Impactful Studies Challenge the Status Quo at GI Conference

Tanios Bekaii-Saab, MD

David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research I

Chair and Consultant, Division of Hematology and Medical Oncology

Professor, Mayo Clinic College of Medicine and Science

Mayo Clinic

Phoenix, AZ

Given the wide spectrum that characterizes gastrointestinal (GI) malignancies, a multidisciplinary team approach with the patient at the center leads to an optimal outcome. Implementing this rationale, regardless of the cancer type or its stage, can make a difference in improving the likelihood of survival, according to Tanios S. Bekaii-Saab, MD, cochair of the 2024 International Symposium of Gastrointestinal Oncology (ISGIO), sponsored by Physicians’ Education Resource® (PER®), LLC, from October 11 to 12, 2024, in Hollywood, Florida.

Joining him as the other cochair is Eileen O’Reilly, MD, the Winthrop Rockefeller Endowed Chair of Medical Oncology, chair of the Human Research Protection Program and Institutional Review Board, and codirector of medical initiatives at the David M. Rubenstein Center for Pancreatic Cancer Research at Memorial Sloan Kettering Cancer Center, New York, New York.

Bekaii-Saab, leader of the gastrointestinal cancer program at Mayo Clinic Comprehensive Cancer Center, medical director of the Cancer Clinical Research Office, and vice chair and section chief for medical oncology in the Department of Internal Medicine at Mayo Clinic in Phoenix, Arizona, noted that the meeting covers a wide range of disease groups and addresses the findings from impactful trials in 2024.

Impactful Trials

“I think there are a number of trials that are impactful and likely to change standards of care quite a bit, and others will add [treatment] options that community oncologists will need to consider,” Bekaii-Saab said. For hepatocellular carcinoma (HCC), the role of first-line immunotherapy in unresectable advanced disease is undergoing closer scrutiny. In the phase 3 CheckMate 9DW trial (NCT04039607), presented at the 2024 American Society for Medical Oncology Annual Meeting, first-line nivolumab (Opdivo) in combination with ipilimumab (Yervoy) led to a statistically significant and clinically meaningful improvement in overall survival (OS) compared with investigator’s choice of sorafenib (Nexavar) or lenvatinib (Lenvima).¹

Although combinations with first-line PD1/PD-L1 inhibitors have shown benefits over sorafenib and are now the standard of care in unresectable HCC, the prognosis remains poor. CheckMate 9DW evaluated 668 patients who were randomly assigned to receive 1 mg/kg of nivolumab, and 3 mg/kg of ipilimumab every 3 weeks, followed by 408 mg of nivolumab every 4 weeks or investigator’s choice of 8 or 12 mg of lenvatinib once daily, or sorafenib 400 mg twice a day.¹

After a median follow-up of 35.2 (range, 26.8-48.9) months, the median OS in the nivolumab plus ipilimumab arm was 23.7 months vs 20.6 months for patients treated with lenvatinib or sorafenib (HR, 0.79; 95% CI, 0.65-0.96; P = .0180). At 24 months, OS rates of 49% (95% CI, 44%-55%) vs 39% (95% CI, 34%-45%) were reported for the nivolumab plus ipilimumab arm vs the lenvatinib or sorafenib arm, respectively. Investigators also reported that the objective response rate was also higher in the nivolumab plus ipilimumab arm (36%) vs the lenvatinib/sorafenib arm (13%; P < .0001).¹

“These findings will make treatment choices more complex for the treating oncologist,” Bekaii-Saab said. “You could treat with monoclonal antibody targeting VEGF (bevacizumab) plus a PDL1 inhibitor as one option vs. two checkpoint inhibitors with a PD1/PDL1 inhibitor plus a CTLA4 inhibitor. There are pluses and minuses for each option, so the question is, which patients will reap the greatest benefit,” Bekaii-Saab continued.

Another impactful trial is the ongoing phase 2 MOUNTAINEER study (NCT03043313) of patients with previously treated HER2-positive colorectal cancer (CRC).² Efficacy was determined in 84 patients enrolled in the trial.

Initially, the trial was designed as a single-cohort study but was expanded after an interim analysis. Patients in cohort A were given 300 mg of tucatinib (Tukysa) twice daily plus 8 mg/kg of trastuzumab (Herceptin) as an initial loading dose, then 6 mg/kg every 21 days for the duration of treatment (until progression). After expansion, patients were randomly assigned (4:3), using an interactive web response system and stratified by primary tumor location, to receive either tucatinib plus trastuzumab (cohort B) or tucatinib monotherapy (cohort C).²

The investigators reported that the combination of tucatinib and trastuzumab had clinically meaningful antitumor activity and favorable tolerability. The major efficacy measures were overall response rate and duration of response (DOR) as assessed by blinded independent central review (RECIST version 1.1.). The overall response rate was 38% (95% CI, 28%-49%), and the median DOR was 12.4 months (95% CI, 8.5-20.5).2 Findings led to the approval of the combination in patients with wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.³ “Long-term follow-up shows that [the combination] is maintaining survival results, with higher ongoing progression-free survival [PFS] and [DOR],” Bekaii-Saab added.

