of Washington School of Medicine, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

Andrea Cercek, MD

Andrea Cercek, MD: Medical Oncologist, Memorial Sloan Kettering Cancer Center

“I’m doing research in [a subset of patients] with CRC who have mismatch repair deficient or MSI-H tumors that are locally advanced. We normally give [these patients] standard FOLFOX followed by chemoradiation, [but in this study] we have replaced chemotherapy with a PD-1 inhibitor. We are hoping to improve responses with that combination.”

Evan Ya-Wen Yu, MD, a professor in the Department of Medical Oncology, University of Washington School of Medicine, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

Eileen M. O’Reilly, MD

Eileen M. O’Reilly, MD: Winthrop Rockefeller Endowed Chair in Medical Oncology; Co-Director, Medical Initiatives, David M. Rubenstein Center for Pancreatic Cancer Research, Section Head, Hepatopancreaticobiliary & Neuroendocrine Cancers, and Medical Oncologist, Memorial Sloan Kettering Cancer Center

“The area that is of great interest to us is DNA damage-response gene targeting and DNA damage-repair strategies in pancreatic cancer. We have a big interest in that [area of research], both clinically and preclinically. We want to understand the biology there and the signals that we can build on. We absolutely want to [enhance the benefit seen with] first-line platinum-based [approaches] in this patient population, and we also want to build on the PARP inhibitor story. In general, maintenance approaches in pancreatic cancer are starting to [be examined more often] and [hopefully we will have] real data that we can add to going forward.”

Evan Ya-Wen Yu, MD, a professor in the Department of Medical Oncology, University of Washington School of Medicine, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

Ghassan K. Abou-Alfa, MD

Ghassan K. Abou-Alfa, MD: Medical Oncologist, Memorial Sloan Kettering Cancer Center

“We continue [to work on] the HIMALAYA trial and we are eager to see where [the trial] is going to take us. That is really an important trial of durvalumab and tremelimumab [in patients with advanced hepatocellular carcinoma].

We [are also] continuing our global efforts in trying to further understand patients [with regard to] demographics, ethnicity, risk factors, and further details of who will benefit from what [treatment]; we’re [examining this] at the DNA, RNA, and protein levels. Lastly, we’re definitely trying to learn what we can about CAR T-cell therapies [in this space].”

Evan Ya-Wen Yu, MD, a professor in the Department of Medical Oncology, University of Washington School of Medicine, and clinical trials core director, Genitourinary Medical Oncology, Seattle Cancer Care Alliance

Diane M. Simeone, MD

Diane M. Simeone, MD: Laura and Isaac Perlmutter Professor of Surgery, Department of Surgery; Professor, Department of Pathology; Associate Director, Translational Research,

Perlmutter Cancer Center, and Director, Pancreatic Cancer Center, NYU Langone Health

“Aside from the work that I’m doing in my own lab, we have 2 big national projects that I believe have the potential to be transformational for the field [of pancreatic cancer]. One is a new adaptive platform trial called Precision Promise; it is a new way to conduct clinical trials in pancreatic cancer. This is a large, national effort that has been done in conjunction with the Pancreatic Cancer Action Network and the FDA. There’s also a matching pharmaceutical consortium, so it’s really a whole new way to do clinical trials for patients.

[The approach is] much more patient-centric and many more learning [opportunities are] built into the clinical trials. Every patient is going to get biopsies before treatment and on treatment so that we can learn why [therapies] might work in some patients and not in others. We also [want to] see if an individual tumor’s genomic signature can be used as a predictor of how they might respond to a particular therapy. [This trial is] starting to open at different sites around the country, including at NYU Langone Health.

Also, a relatively new effort, but one that I’m equally excited about, is something called the Pancreatic Cancer Detection Consortium [PRECEDE].

Another big gap in the field is that we [didn’t have] a large group of heritable patients at high risk for pancreatic cancer assembled. [We needed this] so that we could do important work in understanding who is at risk, what the risk is, and what we’re going to do about it. With some generous funding from Project Purple, and with NYU Langone Health serving as the coordinating center, we now have 35 centers worldwide that are a part of this centralized standardization of data collection and biosample collection.

We will be following close to 4000 high-risk patients longitudinally, so I believe that this platform is going to be a terrific way to make new discoveries regarding cancer susceptibility genes, to develop and validate an early detection blood test, and [to perform] all kinds of important research in that early detection space.”