ASCO 2024 Meeting Report — Gastrointestinal Cancers

The 2024 American Society of Clinical Oncology (ASCO) annual meeting, held May 30 to June 3 in Chicago, showcased important and potentially practice-changing studies across a broad spectrum of gastrointestinal (GI) malignancies. The role of radiation therapy in upper GI cancers, the role of surgery in metastatic colorectal cancer, and the application of immune checkpoint inhibitors in GI cancers were key themes in the presentations. Here, Associate Editor Dr. David Ilson reviews key trials.

The plenary session included the German ESOPEC study comparing two preoperative strategies in locally advanced adenocarcinoma of the esophagus and gastroesophageal junction (GEJ; abstract LBA1). Researchers randomized patients to receive either perioperative chemotherapy alone (4 pre- and 4 postoperative cycles of 5-FU, leucovorin, oxaliplatin, and docetaxel [FLOT]) or neoadjuvant chemoradiotherapy (carboplatin, paclitaxel, and 41.4 Gy of radiation therapy [CROSS]). Of 438 patients, 80% had clinical stage T3–4 disease and 79% were clinical node positive.

At a median follow-up of 55 months, the primary endpoint of overall survival (OS) was superior for FLOT compared with CROSS (median, 66 vs. 37 months; hazard ratio, 0.70; P=0.012) as was 3-year OS (57.4% vs. 50.7%) and 5-year OS (50.6% vs. 38.7%). Median progression-free survival (PFS) was also superior for FLOT (38 vs. 16 months, respectively; HR, 0.66; P=0.001), as was the rate of pathologic complete response (16.8% vs. 10.0%).

For patients with resectable esophageal or GEJ adenocarcinoma, FLOT has emerged as the preferred preoperative therapy without the need to add concurrent preoperative radiotherapy.

In resected pancreatic cancer, the role of adding radiation therapy to adjuvant chemotherapy was addressed in the NRG/RTOG trial 8048 (abstract 4005). Of 354 patients completing five cycles of adjuvant systemic therapy (67% with single-agent gemcitabine, 28% with gemcitabine/erlotinib), half received 50.4 Gy of radiation therapy in 28 fractions with concurrent capecitabine or infusional 5-FU. No patient received adjuvant FOLFIRINOX. Most patients had pathologic stage T3 disease (81%) and N1 status (74%); 17% had a positive surgical margin.

The primary endpoint of OS did not show superiority for the addition of radiation therapy to chemotherapy compared with chemotherapy alone (median, 2.3 vs. 2.6 years; HR, 0.97; P=0.38). There was a suggestion of improved 5-year OS with chemoradiotherapy over chemotherapy alone in the minority of patients with N0 disease (48.1% vs. 28.6%; HR, 0.57) but not in those with N1 disease or a positive surgical margin.

The standard of care for resected pancreatic cancer remains adjuvant chemotherapy alone. Any positive subset results from this trial will be difficult to interpret given use of inferior adjuvant gemcitabine rather than contemporary FOLFIRINOX.

The role of surgical therapy in the management of metastatic colorectal cancer was explored in three separate trials.

TransMet

The TransMet trial compared systemic chemotherapy alone to liver transplant plus chemotherapy in patients with colorectal cancer with unresectable, liver-confined metastases (abstract 3500). Patients with no extrahepatic disease, BRAF wild-type status, and response to a minimum of 3 months and no more than 3 lines of systemic chemotherapy were randomized to liver transplant or continuation of chemotherapy.

Among the 94 patients, the median number of liver nodules was 20, 24% had RAS mutations, and 15% had right-sided primary tumors; 35% received an anti-VEGF-targeted therapy and 59% received an EGFR-targeted therapy. Seventy-seven percent of patients underwent transplant per protocol and 80% continued chemotherapy per protocol; 9 patients underwent nonprotocol liver resection or transplant.

The primary endpoint of 5-year OS was superior for transplant over continued chemotherapy in the intention-to-treat population (57% vs. 13%; HR 0.37; P=0.0003), with a larger difference in the per-protocol population (73% vs. 9%; HR 0.16; P<0.0001). After transplant in the per-protocol population, 72% of patients developed recurrence, but 42% were subsequently rendered free of disease with surgery or ablation, with 5-year PFS of 36% in the surgery/ablation salvage population.

