Publication

Article

Oncology Live®
Vol. 24/ No. 10
Volume 24
Issue 10
Pages: 47

Claudin-18.2 Emerges as a Novel Therapeutic Target in GI Malignancies

CLDN18.2 has become a promising target for the treatment of patients with digestive malignancies, such as gastric cancer, gastroesophageal junction cancer, esophageal cancer, and pancreatic cancer, because of its limited expression in healthy tissues and abnormal overexpression in a range of malignancies.

Kohei Shitara, MD

Kohei Shitara, MD

CLAUDIN-18 Splice Variant 2

(claudin-18.2; CLDN18.2) has become a promising target for the treatment of patients with digestive malignancies, such as gastric cancer (GC), gastroesophageal junction (GEJ) cancer, esophageal cancer, and pancreatic cancer, because of its limited expression in healthy tissues and abnormal overexpression in a range of malignancies.1 Multiple clinical trials of CLDN18.2-targeted therapies, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, are ongoing, with some showing promising early results.1 If these findings hold up in larger trials, standardizing methods of CLDN18.2 detection and positivity thresholds, optimizing novel therapies’ efficacy and safety profiles, and finding rational therapeutic combinations with existing agents will be help to integrate CLDN18.2-targeted therapies into clinical practice.1

CLDN18.2 in Heatlhy and Malignant Cells

The claudin family has 27 known members, and their expression pattern in cancer cells depends on the tumor cells’ origin.2 In healthy cells, CLDN18.2 expression is limited to the tight junctions of differentiated gastric mucosal membrane epithelial cells, where this protein’s primary functions are to preserve the barrier function of gastric mucosa, control cell lineage differentiation, and prevent leakage of sodium and hydrogen ions in gastric acid.1

Elevated expression of CLDN18.2 often accompanies cancer, particularly malignancies of the digestive system.1 By performing immunohistochemistry (IHC) on whole tissue sections, CLDN18.2 protein expression was identified in 42.2% of a cohort of 481 patients in Germany who had undergone total or partial gastrectomy for GC or GEJ. The intensity of positive expression was distributed among histoscores of up to 1+ (weak; 14.8% of the positive samples), 2+ (intermediate; 13.3%), or 3+ (strong, 14.1%). Samples were classified as having high expression if 40% or more of tumor cells showed 2+ or greater staining intensity whereas malignancies with 10% or more of tumor cells showing any expression were classified as having low expression levels.3

In contrast, IHC analysis of formalin-fixed, paraffin-embedded tissue sections identified CLDN18.2 expression in approximately 74.4% of 367 Korean patients with GC, with 108 (29.4%) samples classified as CLDN18.2 positive based on IHC scores of 2+ or higher with staining on 40% or more of tumor cells.4 In a study of tissue samples from 263 Japanese patients, CLDN18.2 expression was observed in 87% and 80% of primary gastric tumors and lymph node metastases, respectively, with 52% and 45%, respectively, classified as having moderate to strong expression of 2+ or greater on IHC testing.5

These variations suggest that ethnic differences, among other factors, should be further investigated in assessing the impact of CLDN18.2 expression in GC.4 However, not all studies of tumor CLDN18.2 expression have been conducted in gastric tumors. In one study of 202 patients with primary pancreatic tumors, CLDN18.2 expression in at least 1% of tumor cells was found in 59.2% of primary pancreatic adenocarcinomas, 69.4% of lymph node metastases, and 65.7% of liver metastases.6

Rationale for Targeting CLDN18.2

Malignant transformation of gastric epithelial tissue leads to disruption of cell polarity and then to exposure of CLDN18.2 epitopes on the cell surface.1 Although targeted monoclonal antibodies are largely unable to access CLDN18.2 located in tight-junction supramolecular complexes in normal tissue, the perturbations in cell polarity that expose CLDN18.2 epitopes may theoretically enable CLDN18.2targeted antibodies to bind to CLDN18.2 in malignant tissues with minimal off-target effects, making CLDN18.2 an attractive target for therapy.1

