ESMO Meeting Report: Gastrointestinal Cancers

Pivotal new studies and updates of previously reported studies, some potentially practice changing, were presented at this year's European Society for Medical Oncology (ESMO) Congress held September 13–17 in Barcelona, Spain. Here, NEJM Journal Watch Oncology and Hematology Associate Editor David Ilson reviews some of the key presentations in GI cancers.

Two important trials evaluated preoperative immune checkpoint inhibitor therapy for patients with mismatch repair protein deficient (dMMR)/microsatellite instability (MSI)–high colon cancer.

Niche-2

Researchers reported updated 3-year disease-free survival (DFS) results from the industry-sponsored NICHE-2 trial (abstract LBA24). Patients with locally advanced dMMR colon cancer were treated with two doses of nivolumab on days 1 and 15, and one dose of ipilimumab on day 1, followed by surgical resection within 6 weeks. Of 111 patients, 64% had clinical stage T4 disease. All patients underwent curative surgery.

At a median post-surgery follow up of 36.5 months, 100% of patients remained free of disease. Prior to therapy, 92% of 108 tested patients were positive for circulating tumor DNA (ctDNA). Prior to surgery, ctDNA was cleared in 94% of patients achieving a pathologic complete response at surgery, and in 70% with a major pathologic response at surgery; 16 patients had persistent but reduced ctDNA levels. At long-term follow-up after surgery all patients remained ctDNA negative.

Given the 100% rate of DFS at 3 years in these patients with dMMR colon cancer, preoperative ipilimumab and nivolumab followed by surgery may emerge as a therapy option for patients with locally advanced disease and planned surgery. With the striking degree of efficacy from only two immune checkpoint inhibitor treatments, use of chemotherapy as a surgical adjuvant therapy in these patients will be increasingly questioned.

IMHOTEP

In the phase 2 IMHOTEP trial, patients with locally advanced, resectable dMMR/MSI-high colorectal cancer received pembrolizumab (400 mg every 6 weeks for 1–2 cycles), followed by surgery, followed by adjuvant pembrolizumab at the same dose for 1 year (abstract 5040). Of the 87 patients, 83% had colon primaries and 17% had rectal primaries. The primary endpoint, pathologic complete response (pCR) at surgery, was achieved in 54% of patients (55% with colon and 46% with rectal cancers) and was higher with two pembrolizumab cycles than with one (68% vs. 47%).

The study supports administration of more than one treatment with pembrolizumab to enhance pathologic response. DFS and OS data are pending. This trial adds to the consistent observation of high rates of pCR to immune checkpoint inhibitor therapy in patients with dMMR/MSI-high colorectal cancer. In rectal cancer, given the need for a permanent colostomy with conventional chemotherapy and radiotherapy in some patients, the use of immune checkpoint inhibitor therapy has led to potential nonoperative management in patients with dMMR/MSI-high rectal cancer achieving a clinical complete response. The optimal use of these agents, including single-agent versus combination therapy; the optimal duration of therapy; and the expanded potential for nonoperative management in responding patients remain open research questions.

TOPGEAR

Investigators presented practice changing results from the randomized, open-label, phase 3 TOPGEAR trial (abstract LBA5). As we reported separately, the findings reinforce that adding radiation therapy to chemotherapy has no role in the management of patients with gastroesophageal adenocarcinoma undergoing preoperative chemotherapy followed by surgery (NEJM JW Oncol Hematol Oct 16 2024 and N Engl J Med 2024 Sep 13; [e-pub].). Perioperative chemotherapy alone, without radiation therapy, is the standard of care for these patients.

KEYNOTE-811

An important, awaited update was presented on the industry-supported, randomized KEYNOTE-811 trial evaluating the addition of pembrolizumab to trastuzumab and chemotherapy in the first-line treatment of advanced HER2-positive esophagogastric adenocarcinoma (abstract 14000). Prior reports from this trial indicated that, compared with placebo, adding pembrolizumab improved progression-free survival (PFS) and response rates, with benefits seen in patients with PDL-1 combined positive scores (CPS) >1% (NEJM JW Oncol Hematol Dec 13 2023 and Lancet 2023 Dec 9; 402:2197).

