ASCO Gastrointestinal Cancers Symposium 2023 — Meeting Report

Celebrating a 20-year milestone, the 2023 ASCO Gastrointestinal Cancers Symposium, held January 19 to 21 in San Francisco, was a key venue for important and awaited trial results across the spectrum of gastrointestinal malignancies. NEJM Journal Watch Oncology and Hematology Associate Editor David H. Ilson, MD, PhD, reports on some of the most clinically impactful presentations. Abstracts can be viewed in the symposium's meeting library.

In the phase 3 NRG/RTOG trial 1112, researchers compared sorafenib alone versus sorafenib plus stereotactic body radiotherapy (SBRT) in advanced hepatocellular cancer (HCC; abstract 489). Patients with HCC not amenable to surgery, ablation, or transarterial chemoembolization (TACE), with lesion sum ≤20 cm and limited distant metastatic disease were randomized to either sorafenib 400 mg twice daily or SBRT (27.5–50 Gy in 5 fractions) followed by sorafenib 200 mg twice daily for 28 days then increased to 400 mg twice daily. Of 193 patients, 41% had hepatitis C and 19% had hepatitis B or B and C, 74% had macrovascular invasion, and 4% had distant metastases.

The primary endpoint of overall survival (OS) was improved from a median of 12.3 months with sorafenib alone to 15.8 months with the addition of SBRT (hazard ratio, 0.77; one sided P=0.0554). Progression-free survival (PFS) was also improved with the addition of SBRT, from 5.5 to 9.2 months HR 0.55; 2-sided P=0.0001). Incidence of treatment-related adverse events did not differ with and without SBRT.

These provocative results indicate that liver-directed SBRT may improve survival when added to systemic therapy in patients with HCC largely confined to the liver. Further evaluation of SBRT with more active contemporary systemic therapies in HCC is needed.

The industry-sponsored, open-label, randomized, phase 3 NAPOLI-3 trial compared standard two-drug chemotherapy with gemcitabine/nab-paclitaxel versus three-drug therapy with infusional 5-FU, oxaliplatin, and nanoliposome-encapsulated irinotecan (NALIRIFOX) in 770 patients with advance pancreatic cancer (abstract LBA661).

At a median follow up of 16.1 months, OS — the primary outcome — was improved with NALIRIFOX compared to gemcitabine/nab-paclitaxel (median, 11.1 vs. 9.2 months; HR, 0.84; P=0.04). PFS was also improved with NALIRIFOX (median, 7.4 vs. 5.6 months; HR, 0.70; P=0.0001). Grade 3/4 treatment-related adverse events that were more frequent with NALIRIFOX than with gemcitabine/nab-paclitaxel included diarrhea (20.3% vs. 4.5%) and nausea (11.9% vs. 2.6%); those that were more frequent with gemcitabine/nab-paclitaxel than with NALIRIFOX included anemia (17.4% vs. 10.5%) and neutropenia (24.5% vs. 14.1%).

This first head-to-head comparison of two-drug versus three-drug therapy in advanced pancreatic cancer supports both use of NALIRIFOX and FOLFIRINOX as the preferred first-line regimens in patients who are considered candidates for three-drug therapy.

The randomized, open-label, phase 3 SWOG 1815 trial compared standard two-drug gemcitabine/cisplatin therapy with a three-drug regimen adding nab-paclitaxel in patients with advanced biliary cancers (abstract LBA490). Of 441 patients, 67% had intrahepatic primary tumors, 16% had gallbladder primary tumors, and 17% had extrahepatic primary tumors; 73% had distant metastatic disease.

There was no significant difference in OS — the primary endpoint — with three-drug versus two-drug therapy (median, 14.0 and 12.7 months; HR, 0.93; P=0.58). The response rate was numerically but not statistically significantly higher with three-drug versus two-drug therapy (34% and 25%; P=0.11) and there was no significant difference in PFS (median, 8.2 and 6.4 months; HR, 0.92; P=0.47). An exploratory analysis indicated potential survival benefits in patients with locally advanced versus metastatic disease and in the small subset of patients with gallbladder primary tumors. The rate of grade 3/4 hematologic toxicity was higher with three-drug versus two-drug therapy (60% vs. 45%) as was the rate of therapy discontinuation for toxicity (24% vs. 19%).