Determining Optimal Therapy

Another study that Bekaii-Saab finds intriguing is the landmark PASS-01 trial (NCT04469556).⁴ PASS-01 is a multi-institutional randomized phase 2 trial evaluating the benefit of mFFX (first-line leucovorin calcium, fluorouracil, irinotecan hydrochloride, and oxaliplatin) vs gemcitabine plus nab-paclitaxel (GnP) compared with gemcitabine alone. Patients with de novo metastatic pancreatic ductal adenocarcinoma (PDAC) who had a good ECOG performance status and who have undergone baseline tumor biopsies with tissue prepared for whole genome and RNA sequencing were enrolled. The primary objective was to determine PFS benefit, and secondary end points included overall response rate, DOR, and OS by chemotherapy and biomarkers of response.⁴

It is hoped that the data generated from PASS-01 can help to determine the most effective treatment for individual patients. Other trials that compare doublet vs triplet therapy in PDAC are ongoing, including the phase 3 NAPOLI 3 trial (NCT04083235).⁵

In NAPOLI 3, patients with confirmed but untreated metastatic PDAC (mPDAC) were randomly assigned to receive NALIRIFOX (liposomal irinotecan plus 5-fluorouracil/leucovorin and oxaliplatin) vs GnP. The primary end point was OS; secondary end points were PFS, overall response rate, and safety.5 A total of 770 patients were evaluated, with 383 patients receiving NALIRIFOX and 387 receiving GnP.⁵

At a median follow-up of 16.1 months, 544 events had been reported. The median OS was 11.1 months in the NALIFIROX arm compared with 9.2 months in the GnP arm (HR, 0.84; 95% CI, 0.71-0.99; P = .04). PFS also favored the treatment arm (7.4 months vs 5.6 months; HR, 0.70; 95% CI, 0.59-0.84; P = .0001).⁵

Grade 3/4 treatment-emergent adverse events with 10% frequency or higher in patients receiving NALIRIFOX vs GnP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%).⁵

The investigators concluded that first-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvements in OS and PFS compared with GnP in treatment-naive patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components.⁵

Pushing Forward

“One key element to move forward is to evaluate immunotherapy and microsatellite stable colorectal cancer,” Bekaii-Saab told Targeted Therapies in Oncology regarding advancing the field of GI cancer. “The data are promising but not quite convincing,” he continued. “As of yet, we don’t have large studies that have established the role of immunotherapy in select patients.”

Bekaii-Saab noted the findings from the phase 1b/2 ARC-9 trial (NCT04660812), which evaluated the safety and efficacy of etrumadenant (E), an orally bioavailable, selective, A2A and A2B receptor antagonist, combined with zimberelimab (Z), an anti–PD-1 antibody, and FOLFOX/bevacizumab (Avastin; FB) or regorafenib (Stivarga) in 3 cohorts of patients with metastatic colorectal cancer.6 At the data cutoff of November 13, 2023, after a median follow-up of 20.4 months, patients in cohort B who received EZFB showed a statistically significant improvement in PFS (HR, 0.27; 95% CI, 0.17-0.43; P < .0001) and OS (HR, 0.37; 95% CI, 0.22-0.63; P = .003) vs regorafenib.⁶

Investigators reported that patients treated with EZFB had significantly improved efficacy outcomes compared with regorafenib in patients with refractory metastatic CRC who were previously treated with FOLFOX regimens, with no unexpected toxicities.⁶ “There are a number of these studies that are challenging the current treatment landscape, and I think a conference such as ISGIO summarizes the findings of the year and gives the specialty oncologist as a well as the community oncologist a good flavor of how to best practice gastrointestinal oncology,” Bekaii-Saab concluded.

REFERENCES:

1. Galle PR, Decaens T, Kudo M, et al. Nivolumab (NIVO) plus ipilimumab (IPI) vs lenvatinib (LEN) or sorafenib (SOR) as first-line treatment for unresectable hepatocellular carcinoma (uHCC): first results from CheckMate 9DW. J Clin Oncol. 2024;42(suppl 17):LBA4008. doi:10.1200/JCO.2024.42.17_suppl.LBA4008

2. Strickler JH, Cercek A, Siena S, et al; MOUNTAINEER investigators. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. 2023;24(5):496-508. doi:10.1016/S1470-2045(23)00150-X

3. FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. FDA. January 19, 2023. Accessed July 7, 2024. https://tinyurl.com/mr47x25t

4. Knox JJ, Jaffee EM, O’Kane GM, et al. PASS-01: Pancreatic adenocarcinoma signature stratification for treatment–01. J Clin Oncol. 2022;40(suppl 4):TPS635. doi:10.1200/ JCO.2022.40.4_suppl.TPS635

5. Wainberg ZA, Melisi D, Macarulla T, et al. NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan+5-fluorouracil/leucovorin+oxaliplatin (NALIRIFOX) versus nab-paclitaxel+gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). J Clin Oncol. 2023;41(suppl 4):LBA661. doi:10.1200/ JCO.2023.41.4_suppl.LBA661

6. Wainberg ZA, Han SW, Lee S, et al. ARC-9: A randomized study to evaluate etrumadenant based treatment combinations in previously treated metastatic colorectal cancer (mCRC). J Clin Oncol. 2024;42(suppl 16):3508. doi:10.1200/ JCO.2024.42.16_suppl.3508