Evolution of Perioperative Immunotherapy in Resectable Esophageal Cancer

The emergence of immunotherapy for esophageal cancer provided a glimmer of hope to patients and clinicians affected by the historically poor-prognosis disease. The glimmer has not only persisted but perhaps grown brighter as immunotherapy’s role in esophageal cancer has evolved and expanded over the past 7 years.

The FDA granted accelerated approval to pembrolizumab (Keytruda) in 2019 for previously treated, recurrent, locally advanced or metastatic esophageal squamous cell carcinoma. Nivolumab (Opdivo) followed a year later. Pembrolizumab then moved up to first line (in combination with chemotherapy) for unresectable locally advanced or metastatic esophageal adenocarcinoma. By then, trials of immunotherapy in the adjuvant setting had already begun.

Most recently, use of immunotherapy has expanded into neoadjuvant and perioperative therapy for operable esophageal cancer. The latest version of the National Comprehensive Cancer Network (NCCN) esophageal guidelines, released earlier this month, lists FLOT chemotherapy (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) plus the PD-L1 inhibitor durvalumab (Imfinzi) as a preferred regimen for multiple subgroups of patients: PD-L1 combined positive score (CPS) ≥1 or tumor area positivity (TAP) ≥1%, CPS <1 or TAP <1%, clinically node-negative tumors, and diffuse-type esophagogastric junction adenocarcinoma.

For patients with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors, four PD-(L)1 inhibitors (two in combination with CTLA-4 inhibitors) are among the preferred regimens for neoadjuvant/perioperative therapy.

Momentum for perioperative therapy has carried over from chemotherapy, according to Shadia Jalal, MD, of the Indiana University Simon Comprehensive Cancer Center in Indianapolis. For years, the standard approach to resectable esophageal cancer consisted of FLOT-based chemoradiation followed by surgery. Then the ESOPEC trial showed that perioperative chemotherapy improved overall survival (OS) by almost 2.5 years as compared with neoadjuvant chemoradiation and surgery.

ESOPEC had a number of limitations — incomplete chemotherapy in the chemoradiation arm, limited patient diversity, and no adjuvant immunotherapy. Nonetheless, the results persuaded many oncologists to shift toward perioperative therapy, said Jalal, a member of the NCCN guidelines panel on esophageal cancer.

“Then last year, we had the MATTERHORN trial, where immune therapy was incorporated into the perioperative regimen [and improved overall survival compared with perioperative chemotherapy],” Jalal told MedPage Today. “Since then, we’ve really moved toward perioperative chemotherapy with immune therapy as compared to chemotherapy.”

“There is no ‘one size fits all,'” she added. “For example, if you have a patient that you’re not sure is a surgical candidate or is hesitant about surgery, you want to make sure you give them a definitive regimen. In those patients, you probably should go the chemotherapy-with-radiation route. But in general, I would say perioperative chemo with immune therapy has moved into the standard.”

Prior to MATTERHORN, several small phase II studies had shown consistently high response rates in MSI-H/dMMR cancers with neoadjuvant/perioperative therapy that included a PD-(L)1 inhibitor, said Kei Muro, MD, PhD, of Aichi Cancer Center Hospital in Nagoya, Japan, at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium earlier this year.

The NEONIPIGA trial of 32 patients with MSI-H/dMMR gastric or gastroesophageal junction adenocarcinoma showed a pathologic complete response (pCR) rate of 58.6%, a histologic response rate of 72.4%, and a surgery rate of 90.6% with nivolumab and ipilimumab (Yervoy)-based neoadjuvant therapy.

The INFINITY trial of 18 patients showed a pCR rate of 60%, histologic responses in 80%, and a 93.3% surgery rate with neoadjuvant tremelimumab (Imjudo) and durvalumab. The DANTE trial of 23 patients compared perioperative FLOT plus atezolizumab (Tecentriq) or perioperative FLOT alone. The immunotherapy regimen led to higher pCR and histologic response rates, and almost all of the patients had surgery.

Despite the trials’ small numbers, the results’ consistency is supported by enrollment limited to patients with clinical stage II/III MSI-H/dMMR gastric/gastroesophageal junction cancers, said Muro.

Beyond the MSI-H/dMMR subgroups, not all trials have produced clear wins for neoadjuvant/perioperative immunotherapy, he added. The 1,000-patient KEYNOTE-585 trial, comparing perioperative pembrolizumab and chemotherapy versus chemotherapy alone, met the pCR endpoint but not event-free survival. An updated analysis showed the trial did not meet the overall survival endpoint despite a 16-month improvement over the control arm.

The Asia-based ATTRACTION-5 trial that included 800 patients also failed to meet the primary endpoint of recurrence-free survival with adjuvant nivolumab plus chemotherapy versus chemotherapy alone.

Aside from the different PD-(L)1 agents, KEYNOTE-585, MATTERHORN, and ATTRACTION-5 involved different types of patients with respect to disease stage, nodal status, and primary tumor location. The chemotherapy regimens were not consistent across the trials, nor were the treatment schedules. The differences point to a number of unresolved or untested issues related to perioperative immunotherapy, which were discussed by Do-Youn Oh, MD, PhD, of Seoul National University Hospital, during an education session at the ASCO annual meeting.

Perioperative therapy for resectable gastroesophageal cancer has become an accepted standard in North America, but has yet to become a worldwide standard, said Oh. In Europe, perioperative therapy is recommended for ≥cT2 disease. Asian guidelines recommend adjuvant chemotherapy and D2 lymphadenectomy for pathologic stage II-III disease. North America and Europe recommend FLOT chemotherapy, whereas CAPOX (capecitabine and oxaliplatin) or the oral fluoropyrimidine S-1 is the Asian standard.

Is evidence supporting perioperative immunotherapy “robust enough to be implemented into a daily routine practice globally?” Oh asked.

“Many studies are ongoing, with long-term survival outcomes still pending,” she continued. “Is pathologic response, especially pathologic [complete response], a good surrogate for long-term survival? There is a debate on this topic in the resectable gastric cancer field. When you look into all the clinical trials, testing the perioperative approach, and applying cytotoxic chemotherapy and chemoimmunotherapy and even chemoimmuno-antiangiogenic combinations, based on a biomarker-selective strategy, we see a trend of increasing pathologic response, major pathologic responses. Hopefully, we will soon see this is translated into a long-term survival benefit in those ongoing clinical trials.”

Biomarker-informed patient selection could prove to be the key to successful implementation of perioperative immunotherapy.

“There are five tumor microenvironment ecosystem types in resectable gastric cancer,” said Oh. “According to the different ecotype, the response to neoadjuvant chemo or neoadjuvant [and perioperative] chemoimmunotherapy is quite different. The information on the tumor microenvironment might be helpful for us in making more personalized treatment decisions for patients.”

“Further, with the implementation of multiomic data, we can divide resectable gastric cancer into several subtypes, and this kind of information might be helpful for us to select the optimal patient pool for neoadjuvant or perioperative chemoimmunotherapy,” she added.

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