Monoclonal Antibodies

Zolbetuximab

Zolbetuximab is a novel chimeric immunoglobulin G1 (IgG1) monoclonal antibody that binds to CLDN18.2 on the surface of cancer cells and triggers cell death by activating antibody-dependent cellular cytotoxicity (ADCC) and complement- dependent cytotoxicity (CDC) pathways.7

Adding zolbetuximab to chemotherapy showed a survival advantage over a first-line standard chemotherapy regimen in the SPOTLIGHT trial (NCT03504397), marking the first phase 3 results to show the benefits of targeting CLDN18.2 in any tumor type, investigations said in reporting the findings in Lancet in April 2023.8 The study enrolled 565 patients from 20 countries with previously untreated CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic GC or GEJ. CLDN18.2 positivity was defined as 75% or more of tumor cells showing moderate to strong CLDN18.2 membranous staining on IHC testing.8

Participants were randomly assigned to receive zolbetuximab (n = 283) or placebo (n = 282) plus mFOLFOX6 (modified folinic acid, fluorouracil, and oxaliplatin).

After a median follow-up of approximately 13 months, the median progression-free survival (PFS) was 10.61 months (95%CI, 8.9012.48) in patients who received zolbetuximab plus mFOLFOX6; it was 8.67 months (95% CI, 8.21-10.28) for those who received placebo plus mFOLFOX6 (HR, 0.75; 95% CI, 0.60-0.94; P = .0066).8 Median overall survival (OS) was 18.23 months in the zolbetuximab group and 15.54 months in the placebo group (HR, 0.75; 95% CI, 0.60-0.94; P = .0053).8 The overall incidence of all-grade and grade 3 or higher treatment-emergent adverse events (TEAEs) was similar between the groups, at greater than 99% for all-grade TEAEs, and 87% and 78% for the zolbetuximab and placebo groups, respectively, for grade 3 or higher TEAEs. The most common events in the zolbetuximab and placebo groups, respectively, were nausea (82% and 61%), vomiting (67% and 36%), and decreased appetite (47% and 33%).8

Kohei Shitara, MD, and colleagues concluded that zolbetuximab plus mFOLFOX6 led to one of the longest median OS reported in phase 3 trials of patients with locally advanced unresectable or metastatic GC or GEJ adenocarcinoma, according to a presentation at the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium in January. Shitara is chief of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East in Kashiwa, Japan. The survival benefits were observed across most subgroups and could represent a new standard-ofcare regimen for patients with CLDN18.2-positive, HER2-negative disease, investigators said.9

Zolbetuximab also was studied in combination with capecitabine plus oxaliplatin (CAPOX) in the phase 3 GLOW trial (NCT03653507), which reported significantly longer PFS and OS compared with placebo plus CAPOX in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic GC or GEJ cancer. CLDN18.2 positivity was defined as 75% or more of tumor cells with strong to moderate membranous CLDN18.2 staining via IHC testing.10

The median PFS by independent review among participants in the zolbetuximab arm (n = 254) was 8.21 months (95% CI, 7.46-8.84) vs 6.80 months (95% CI, 6.14-8.08) in the placebo arm (HR, 0.687; 95% CI, 0.544-0.866; P = .0007). The median OS was 14.39 months (95% CI, 12.29-16.49) in the zolbetuximab group vs 12.16 (95% CI, 10.28-13.67) in the placebo group (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).10

Similarly, the phase 2 FAST trial (NCT01630083) found that PFS and OS were significantly better with the addition of zolbetuximab to epirubicin, oxaliplatin, and capecitabine in patients with previously untreated locally advanced, inoperable, or metastatic GC, GEJ, or esophageal adenocarcinoma with moderate to strong CLDN18.2 expression in 40% or more of tumor cells. Findings showed that adding zolbetuximab resulted in significantly lower risk for a PFS event of 55% compared with 74% with chemotherapy alone (HR, 0.44; 95% CI, 0.29-0.67; P < .0005). Median OS was 13.0 months with zolbetuximab vs 8.3 months with chemotherapy alone (HR, 0.55; 95% CI, 0.39-0.77; P < .0005).11