These findings suggest that in highly selected patients, there is a potential for increase in overall and disease-free survival with the inclusion of liver transplant in the management of unresectable, liver-confined metastatic colorectal cancer.

Orchestra

The phase 3, multicenter ORCHESTRA trial explored the addition of aggressive surgical debulking to first-line chemotherapy in oligometastatic colorectal cancer (abstract LBA3502). After 2 months of initial chemotherapy, patients were randomized to either continue chemotherapy or undergo resection of multisite metastatic disease followed by reinitiation of chemotherapy.

Of 382 patients, 27% had right-sided primary tumors, 57% had BRAF or RAS mutations, 95% received capecitabine/oxaliplatin, and 78% received bevacizumab. Forty-four percent had liver and lung metastases only, and 32% had peritoneal disease.

Greater than 80% tumor debulking was achieved in 72% of patients. OS, the primary endpoint, was not improved with the addition of surgery compared with chemotherapy alone (median 30.0 vs. 27.5 months; HR, 0.88; P=0.23). PFS did not differ between groups (median, 10.5 vs. 10.4 months, respectively; HR, 0.83; P=0.08).

These results call into question the role of surgery added to systemic chemotherapy in patients with multisite metastatic colorectal cancer.

Collision

The phase 3, randomized COLLISION trial compared surgical resection to thermal ablation in patients with limited liver-confined metastatic disease with 10 or fewer lesions, none larger than 3 cm (abstract LBA3501). Patients were selected by a multidisciplinary review panel. Of 296 patients, 25% had right-sided primary tumors, 17% had RAS mutations, and 4% had BRAF mutations. The median number of liver lesions was 2, with a mean size of 14 mm.

Among patients assigned to the surgery arm, 61% underwent surgery alone and 35% had resection and ablation, whereas among patients assigned to the ablation arm, 80% underwent ablation alone and 18% had limited resection and ablation.

There was no difference in the primary endpoint of OS for the two approaches (HR, 1.051; P=0.813) or in distant metastatic PFS (HR, 1.030; P=0.836) or in liver PFS. Treatment-related mortality was 0% for ablation compared with 2.1% for surgery, and the ablation arm had fewer treatment-related serious adverse events (7% vs. 20%).

These results support liver ablation as an appropriate treatment alternative to surgical management in colorectal cancer and limited liver metastases.

In metastatic gastroesophageal junction (GEJ) adenocarcinoma, the phase 3, German IKF-575/RENAISSANCE trial randomized patients with previously untreated limited metastatic disease to chemotherapy with FLOT or 2 months of FLOT followed by surgical resection of metastases followed by additional chemotherapy (abstract 4001). Limited metastatic disease was defined as retroperitoneal lymph node (RPLN) metastases with or without one organ site of metastatic disease.

Of the 139 patients, 79% had GEJ Siewert type II or III or distal gastric cancers, 20% had only RPLN metastases, 32% had liver metastases, and 29% had peritoneal metastases. Surgery was performed in 91% of patients randomized to the surgery arm and in 21% of those randomized to chemotherapy-only (mainly the primary tumor).

OS, the primary endpoint, was not improved with the addition of surgery to chemotherapy over chemotherapy alone (median, 18.5 vs. 23.6 months; HR, 1.037; P=0.8610); early mortality was higher in the surgery arm. There was a potential OS benefit from surgery over chemotherapy alone in the subgroup of patients with RPLN–metastases-only disease and negative trends in those with liver and peritoneal disease.

Results from this trial do not support resection of metastatic disease after a brief period of induction chemotherapy in patients with gastroesophageal adenocarcinoma.

The use of immune checkpoint inhibitors in the treatment of microsatellite instability (MSI)–high colorectal cancer was explored in three presentations of updated and novel results.

Dostarlimab

One of the most striking was an update of a previously reported single-institution trial of 6 months of dostarlimab as the primary treatment for locally advanced, MSI-high rectal cancer (abstract LBA3512). In an updated series of 48 patients, 48% had clinical stage T3 disease and 31% T4, 85% were node positive, and 51% had germline mutations consistent with Lynch syndrome.

At a median follow-up of 18 months, 100% of 42 evaluable patients achieved the primary outcome of a clinical complete response to dostarlimab, without use of chemotherapy, radiation therapy, or surgery. Although follow-up is ongoing, this stunning result supports the primary use of dostarlimab as treatment for locally advanced, MSI-high rectal cancer.