This important trial indicates that three-drug therapy does not offer benefit over two-drug therapy for patients with metastatic biliary cancers, with the potential exception of those with locally advanced disease or gallbladder primary tumors.

The SUNLIGHT study, an international industry-sponsored, open-label, randomized, phase 3 trial, compared late-line treatment with trifluridine/tipiracil with or without bevacizumab in patients with chemotherapy-refractory colon cancer (abstract 4).

Among the 492 patients treated, the primary endpoint of OS was significantly improved with the addition of bevacizumab (median, 10.8 vs. 7.5 months without bevacizumab; HR, 0.61; P<0.001). PFS was also improved (median, 5.6 vs. 2.4 months; HR, 0.44; P<0.001). There was no significant increase in treatment-related grade 3/4 serious adverse events with the addition of bevacizumab.

Combining bevacizumab with trifluridine/tipiracil represents a new standard of care for colorectal cancer and this trial supports continuation of bevacizumab into serial lines of chemotherapy.

The industry-sponsored, double-blind, phase 3 INTEGRATE IIa trial compared treatment with regorafenib versus placebo in 251 patients with gastroesophageal adenocarcinoma who had received at least two or more prior chemotherapy regimens (abstract LBA294).

The primary endpoint of OS was improved with regorafenib compared to placebo (median 4.5 vs. 4.0 months; HR, 0.70; P=0.011), as was 12-month survival (19% vs. 6%). PFS was also improved with regorafenib (median, 1.8 vs. 1.6 months; HR, 0.52; P<0.001). No new safety signals were observed.

Regorafenib may emerge as a new late-line therapy option for refractory gastroesophageal adenocarcinoma.

The SPOTLIGHT trial evaluated the addition of zolbetuximab to first-line chemotherapy with modified FOLFOX6 in patients with advanced gastric and esophageal adenocarcinoma overexpressing claudin-18.2 (abstract LBA292). In this international, industry-sponsored, phase 3 trial, 565 patients were randomized to the addition of zolbetuximab or placebo.

The primary endpoint of PFS was improved with the addition of zolbetuximab compared with placebo (median, 10.61 vs. 8.67 months; HR, 0.751; P=0.0066). OS was also improved with zolbetuximab (median, 18.23 vs. 15.54 months; HR, 0.750; P=0.0053). Anti-tumor response rates were similar in the two groups. Although rates of nausea, vomiting, and anorexia were higher with zolbetuximab, rates of serious treatment-related adverse events were similar in the two treatment arms (43.5% and 44.8%).

Zolbetuximab added to first-line chemotherapy in gastroesophageal cancers overexpressing claudin-18.2 will likely become a new care standard.

The industry-sponsored, international, placebo-controlled, phase 3 Rationale 305 trial evaluated the addition of the anti PD-1 antibody tislelizumab to first-line chemotherapy with capecitabine/oxaliplatin or infusional 5-FU/cisplatin in 546 patients with gastric or gastroesophageal junction adenocarcinoma testing positive for PDL-1 ≥5% based on a tumor-associated score (abstract 286).

At a median follow-up of 11.8 months, OS was superior with tislelizumab compared with placebo (median, 17.2 vs. 12.6 months; HR, 0.74; P=0.0056). Also improved with tislelizumab over placebo were PFS (7.2 vs. 5.9 months, HR 0.67), rate of response (50.4% vs. 43.0%), and response duration (9.0 vs. 7.1 months). No new safety signals were observed.

Tislelizumab is another anti PD-1 antibody shown to improve treatment outcomes when added to first-line chemotherapy for patients with PDL-1–positive gastroesophageal cancer.

The industry-sponsored, multicenter phase 2 INFINITY trial evaluated the combination of tremelimumab and durvalumab as preoperative treatment over 12 weeks in patients with resectable MSI-high gastric or gastroesophageal junction adenocarcinoma (abstract 358).

Of 15 evaluable patients (14 underwent surgery), 9 (60%) had a pathologic complete response and another 3 (20%) had near pathologic complete response. An additional two patients with clinical complete response declined surgery. Grade 3 or higher immune treatment-related serious adverse events occurred in three patients and were treated with high-dose steroids.

This patient series adds to the accumulating evidence of high rates of pathologic complete response to immune checkpoint inhibitor therapy in MSI-high gastrointestinal cancers and continues the debate about potential nonoperative management in patients achieving a clinical complete response.