The benefits of zolbetuximab appeared to be particularly prominent in the subgroup of patients with at least 70% of tumor cells staining positive for CLDN18.2 protein expression via IHC (median PFS, 9.0 months vs 5.7 months with chemotherapy alone; HR, 0.38; 95% CI, 0.23-0.62; P < .0005; median OS, 16.5 months vs 8.9 months with chemotherapy alone; HR, 0.50; 95% CI, 0.33-0.74; P < .0005).11 The most commonly reported TEAEs were nausea (81.8% and 76.2%), vomiting (67.5% and 54.8%), anemia (45.5% and 35.7%), and neutropenia (44.2% and 34.5%) in the zolbetuximab and placebo groups, respectively.11

Astellas Pharma Inc, the company developing zolbetuximab, plans to use findings from the SPOTLIGHT and GLOW trials to establish a foundation for regulatory submissions to the FDA and agencies around the world.7

In pancreatic cancer, antitumor activity of zolbetuximab with or without gemcitabine in preclinical models of CLDN18.2-positive pancreatic tumors prompted the initiation of a phase 2 open-label, randomized study (NCT03816163) that is assessing the efficacy and safety of zolbetuximab plus gemcitabine and nab-paclitaxel (arm 1) compared with the chemotherapy agents alone (arm 2) in patients with metastatic disease with moderate to strong CLDN18.2 expression in 75% or more of tumor cells in IHC testing.12 The trial began with a safety lead-in phase to confirm the recommended phase 2 dose, followed by randomly assigning 2:1 approximately 357 patients to the zolbetuximab-containing or the chemotherapy-alone regimen.12 The primary end points include dose-limiting toxicities (DLTs) in the safety lead-in phase, OS in the randomization phase, and safety and tolerability in both trial phases.12

ASKB589

ASKB589 is a humanized IgG1 monoclonal antibody that binds to CLDN18.2 with high affinity and has enhanced ADCC activity.13 Preliminary safety and efficacy data from an ongoing phase 1/2 dose-escalation and dose-expansion study (NCT04632108) showed no DLTs among 51 patients with advanced solid tumors who received ASKB589.13 In part B of the trial, the addition of ASKB589 to capecitabine plus oxaliplatin resulted in partial responses in 9 of 12 evaluable patients and stable disease in the remaining 3 patients for an overall response rate (ORR) of 75% and a disease control rate (DCR) of 100%.13 The most common treatment-related adverse events (TRAEs) with ASKB589 plus chemotherapy included nausea (76%), vomiting (66%), hypoalbuminemia (52%), granulocytopenia (38%), and hypoleukemia (33%).13

Osemitamab

Osemitamab (TST001), the second most advanced CLDN18.2-targeting antibody in terms of clinical development, is a humanized IgG1 antibody that binds to the extracellular domains of the CLDN18.2 protein and exerts anticancer effects via ADCC and CDC processes.14 Based on preclinical findings that osemitamab has strong antitumor activity as a single agent and synergizes with immune checkpoint inhibitors in CLDN18.2-positive tumors, the phase 1/2a TranStar102 trial (NCT04495296) was initiated. For this study, CLDN18.2 positivity is defined as membranous staining of 1+ or greater intensity in 10% or more of tumor cells by IHC testing.