In the current presentation investigators reported the third interim analysis for OS in 698 patients at a median follow-up of 50.2 months. In patients with CPS >1%, superior OS was achieved with pembrolizumab versus placebo (median, 20.1 vs. 15.7 months; HR 0.79,) and superiority for PFS was also maintained (median, 10.9 vs 7.3 months; HR, 0.72). In patients with CPS<1%, OS was not improved with pembrolizumab versus placebo (median, 18.2 vs. 20.4 months; HR 1.10). Among all patients, the superior response rate with the addition of pembrolizumab compared with placebo was maintained (72.6% vs. 60.1%).

The trial firmly establishes the addition of pembrolizumab to first-line trastuzumab/chemotherapy in patients with HER2-positive esophagogastric adenocarcinoma. The PFS and OS benefit is limited to patients with PDL-1 CPS >1%.

Investigators reported a retrospective analysis of 1887 patients with gastroesophageal adenocarcinoma who received perioperative FLOT chemotherapy in 12 countries (abstract 1402MO). Patients were categorized by pathologic response and outcomes were compared between those who did and those who did not receive any additional post-surgery adjuvant FLOT. Median follow-up was 25.5 months. Among 459 patients with minimal or no response, DFS did not differ with and without additional adjuvant FLOT (HR, 1.03). A difference in OS became nonsignificant after adjustment for baseline characteristics (HR, 0.96). Among 221 patients with pCR, there also was no significant difference in DFS (HR, 0.88) or OR (HR, 0.69) with versus without additional adjuvant FLOT. However, among1207 patients with partial response, additional adjuvant FLOT improved DFS (HR, 0.68) and OS (HR, 0.55).

These informative and hypothesis-generating results suggest a benefit for continuing adjuvant FLOT after surgery only in patients with partial response and not in those with no response or pathologic complete response. However, the standard of care remains to treat all patients with postoperative adjuvant FLOT. As with all retrospective patient analyses, the potential for bias and patient selection exists.

LEAP-012

Results were presented for the industry-supported, randomized, double-blind, phase 3 LEAP-012 trial comparing standard transarterial chemoembolization (TACE) alone versus TACE combined with lenvatinib (8–12 mg daily) plus pembrolizumab (400 mg IV every 6 weeks) for up to 2 years in patients with intermediate stage hepatocellular cancer (HCC; abstract LBA3). A total of four TACE treatments were permitted, with up to two per tumor.

Among the 480 patients, the primary endpoint of PFS was significantly improved with lenvatinib/pembrolizumab compared with placebo (median,14.6 vs. 10.0 months; HR, 0.66). Overall survival results have not yet matured. Grade 3–5 treatment-related adverse events were more frequent in the lenvatinib/pembrolizumab group compared with placebo (71.3% vs. 31.5%).

These findings add to the accumulating data supporting combining systemic therapy with regional therapies in HCC. However, a trial comparing the combination of lenvatinib/pembrolizumab versus lenvatinib alone in patients with metastatic or unresectable HCC failed to show superior survival for the combination regimen (NEJM JW Oncol Hematol Dec 21 2023 and Lancet 2023; 24:1399). Whether the approved combined immune checkpoint inhibitor therapies, or anti-VEGF/immune checkpoint inhibitor therapy will provide benefit when added to regional therapies in HCC is the subject of ongoing trials.

CABINET

Lastly, updated results were reported for the industry-supported, randomized, phase 3 CABINET trial comparing cabozantinib (60 mg/day) with placebo in patients with enteropancreatic neuroendocrine cancers and disease progression on prior treatment with somatostatin analogues, everolimus, and/or sunitinib (abstract 11410). As we reported in our separate coverage (NEJM JW Oncol Hematol Oct 25 2024 and N Engl J Med Sep 16; [e-pub]), the primary endpoint of PFS was significantly improved with cabozantinib compared with placebo. This finding will likely lead to the adoption of cabozantinib as a new active agent to treat enteropancreatic neuroendocrine cancers.