Updates from ASCO 2024: Upper Gastrointestinal Cancer and Pancreatic Cancer

Educational Objectives

The goal of this program is to improve the diagnosis and management of upper gastrointestinal and pancreatic cancers. After hearing and assimilating this program, the clinician will be better able to:

1. List characteristics of patients with esophageal adenocarcinoma who derive most benefit from FLOT therapy.
2. Optimize use of sotorasib in patients with KRAS G12C pancreatic cancer.

Summary

Management of locally advanced resectable esophageal adenocarcinoma: includes chemoradiation therapy (CRT) with surgery and adjuvant nivolumab for residual tumor or perioperative chemotherapy (FLOT; fluorouracil, leucovorin, oxaliplatin, and docetaxel); most centers in the United States use neoadjuvant CROSS regimen for the treatment of esophageal adenocarcinoma and FLOT regimen for gastric adenocarcinoma

The ESOPEC trial: by Hoeppner et al (2016) randomized 438 patients with adenocarcinoma of the esophagus to FLOT vs CROSS regimen; when the trial was conducted, adjuvant nivolumab was not the standard of care; the primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), postoperative pathological stage, and postoperative complications; the median OS in the FLOT arm was 66 mo compared with 37 mo in the CROSS arm (hazard ratio, 0.77); the median PFS in FLOT and CROSS arms were 38 and 16 mo, respectively; perioperative chemotherapy (FLOT) was particularly beneficial for patients who were <60 yr of age, and patients who had a higher stage of disease (T3 or T4), or had node-positive disease; pathologic complete response (pCR) rates in the FLAT and CROSS arms were 16% and 10%, respectively; postoperative complications were higher in the CROSS arm

Practice considerations: CROSS regimen may be beneficial in patients with early-stage and node-negative disease; FLOT chemotherapy may be suitable for younger patients with good Eastern Cooperative Oncology Group (ECOG) performance scale and locally advanced resectable esophageal adenocarcinoma; definitive CRT is an option in patients who are not candidates for surgery or FLOT

Immunotherapy: the Checkmate 577 trial by Kelly et al (2017) showed significant improvement in disease-free survival with addition of adjuvant nivolumab in patients with esophageal and gastroesophageal junction cancer having pathologic residual disease after surgery; the EA2174 trail by Eads et al (2024) investigated the use of nivolumab and ipilimumab in patients with esophageal and gastroesophageal junction adenocarcinoma; patients were first randomized to receive carboplatin, paclitaxel, and radiation therapy, or carboplatin, paclitaxel, nivolumab, and radiation therapy; results showed no difference in pCR with the addition of nivolumab; the Keynote 585 study by Bang et al (2019) showed increase in pCR when pembrolizumab was added to perioperative FLOT with no difference in event-free survival or OS

Biomarkers: established biomarkers include mismatch repair (MMR), human epidermal growth factor receptor 2 (HER2), and programmed death-ligand 1 (PD-L1); evolving biomarkers focus on HER2-negative cancers, eg, Claudin 18.2, fibroblast growth factor receptors (FGFR)

MMR: the speaker performs MMR testing for all patients with upper gastrointestinal cancer regardless of stage or age; evidence suggests neoadjuvant immunotherapy improves pCR in patients with deficient MMR; MMR testing in the metastatic setting is used to identify patients who may benefit from immunotherapy in combination with chemotherapy

HER2: in patients with HER2 positivity, if PD-L1 is positive, the speaker uses a combination of trastuzumab, chemotherapy, and immunotherapy; immunotherapy might be detrimental to HER2-positive PD-L1-negative patients; for patients with HER2-negative status, if the PD-L1 combined protein score (CPS) is >5, immunotherapy and chemotherapy is approved based on global trials; if CPS is negative, the speaker uses chemotherapy alone; for patients with an intermediate CPS (1-4), a careful discussion with the patient is needed

