Exploring New Approaches for Locally Advanced Gastroesophageal Adenocarcinomas: TNT, Irinotecan, and ctDNA

In this issue of Clinical Cancer Research, Wo and colleagues assessed the feasibility and preliminary efficacy of 25 patients treated with neoadjuvant FOLFIRINOX then CROSS-chemoradiotherapy (CRT) for resectable locally advanced gastroesophageal adenocarcinoma (LAGEA; ref. 1). In the United States, LAGEA (i.e., stage II/III: ≥T3, any N; or any T, N+ by American Joint Committee on Cancer staging) accounts for approximately 30% of newly diagnosed patients. Despite best currently available treatments including chemotherapy, radiotherapy, surgery, and immunotherapy in varying acceptable combinations, sequences, and strategies, the prognosis remains poor with more than 50% of patients eventually having recurrence (2). The disease is defined by heterogeneity, including heterogeneity by etiology, anatomy [esophagus, gastroesophageal junction (GEJ), stomach], geography (Asian vs. non-Asian), histology (adenocarcinoma, AC; squamous cell, SCC), pathology (intestinal, diffuse, mixed), biology (chromosomal-instable, genomically-stable, microsatellite-instable, Ebstein-Bar-Virus–related), and underlying molecular profiles (HER2, PDL1, EGFR, FGFR2, MET, claudin, etc.). Excluding esophageal SCC, GEA is comprised of esophagus, GEJ AC, and stomach AC, and retains all of the remaining above layers of heterogeneity. This heterogeneity of GEA is compounded by the diverse clinical trials conducted previously for LAGEA, varying in composition of each of these underlying factors and also the trial designs and actual treatments implemented (chemotherapy before, after, before and after; with/without radiation). While many perioperative strategies added to surgery demonstrated superiority compared with surgery alone, most were not directly compared with each other. Consequently, this has led to a fragmented treatment landscape varying by geographical, institutional, and even individual physician preferences.

For distal gastric cancer, FLOT chemotherapy for 2 months before and after surgery (FLOT4 study, NCT01216644) demonstrated superiority compared with the previous standard regimen, ECF (MAGIC study; ref. 2). Other treatment sequences include surgery first then adjuvant CapeOx chemotherapy for 6 months (CLASSIC study, NCT00411229). However, FLOT perioperatively is a preferred approach because this allows for tumor downstaging and improved complete resection (R0) rates, early treatment of possible micrometastatic disease, and a buffer period to allow ultra-aggressive disease to declare itself thus sparing patients from unnecessary invasive surgery that ultimately would not have helped. The adjuvant chemotherapy component of perioperative therapy may contend with tumor seeding during surgery, but its overall utility has been questioned. While adjuvant CRT was previously a standard approach, three randomized phase III studies demonstrated no benefit compared with adjuvant chemotherapy alone, and the CRITICS study per protocol subset analysis demonstrated improved survival with the continued adjuvant chemotherapy compared to switching to CRT, supporting post-operative therapy even after completion of neoadjuvant chemotherapy (3).

While distal gastric cancer has thus recently become more streamlined with FLOT, divergent treatment strategies persist for proximal esophageal/GEJ AC. This still includes perioperative chemotherapy with FLOT, because approximately 56% of patients in the FLOT4 study had esophageal/GEJ adenocarcinomas. The other strategy includes neoadjuvant CRT with carboplatin/paclitaxel and 41.4 Gy radiation over approximately 5 weeks then surgery (CROSS study; ref. 2). Recently, the NeoAegis study (NCT01726452) compared the MAGIC versus CROSS regimens, and demonstrated no clear winner for DFS/OS, despite CROSS having better localized pathologic outcomes. By extension, because FLOT was better than MAGIC (FLOT4 study), evidence currently points to superiority of FLOT over CROSS, with the argument that potent triplet systemic therapy is optimal to control micrometastatic disease compared to doublet chemotherapy within the CROSS regimen. However, the ongoing ESOPEC study (FLOT vs. CROSS, NCT02509286) is fully accrued and may provide further guidance when data mature. Ongoing studies evaluating immune checkpoint inhibitors are built upon both of these backbone approaches.