Sintilimab

Another trial in locally advanced MSI-high colon cancer compared treatment with single-agent sintilimab with versus without the anti-CTLA-4 antibody, IBI310, followed by surgery, with therapy given for only 6 weeks (abstract 3505). Of 101 patients randomized to treatment, 68% had clinical stage T4 disease, 31% T3, 50% N1, and 30% N2.

The pathologic complete response (pCR) rate at surgery favored combination immunotherapy over single-agent sintilimab (78.4% vs. 46.7%; P=0.0015). Additional adjuvant chemotherapy was administered to 37% of patients in the combination therapy group and 44% in the single-agent group. Further follow-up is anticipated.

The findings argue for superior pathologic complete responses with combined anti-PD-1 and anti-CTLA-4 compared with single-agent anti-PD-1 therapy. However, in the trial discussed above, treatment with single-agent dostarlimab for 6 months achieved a 100% clinical complete response rate without surgery or other treatments. The debate continues about the optimal regimen of immunotherapy and therapy duration in MSI-high colorectal cancer. The findings suggest that monotherapy with an anti–PD-1 agent may suffice, and that extending therapy out longer or delaying referral to surgery or both may result in more, if not all, patients avoiding surgery or other treatments.

Checkmate 8HW

In metastatic MSI-high colorectal cancer, researchers presented updated results from the industry-sponsored, phase 3, randomized Checkmate 8HW trial comparing treatment with first-line chemotherapy, single-agent nivolumab, or the combination of ipilimumab and nivolumab (abstract 3503).

The prespecified interim analysis showed superior PFS with ipilimumab/nivolumab compared with chemotherapy at a median of 24.3 months (median, not reached vs. 5.9 months; HR, 0.21; P<0.0001) and at 12 months (79% vs. 21%) and 24 months (72% vs. 14%). The updated analysis showed that, despite 67% of patients in the chemotherapy arm crossing over to immunotherapy, PFS after subsequent therapy (PFS2) also markedly favored initial use of ipilimumab/nivolumab over chemotherapy (median, not reached vs. 29.9 months; HR, 0.27), with superior PFS2 at 12 months (89% vs. 65%) and 24 months (83% vs. 52%).

These updated results reinforce the superiority of first-line ipilimumab/nivolumab over chemotherapy in MSI-high metastatic colorectal cancer and support this therapy as a standard of care. Missing still are the data from the single-agent nivolumab treatment arm.

In first-line treatment of advanced hepatocellular cancer, results were presented from the industry-supported, phase 3, randomized Checkmate 9DW trial comparing the combination of ipilimumab and nivolumab to investigator's choice of lenvatinib or sorafenib (abstract LBA4008). Of 668 patients, 34% had hepatitis B and 29% had hepatitis C; 40% were treated in Asia and 43% were treated in Europe or North America.

OS, the primary endpoint, was superior for ipilimumab/nivolumab compared with lenvatinib or sorafenib (median, 23.7 vs. 20.6 months; HR, 0.79; P=0.018). Response rate was superior for ipilimumab/nivolumab compared with lenvatinib or sorafenib (36% vs. 13%; P<0.0001) as was response duration (median, 30.4 vs. 12.9 months). PFS trended superior with ipilimumab/nivolumab (HR, 0.87). Serious grade 3/4 treatment-related adverse events were higher with ipilimumab/nivolumab compared with lenvatinib or sorafenib (25% vs. 13%).

Ipilimumab/nivolumab, an already-approved treatment for hepatocellular cancer, will emerge as another first-line therapy option in this disease.

Lastly, exciting data were presented from a phase 2 study of the novel radiolabeled somatostatin analogue agent ²¹²Pb-DOTAMTATE, an alpha-radiotherapy emitter (abstract 4020). The study enrolled two cohorts of patients with somatostatin receptor–expressing gastroenteropancreatic neuroendocrine tumors: peptide receptor radionuclide therapy (PRRT)–naive (36 patients) and PRRT-refractory (30 patients).

High rates of response were seen in both PRRT-naive (62.5%) and refractory cohorts (55.6%). Encouraging outcomes at 24 months for PFS (74.3%) and OS (90.7%) were achieved in the PRRT-naive cohort. Further development of this novel class of agents is ongoing.