The study includes dose-escalation and dose-expansion phases evaluating osemitamab in combination with nivolumab (Opdivo), a PD-1 inhibitor, plus CAPOX (cohort G) or with nivolumab (cohort H) in patients with GC or GEJ adenocarcinoma.14 Patients with HER2-negative or unknown locally advanced or metastatic disease who have not received prior first-line therapy will be assigned to cohort G; participants with disease recurrence after at least 2 prior systemic therapies will be eligible for cohort H.14

Investigators are scheduled to present an update on PFS and duration of response from TranStar102 at the 2023 ASCO Annual Meeting in June. A poster on the phase 1/2 TranStar101 study (NCT04396821) evaluating osemitamab plus nivolumab with or without mFOLFOX6 in patients with GC or GEJ adenocarcinoma or with gemcitabine plus nab-paclitaxel in participants with pancreatic adenocarcinoma also is on the agenda.15

Bispecific Antibodies

PT886

PT886 is a bispecific antibody that targets CLDN18.2 and CD47, a member of the immunoglobulin superfamily that is overexpressed in multiple tumor types and decreases phagocyte activity by binding to SIRPα on phagocytic cells.16 PT886 uses IgG1 to exert ADCC via natural killer cells and antibody-dependent cellular phagocytosis via macrophages while targeting CD47 removes the inhibition of macrophage-mediated phagocytosis.16 An open-label, dose-escalation and dose-expansion phase 1 study (NCT05482893) has been initiated at The University of Texas MD Anderson Cancer Center in Houston to study the safety, tolerability, pharmacokinetics, and preliminary efficacy of PT886 in patients with unresectable or metastatic GC, GEJ adenocarcinoma, or pancreatic ductal adenocarcinoma for which no standard therapies are available.16

TJ-CD4B

TJ-CD4B is being evaluated in a phase 1 dose-escalation and dose-expansion study (NCT04900818) in patients with advanced solid tumors, namely GC, GEJ carcinoma, esophageal adenocarcinoma, and pancreatic ductal carcinoma, in which it was found to be safe and well tolerated at a weekly dose up to 3 mg/kg.17 The clinical trial investigators are planning to study the drug in biomarker-selected populations.17

ANTIBODY-DRUG CONJUGATES

CMG901

CMG901 is an ADC that is composed of an antiCLDN18.2 monoclonal antibody joined to a cytotoxic payload (monomethyl auristatin E ) by a cleavable linker. It has demonstrated anticancer activity via bystander killing, ADCC, and CDC.18 The FDA granted CMG901 a fast track designation in April 2022 as a monotherapy for treatment of patients with unresectable or metastatic GC and GEJ cancer that is relapsed and/or refractory to approved therapies.18

Interim results of a phase 1a trial (NCT04805307), which is being conducted in China, involved 13 patients with advanced GC or GEJ cancer and 14 patients with pancreatic cancer.19 Findings showed that CMG901 was well tolerated (the rate of grade 3 or higher TRAEs was 11.1%, and no grade 4 or 5 TRAEs were reported) and led to an ORR and DCR of 75% and 100%, respectively, in the 8 patients with CLDN18.2-positive GC or GEJ cancer.19 The phase 1b dose-expansion phase of the trial is enrolling patients with GC/GEJ adenocarcinoma, pancreatic cancer, and other solid tumors, and multiple phase 2 and 3 trials are in the planning stages.19

CAR T-Cell Therapies

CT041

CT041 is composed of autologous T cells genetically engineered to express a CLDN18.2-targeted CAR, which includes a humanized scFv specific to CLDN18.2, a CD8α hinge region, a CD28 costimulatory domain, and a CD3ζ signaling domain.20 In an interim analysis of a phase 1 trial (NCT03874897) that included patients with CLDN18.2-positive cancers (expression intensity of 2+ or greater and positive tumor cell rate 40% or higher) of the digestive system, all patients experienced a grade 3 or higher hematologic toxicity related to the preconditioning regimen, and 94.6% of patients had grade 1 or 2 cytokine release syndrome (CRS), although no cases of grade 3 or higher CRS were observed.20 The ORR and DCR were 48.6% (95% CI, 31.9%-65.6%) and 73.0% (95% CI, 55.9%-86.2%), respectively, among all patients and 57.1% (95% CI, 37.2%-75.5%) and 75% (95% CI, 55.1%-89.3%), respectively, among patients with GC.20 A single-arm, open-label phase 1b trial (NCT04404595) that enrolled a US-based population with CLDN18.2-positive, advanced GC or pancreatic adenocarcinoma found that all CRS events were grade 1 or 2; no DLTs, treatment-related deaths, immune effector cell–associated neurologic syndrome, or severe gastrointestinal-related adverse events were reported. The only grade 4 events were hematologic toxicities associated with the conditioning regimen.21 Among 8 evaluable patients, 3 patients (all of whom had GC) had a clinical response.21