Regardless, both backbone approaches come with toxicity and the prognosis for LAGEA remains poor, leaving much room for improvement. Because only 50%–60% of patients complete the adjuvant component of FLOT, typically due to poor performance postoperatively, one approach is to attempt to complete all/more of the therapy preoperatively using total neoadjuvant therapy (TNT). In addition, while FLOT is the standard triplet chemotherapy backbone, perioperative FOLFIRINOX has emerged as an alternate triplet chemotherapy with similar efficacy to FLOT, yet having less overlapping toxicity, namely neuropathy, and an apparent generally overall better tolerability, particularly using UGT1A1 genotype-directed irinotecan dosing (gFOLFIRINOX; ref. 4). Also, despite ongoing debate regarding perioperative triplet chemotherapy versus neoadjuvant CRT ± adjuvant nivolumab for esophageal/GEJ adenocarcinomas based on CHECKMATE-577 (NCT02743494), another approach is to consider an induction of triplet chemotherapy followed by CRT, attempting to optimize outcomes on all fronts. Limited data exist to recommend this as a routine strategy to date particularly for the stomach, and an ongoing study, TOPGEAR (NCT01924819), is evaluating this question. No studies, however, have incorporated each of these novel variables (TNT, FOLFIRINOX, and induction triplet chemotherapy then CRT) simultaneously. Finally, circulating tumor DNA (ctDNA) minimal residual disease (MRD) is emerging as a prognostic biomarker at diagnosis, through perioperative treatment, and upon completion of curative treatment in LAGEA (5), with potential to use this to assist with treatment decisions.

To that end, the authors conducted a pilot study of 25 patients evaluating feasibility of induction FOLFIRINOX for eight cycles with prophylactic growth factor, then CROSS-CRT (with 50.4 Gy) then surgery for LAGEA (Esophagus/GEJ 60%, gastric 40%). The authors reported that 92% of patients (23/25) completed the chemotherapy (2 progressed during), 88% of patients (22/25) completed CRT (one died during CRT), and 80% (20/25) had curative-intent surgery (2 with metastases at surgical exploration), meeting the predefined feasibility endpoint requiring ≥72% (18/25) receiving all prescribed preoperative therapy and surgery. By ITT, the R0 resection rate was 80% (20/25) and the pathologic complete response rate (pCR) was 28% (7/25). Although 80% completed all therapy via TNT, a clear improvement over historic completion rates of perioperative/adjuvant therapy, we should note that this is a small cohort from a single tertiary center, subject to both selection and treatment bias; and it was FOLFIRINOX, not FLOT. For example, in a similar pilot study, perioperative gFOLFIRINOX also had similar completion rates without TNT (4). Also, while Wo and colleagues noted good completion rates, the actual outcomes did not appear much better than CROSS/FLOT4 studies, with both R0 and pCR rates similar to what would otherwise be expected. However, the authors enrolled patients with M1 lymph nodes and did not perform baseline staging laparoscopies, each of which possibly negatively affected these results. Also, while TNT sounds appealing, most pivotal studies demonstrating survival benefit have included an adjuvant component (2, 3). As such, prospective studies evaluating the TNT question are warranted (Fig. 1A).

Exploratory correlatives included ctDNA analysis during/after therapy. Interesting findings, yet now somewhat expected, were that ctDNA presence/progression was a negative prognostic factor of clinical outcomes. Notably, 21/25 (84%) patients successfully had tumor-specific mutations identified from baseline tissue, pointing out that some patients will not be assessable for MRD by a “tumor-informed” approach. Of those with adequate tumor sequencing, 4 had ctDNA negativity at baseline, and these as well as those achieving ctDNA-negativity after preoperative therapy both correlated with higher pCR rates (though not statistically significant). Of 16 patients with posttreatment/presurgery evaluation, only 8% (1/12) with ctDNA negativity had disease recurrence, while 75% (3/4) with ctDNA-positivity already recurred (but with median f/u <24 months). Of 14 patients having postsurgery ctDNA analyzed, 0/9 ctDNA negative and 2/5 (40%) ctDNA positive recurred. These MRD data are consistent with mounting evidence that ctDNA-positivity at baseline, after neoadjuvant therapy, and/or most importantly after curative surgery is a negative prognostic biomarker. The question that remains is whether MRD status could dictate therapeutic decisions (i.e., escalation, deescalation, or changing therapy), which currently lacks robust prospective evidence. Studies evaluating early lack of ctDNA response, akin to PET-directed therapy, or adjuvant strategies determined by postoperative ctDNA results may each help to better tailor therapy and optimize future results (Fig. 1B and C).

In summary, the authors conducted a pilot study incorporating novel concepts including TNT with induction FOLFIRINOX then CROSS-CRT before surgery, along with ctDNA correlative analyses. This study serves as a benchmark upon which to continue to evaluate the utility of each of these components seeking to improve outcomes of LAGEA (Fig. 1).

D.V.T. Catenacci reports personal fees from Guardant Health, Tempus, and Natera during the conduct of the study. No other disclosures were reported.

D.V.T. Catenacci is supported by the NIH (P30CA014599).