Neoadjuvant nivolumab plus concurrent chemoradiation in stage II/III esophageal/gastroesophageal junction cancer.

Abstract

142 Background: Neoadjuvant chemoradiation (cRT) prior to surgical resection in stage II/III esophageal/gastroesophageal junction (E/GEJ) cancer results in a complete pathologic response rate (pCR) of 20-30%. The appearance of favorable microenvironment features (enhanced tumor infiltrating lymphocytes, perivascular lymphocytes and tertiary lymphoid structures) after induction therapy in resected EC suggest early stage tumors may respond favorably to immune based therapy and in particular to PD-1 blockade when combined with cRT. Methods: In this pilot study, we administered 2 cycles of induction nivolumab (N) q2 weekly prior to standard of care carboplatin/paclitaxel/radiation plus 3 additional cycles of N on week 1, 3 and 5 of cRT. An Ivor-Lewis esophagectomy (E/MIE) was performed 6-10 weeks after the last IO dose. The primary endpoints of the study were safety and feasibility. We also evaluated the pCR, survival and temporal dynamics of T cell receptor clonotypes. Results: Between August 2017 and July 2018, 16 patients were enrolled on study. Induction N and neoadjuvant N combined with cRT in stage II/III E/GEJ cancers has an acceptable toxicity profile and was not associated with delays in surgery. Toxicities of note include steroid responsive grade 3 dermatitis (1/16), grade 3 hepatitis (1/16) and no cases of pneumonitis. To date, 10 patients with E adenocarcinoma have had an E/MIE and the pCR is 4/10 (40%). T cell receptor sequencing of the tumor bed and serial peripheral blood T cells revealed high peripheral representation of tumor-associated T cells. In one notable case, the highest-frequency intratumoral clone decreased in frequency in the peripheral blood upon treatment and rapidly increased after surgical resection, potentially signifying trafficking to the tumor site. Conclusions: Induction N and N combined with cRT has limited side-effects, did not result in surgical delay or enhanced surgical morbidity/mortality and induced a pCR of 40% in stage II/III E/GEJ cancers. Additional efficacy data on the full cohort and more in depth correlative studies will be presented to validate systemic activation of anti-tumor T cell responses. Clinical trial information: NCT03044613.

Efficacy and safety of neoadjuvant chemotherapy and immunotherapy in locally resectable advanced esophageal squamous cell carcinoma

“…For locally advanced esophageal cancer, ASCO (2019) reported a pilot experiment of nivolumab combined with CRT, a total of 16 patients with stage II-III esophageal cancer or gastroesophageal junction cancer were enrolled. Five patients achieved complete pathological remission, 9 patients achieved pathological downgrade, and 15 patients achieved R0 resection (18). The ASCO (2019) meeting also reported the results of Avelumab combined with neoadjuvant chemotherapy and radiotherapy in the treatment of operable locally advanced esophageal adenocarcinoma.…”

RATIONALE 311: tislelizumab plus concurrent chemoradiotherapy for localized esophageal squamous cell carcinoma

“…While previous trials have investigated the potential benefit of sequential PD-L1 inhibition and CRT, concurrent anti-PD-1/PD-L1 therapy combined with CRT had not been examined in patients with ESCC in a Phase III trial prior to the initiation of the RATIONALE 311 study. Other randomized trials evaluating the activity of CPIs combined with CRT in ESCC with or without esophageal adenocarcinoma have since begun recruiting patients [16,31,32]. Standard of care for patients with inoperable ESCC is definitive CRT consisting of fluoropyrimidine in combination with platinum-based chemotherapy, but the 5-year survival rate still remains at approximately 20% [8,11,12].…”

Platelet-to-lymphocyte ratio is an independent predictor of chemoradiotherapy-related esophageal fistula in esophageal cancer patients

“…Currently, immunotherapy has served as the fourth antitumor strategies following surgery, radiotherapy and chemotherapy (2). Increasing clinical trials investigated the combination of immunotherapy and other antitumor strategies (4)(5)(6)(7)(8)(9). However, there remains a long way of immunotherapy in ESCC.…”