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Adding immunotherapy to neoadjuvant chemotherapy for resectable gastroesophageal cancer led to higher rates of disease downstaging and pathologic complete response (pCR), an exploratory analysis of a randomized trial showed.

Downstaging favored the addition of atezolizumab (Tecentriq) whether defined as no evidence of tumor in the primary lesion (ypT0), residual tumor less than 5 cm (ypT0-2), or no evidence of disease in lymph nodes (ypN0). Histologic complete response, defined as pathologic complete response (pCR) or TRG1a, occurred more often with atezolizumab, and the difference from chemotherapy alone increased particularly in patients with a PD-L1 composite positive score (CPS) ≥10.

Margin-free resection rates and the frequency and severity of adverse events were similar in the two groups, Salah-Eddin Al-Batran, MD, of the Institute of Clinical Research and UTC-University Cancer Center in Frankfurt, Germany, and coauthors reported in the (JCO).

"To our knowledge, this is the first large, randomized trial to report on the safety, histopathologic regression, and surgical-pathologic outcome measures after neoadjuvant chemotherapy combined with an ICI [immune checkpoint inhibitor] for EGA [esophagogastric adenocarcinoma]," the authors stated.

"The current study transitioned to a phase III trial, evaluating whether the favorable pathologic regression and tumor downstaging would translate into survival benefit, and if this effect is dependent on PD-L1 expression," they continued. "In the future, neoadjuvant chemoimmunotherapy has the potential to become a new treatment option in locally advanced gastroesophageal adenocarcinoma. Nevertheless, the challenge will be to identify who will and will not benefit from the addition of immunotherapy."

The trial is the first full report of a randomized controlled trial (RCT) of neoadjuvant chemoimmunotherapy in gastric/gastroesophageal junction adenocarcinoma (GEA), and the results are consistent with those of three other RCTs, according to the authors of an .

"In non-small cell lung cancer and triple-negative breast cancer, improved pathologic response rates after neoadjuvant immunotherapy-containing treatment have translated to improvements in survival," wrote Mojun Zhu, MD, and Harry H. Yoon, MD, both of the Mayo Clinic in Rochester, Minnesota.

"Together, these promising results raise the possibility that neoadjuvant immunotherapy-containing treatment in GEA might improve survival, thereby helping address the fourth-highest cause of cancer mortality in the world," they added.

In summarizing the study's clinical and scientific relevance, JCO deputy editor Andrew H. Ko, MD, of the University of California San Francisco, said the results provide "encouraging early signals of antitumor activity from adding an anti-PD-L1 antibody to perioperative chemotherapy for patients with resectable esophagogastric cancer."

"However," said Ko, "whether the improved rates of pathologic response and downstaging translate into a recurrence-free and overall survival benefit remains to be seen from this and other studies evaluating a similar strategy, and so should not yet be adopted into routine clinical practice."

Multimodality perioperative treatment has consistently improved overall survival (OS) in GEA, Al-Batran and coauthors stated in their introduction. Neoadjuvant therapy increases the likelihood of complete margin-free (R0) resection and induces histopathologic regression, which correlates with improved survival. Perioperative use of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) has increased the rate of complete regression and major histopathologic regression, which also has translated into improved OS.

Nonetheless, long-term survival remains unsatisfactory, the authors continued. The addition of ICIs to chemotherapy has the potential to enhance chemosensitivity and inhibit immune-independent and dependent tumorigenic processes in GEA. Anti-PD-1/L1 antibodies have been approved for patients with unresectable/metastatic disease, but their activity in the neoadjuvant setting has not been established.

Investigators organized a multicenter, randomized phase II trial to examine the impact of adding atezolizumab to FLOT on progression-free/disease-free survival in resectable GEA. The trial initially had a sample size of 295 patients. Following conversion to a phase III study, the required sample size increased to 556 patients, and the primary endpoint was changed to event-free survival. The primary objective of the phase II portion of the study was changed to be exploratory in nature, with only surgical pathology endpoints.

The exploratory analysis included all 295 patients from phase II, all with confirmed GEA and clinical stage ≥cT2 and/or cN+ and no evidence of distant metastasis. Patients were randomized to receive FLOT with or without atezolizumab. Patients assigned to FLOT alone received four preoperative cycles and four postoperative cycles of therapy. Patients assigned to the atezolizumab arm received the agent in combination with FLOT, followed by eight additional cycles of the checkpoint inhibitor.

Baseline characteristics of the patients included microsatellite instability in 8% and a PD-L1 CPS ≥1 in 58%. Rates of surgical morbidity were 45% in the atezolizumab arm and 42% with FLOT alone, and 60-day mortality was 3% with atezolizumab versus 2% without.

Downstaging favored the addition of atezolizumab, regardless of the definition:

• ypT0: 23% vs 15% (P=0.044)
• ypT0-T2: 61% vs 48% (P=0.015)
• ypN0: 68% vs 54% (P=0.012)

Complete regression rates (pCR or TRG1a) also were significantly higher with atezolizumab (24% vs 15%, P=0.032). Margin-free complete resection occurred in a similar proportion of patients treated with atezolizumab/FLOT (96%) or FLOT alone (95%).

The incidence and severity of adverse events were similar between treatment groups. Therapy delay occurred in 80-90% of both groups, and dose modification for chemotherapy occurred at least once in 69% of the atezolizumab group and 54% of the FLOT-only arm. Toxicity was the reason cited for 87% of dose modifications. Rates of serious adverse events (AEs) were 69% with atezolizumab and 66% with FLOT alone.

The most common nonsurgical grade 3/4 AEs were neutropenia, leukopenia, diarrhea, nausea, and peripheral sensory neuropathy, each occurring in a similar proportion of patients in the two treatment groups. Premature discontinuation rates for reasons other than progression or death were 48% with atezolizumab and 45% with FLOT only.

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