Challenges of Targeting CLAUDINS and Next Steps

Although multiple CLDN18.2-targeted therapies appear promising for treatment of patients with CLDN18.2-positive cancers, several challenges need to be addressed in the ongoing development of safe and effective therapies.1 Identifying the optimal drug format for targeting for CLDN18.2 remains an ongoing effort.1 Although bispecific monoclonal antibodies and ADCs are novel approaches that may improve efficacy of CLDN18.2-targeted therapies, the clinical development and application of these molecules overall are less mature than with traditional monoclonal antibodies, which have extensive development experience, well-developed regulatory systems, and a longer history of clinical use.1 CAR T-cell therapies targeting CLDN18.2 share the same obstacles that these agents face in solid tumors overall in terms of the risk of immunosuppressive effects, highly variable response rates, and a complicated and expensive production process.1

Future efforts for developing CLDN18.2-targeted therapies should aim to maximize binding affinity for the target, minimize immunogenicity, and optimize the half-life to exert antitumor activity with minimal adverse effects, investigators said.

Identifying the optimal patient population via biomarker studies also is important for maximizing the potential benefit of CLDN18.2-targeted therapies.1 The variability in CLDN18.2 positivity rates among studies may be caused by discrepancies in detection methods, thresholds for positivity, and patient populations among studies.1 Development of specific reagents that can differentiate CLDN18.2 from other CLDN18 splice variants and standardization of the cutoff for CLDN18.2 positivity are needed to better identify which patients are most likely to benefit from CLDN18.2targeted treatment, investigators said.1

References

1. Cao W, Xing H, Li Y, et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark Res. 2022;10(1):38. doi:10.1186/s40364-022-00385-1

2. Kyuno D, Takasawa A, Takasawa K, et al. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers. 2022;10(1):1967080. doi:10.1080/21688370.2021.1967080

3. Dottermusch M, Krüger S, Behrens HM, Halske C, Röcken C. Expression of the potential therapeutic target claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Arch. 2019;475(5):563-571. doi:10.1007/s00428-019-02624-7

4. Baek JH, Park DJ, Kim GY, et al. Clinical implications of claudin18.2 expression in patients with gastric cancer. Anticancer Res. 2019;39(12):6973-6979. doi:10.21873/anticanres.13919

5. Rohde C, Yamaguchi R, Mukhina S, Sahin U, Itoh K, Türeci Ö. Comparison of claudin 18.2 expression in primary tumors and lymph node metastases in Japanese patients with gastric adenocarcinoma. Jpn J Clin Oncol. 2019;49(9):870-876. doi:10.1093/jjco/hyz068

6. Wöll S, Schlitter AM, Dhaene K, et al. Claudin 18.2 is a target for IMAB362 antibody in pancreatic neoplasms. Int J Cancer. 2014;134(3):731-739. doi:10.1002/ijc.28400

7. Astellas announces zolbetuximabmeets primary endpoint in phase 3SPOTLIGHT trial as first-line treatment inclaudin 18.2 positive, HER2-negativelocally advanced unresectable ormetastatic gastric andgastroesophageal junction (GEJ)cancers. News release. Astellas Pharma Inc. November 17, 2022. Accessed March 7, 2023. https://bit.ly/3YyCLhW

8. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomized, double-blind, phase 3 trial. Lancet. Published online April 14, 2023. doi:10.1016/S0140-6736(23)00620-7

9. Shitara KL, Lordick F, Bang YJ, et al. Zolbetuximab + mFOLFOX6 as 1L treatment for patients with claudin-18.2+ (CLDN18.2+)/HER2– locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl 4):LBA292. doi:10.1200/JCO.2023.41.4_suppl.LBA292

10. Xu RH, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary phase 3 results from GLOW.J Clin Oncol.2023;41(suppl 36):405736. doi:10.1200/JCO.2023.41.36_suppl.405736

11. Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. Ann Oncol. 2021;32(5):609-619. doi:10.1016/j.annonc.2021.02.005

12. Park W, O’Reilly EM, Furuse J, et al. Zolbetuximab plus gemcitabine and nab-paclitaxel (GN) in first-line treatment of claudin 18.2–positive metastatic pancreatic cancer (mPC): phase 2, open-label, randomized study.J Clin Oncol. 2023;41(suppl 4):TPS782. doi:10.1200/JCO.2023.41.4_suppl.TPS782

13. Zhang M, Gong J, Wang J, et al. A phase I/II study of ASKB589 (anti-claudin 18.2 [CLDN18.2] monoclonal antibody) in patients with solid tumors.J Clin Oncol.2023;41(suppl 4):397.doi:10.1200/JCO.2023.41.4_suppl.397

14. Guo W, Germa C, Qi C, et al. TST001 (a high affinity humanized anti-claudin18.2 monoclonal antibody) in combination with nivolumab plus capecitabine and oxaliplatin as first-line or with nivolumab as late-line treatment in locally advanced and metastatic gastric/gastroesophageal junction (G/GEJ) cancer: design of cohorts from a phase I/IIa study (TST001-1002).J Clin Oncol. 2023;41(suppl 4):TPS476. doi:10.1200/JCO.2023.41.4_suppl.TPS476

15. Transcenta to present two clinical trial progress at ASCO. News release. Transcenta Holding Limited; May 8, 2023. Accessed May 11, 2023. bit.ly/41vHzpM

. 16. Overman MJ, Melhem R, Blum-Murphy MA, et al. A phase I, first-in-human, open-label, dose escalation and expansion study of PT886 in adult patients with advanced gastric, gastroesophageal junction, and pancreatic adenocarcinomas. J Clin Oncol.2023;41(suppl 4):TPS765. doi:10.1200/JCO.2023.41.4_suppl.TPS765

17. I-Mab receives FDA orphan drug designation for its novel claudin 18.2 × 4-1BB bispecific antibody TJ-CD4B for the treatment of gastric cancer. News release. I-Mab Biopharma. March 3, 2022. Accessed March 7, 2023.https://bit.ly/3IYRlJI

18. FDA granted CMG901 fast track designation for unresectable or metastatic gastric and gastroesophagealjunction cancer which have relapsed and/or are refractory to approved therapies.News release.Keymed Biosciences. April 19, 2022. Accessed March 7, 2023.https://prn.to/3ZWVNzl

19. Xu R, Wei X, Zhang D, et al. A phase 1a dose-escalation, multicenter trial of anti-claudin 18.2 antibody drug conjugate CMG901 in patients with resistant/refractory solid tumors. J Clin Oncol.2023;41(suppl 4):352.doi:10.1200/JCO.2023.41.4_suppl.352

20. QiC, GongJ, Li J,et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat Med.2022;28(6):1189-1198. doi:10.1038/s41591-022-01800-8

21. Botta GP, Becerra CR, Jin Z, et al. Multicenter phase Ib trial in the U.S. of salvage CT041 CLDN18.2-specific chimeric antigen receptor T-cell therapy for patients with advanced gastric and pancreatic adenocarcinoma.J Clin Oncol.2022;40(suppl 16):2538.doi:10.1200/JCO.2022.40.16_suppl.2538

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