Claudin 18.2: is a tight junction protein involved in paracellular function; positivity is reported on immunohistochemistry IHC as 0 to 3+ based on the staining; the SPOTLIGHT trial by Shitara et al (2023) and GLOW trial by Shah et al (2023) showed significant improvement in PFS and OS with use of zolbetuximab with 5-Fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX); zolbetuximab is not yet approved by the Food and Drug Administration

FGFR 2: the FIGHT trial by Wainberg et al (2024) showed benefit of bemarituzumab with chemotherapy in patients with FGFR 2 positivity

KRAS mutation in pancreatic cancer: 90% of patients with pancreatic cancer have KRAS mutation; the KRAS G12C is present in ≈1% of individuals; other major types include G12D, and G12V; 10% of patients have wild type mutation which could involve targetable alterations; evidence suggests benefit of sotorasib and adagrasib in patients with G12C pancreatic cancer

Readings

Bang YJ, Van Cutsem E, Fuchs CS, et al. KEYNOTE-585: Phase III study of perioperative chemotherapy with or without pembrolizumab for gastric cancer. Future Oncol. 2019;15(9):943-952. doi:10.2217/fon-2018-0581; Goodman KA, Ou FS, Hall NC, et al. Randomized phase II study of PET response-adapted combined modality therapy for esophageal cancer: Mature results of the CALGB 80803 (Alliance) Trial. J Clin Oncol. 2021;39(25):2803-2815. doi:10.1200/JCO.20.03611; Hoeppner J, Lordick F, Brunner T, et al. ESOPEC: prospective randomized controlled multicenter phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the esophagus (NCT02509286). BMC Cancer. 2016;16:503. Published 2016 Jul 19. doi:10.1186/s12885-016-2564-y; Janjigian YY, Van Cutsem E, Muro K, et al. MATTERHORN: Phase III study of durvalumab plus FLOT chemotherapy in resectable gastric/gastroesophageal junction cancer. Future Oncol. 2022;18(20):2465-2473. doi:10.2217/fon-2022-0093; Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer [published correction appears in N Engl J Med. 2023 Feb 16;388(7):672. doi: 10.1056/NEJMx220014]. N Engl J Med. 2021;384(13):1191-1203. doi:10.1056/NEJMoa2032125; Lorenzen S, Götze TO, Thuss-Patience P, et al. Perioperative atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable esophagogastric cancer: Interim results from the randomized, multicenter, phase II/III DANTE/IKF-s633 trial. J Clin Oncol. 2024;42(4):410-420. doi:10.1200/JCO.23.00975; Philip PA, Azar I, Xiu J, et al. Molecular Characterization of KRAS wild-type tumors in patients with pancreatic adenocarcinoma. Clin Cancer Res. 2022;28(12):2704-2714. doi:10.1158/1078-0432.CCR-21-3581; Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: The randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7; 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, randomised, double-blind, phase 3 trial [published correction appears in Lancet. 2023 Jul 22;402(10398):290. doi: 10.1016/S0140-6736(23)01481-2] [published correction appears in Lancet. 2024 Jan 6;403(10421):30. doi: 10.1016/S0140-6736(23)02762-9]. Lancet. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7; Wainberg ZA, Kang YK, Lee KW, et al. Bemarituzumab as first-line treatment for locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma: Final analysis of the randomized phase 2 FIGHT trial. Gastric Cancer. 2024;27(3):558-570. doi:10.1007/s10120-024-01466-w.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose. Dr. Amin's lecture contains information related to the off-label or investigational use of a therapy, product, or device.

Acknowledgements

Dr. Amin was recorded at Annual Practice Updates in Hematology and Oncology, held August 9, 2024, in Chicago, IL, and presented by the University of Chicago Pritzker School of Medicine. For more information about upcoming CME activities from this presenter, please visit cme.chicago.edu. Audio Digest thanks the speakers and the presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0.50 CE contact hours.

Lecture ID:

ON152402

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.