Research presented at the ASCO Annual Meeting 2023 highlights some of the latest developments in gastrointestinal cancer, including data supporting de-escalation of rectal cancer treatment, a novel agent for biliary tract cancer, and ongoing questions about neoadjuvant chemotherapy in both colon and pancreatic cancer.

Results from the phase 3 PROSPECT trial suggested that most patients with intermediate-risk, locally advanced rectal cancer may be able to skip pelvic radiation prior to surgery.1

The phase 2b HERIZON-BTC-01 trial demonstrated the safety and efficacy of the bispecific antibody zanidatamab in the treatment of HER2-amplified biliary tract cancer (BTC).2

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The phase 2 NORPACT-1 trial showed that neoadjuvant chemotherapy did not improve overall survival (OS) when compared to upfront surgery in patients with resectable pancreatic head cancer.3

Similarly, the phase 3 NeoCol trial showed that neoadjuvant chemotherapy did not provide a disease-free survival (DFS) advantage over upfront surgery in patients with locally advanced colon cancer.4

PROSPECT: Radiation Not Always Needed in Rectal Cancer

The PROSPECT trial, which included more than 1000 patients with intermediate-risk, locally advanced rectal cancer, demonstrated that preoperative chemotherapy with selective chemoradiation was noninferior to chemoradiation alone prior to surgery.1

The long-term toxicity of pelvic radiation coupled with advances in chemotherapy, surgical technique, screening, and pelvic imaging motivated investigators to test whether patients could be treated with a chemotherapy-first approach, according to study presenter Deborah Schrag, MD, of Memorial Sloan Kettering Cancer Center in New York, New York.

The PROSPECT trial ( Identifier: NCT01515787) included 1128 patients with clinical T2 node-positive, T3 node-negative, or T3 node-positive rectal cancer who were candidates for sphincter-sparing surgery and chemoradiation.

The patients were randomly assigned to receive either pelvic chemoradiation (n=543) or 6 cycles of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) with chemoradiation added only in select cases (n=585). Patients in the chemoradiation arm received pelvic radiation (5040 cGy for 5.5 weeks) plus capecitabine or fluorouracil, followed by surgery and adjuvant treatment.

Patients in the FOLFOX arm who responded to FOLFOX proceeded to surgery. Patients with a poor response or who were intolerant to FOLFOX received pelvic chemoradiation before surgery. Nine percent of patients in this arm received pelvic chemoradiation. After surgery, patients in both arms received adjuvant chemotherapy with either FOLFOX or capecitabine and oxaliplatin (CAPOX) at the physician’s discretion.

Patients were followed for a median of 58 months. The 5-year DFS rate was 80.8% for patients treated with FOLFOX and selective chemoradiation and was 78.6% for patients treated with standard chemoradiation (hazard ratio [HR], 0.92; 90.2% CI, 0.74-1.14). This met criteria for noninferiority.

The 5-year local recurrence-free survival rate was nearly identical in the FOLFOX and chemoradiation arms — 98.2% and 98.4%, respectively (HR, 1.18; 95% CI, 0.44-3.16). The 5-year OS rate was similar as well — 89.5% and 90.2%, respectively (HR, 1.04; 95% CI, 0.74-1.44).

The complete resection rates, pathologic complete response rates, and use of adjuvant therapy were similar between the FOLFOX and chemoradiation arms. The complete resection rate was 99% and 97%, respectively. The pathologic complete response rate was 22% and 24%, respectively. The proportion of patients who received adjuvant therapy was 82% and 83%, respectively.

The investigators also collected patient-reported data on adverse events (AEs).5 During the neoadjuvant treatment period, patients in the FOLFOX arm reported significantly lower rates of diarrhea. Patients in the chemoradiation arm had lower rates of anxiety, appetite loss, constipation, depression, dysphagia, dyspnea, edema, fatigue, mucositis, nausea, neuropathy, and vomiting.

Dr Schrag said one of the strengths of this study was that it was conducted in regular cancer practices rather than at academic centers. “We’re very confident in the results and that they generalize to practice in North America,” she said. “There were no special biopsies or procedures or tests that you can’t get essentially anywhere in the developed world.”

The PROSPECT trial is definitely practice-changing, said Benjamin L. Schlechter, MD, of Dana-Farber Cancer Institute in Boston, who was not involved in the study. He noted, however, that it is important to keep in mind which patients are appropriate for this approach, which excludes T4 tumors and patients with 4 or more enlarged pelvic lymph nodes.

Pamela Kunz, MD

PROSPECT adds to clinicians’ ability to tailor treatment to patient preferences, such as avoiding the downstream toxicity of radiation, said Pamela Kunz, MD, of the Yale School of Medicine in New Haven, Connecticut, who was not involved in the trial.

“It’s really very exciting because in an era when we think about novel therapies being the newsmakers, I think this idea of, ‘Can we find ways to make treatments better tolerated and improve patient quality of life?’ is really equally important,” Dr Kunz said. 

HERIZON-BTC-01: Zanidatamab Shows Antitumor Activity in BTC

In the phase 2b HERIZON-BTC-01 trial, zanidatamab demonstrated antitumor activity, including rapid and durable responses among patients with treatment-refractory HER2-positive BTC.2

In this trial ( Identifier: NCT04466891), researchers evaluated the HER2-targeted bispecific antibody zanidatamab as monotherapy for patients with locally advanced or metastatic BTC with HER2 amplification. To be eligible, patients needed to have progressed after treatment with a gemcitabine-containing regimen and received no prior HER2-targeted therapies.

The study is ongoing, but recruitment is complete, according to study presenter Shubham Pant, MD, of The University of Texas MD Anderson Cancer Center in Houston.

Patients were divided into 2 cohorts based on HER2 positivity. Dr Pant presented results for 80 HER2-positive patients (IHC 2+ or 3+). The patients had gallbladder cancer (51.3%), intrahepatic cholangiocarcinoma (28.8%), and extrahepatic cholangiocarcinoma (20.0%). The patients’ median age at baseline was 64 (range, 32-79) years, and 88.8% had stage IV disease. They had received a median of 1 prior therapy in the advanced/metastatic setting (range, 1-7).

The primary endpoint was confirmed objective response rate (ORR). The ORR was 41.3% by independent assessment. One patient had a complete response, 32 had partial responses, and 22 had stable disease. The disease control rate was 68.8%, and the clinical benefit rate was 47.5%.

The median duration of response was 12.9 months. The median progression-free survival was 5.5 months, and OS data were not mature.

The most common AEs were infusion-related reactions (35.0%) and diarrhea (47.5%), which were mostly low grade and reversible. Two treatment-related AEs led to discontinuation, and 3 patients had treatment-related AEs that led to dose reductions. There were no grade 4 or 5 treatment-related AEs. 

The findings support zanidatamab as a potential future treatment for HER2-positive BTC, according to Dr Pant. Additional studies are both planned and active, including for the combination of zanidatamab and cisplatin-gemcitabine.

The study also confirms that assessment of HER2 expression should be performed routinely on patients with advanced biliary cancers, said Andrew H. Ko, MD, of the University of California, San Francisco, who was not involved in the study.

“Zanidatamab is just one of several HER2-targeting agents where there’s clearly an encouraging signal,” Dr Ko said.