A Phase 2 Study of Sotigalimab, a CD40 Agonist Antibody, plus Concurrent Chemoradiation as Neoadjuvant Therapy for Esophageal and Gastroesophageal Junction Cancers

<div>AbstractPurpose:<p>Neoadjuvant chemoradiation (NCRT) followed by surgical resection represents a standard approach for patients with locally advanced esophageal/gastroesophageal junction (GEJ) cancers. Sotigalimab is a high-affinity CD40 agonist antibody capable of inducing and expanding antitumor immune responses by activating dendritic cells, T and B lymphocytes, NK cells, and M1 macrophages. This study examined the safety and efficacy of combining sotigalimab with NCRT in patients with esophageal or GEJ cancers.</p>Patients and Methods:<p>Patients with resectable (T1-3 Nx) adenocarcinoma or squamous cell carcinoma of the esophagus or GEJ were eligible. T1N0 and cervical tumors were excluded. Study treatment: weekly carboplatin/paclitaxel with concurrent radiation 5,040 cGy plus 3 to 4 doses of sotigalimab prior to Ivor Lewis esophagectomy. Primary efficacy endpoint was the pathologic complete response (path CR) rate.</p>Results:<p>Thirty-three patients were enrolled (adenocarcinoma 76%, squamous cell carcinoma 24%; and clinical stage III 67%). Ninety percent of patients received all planned doses of sotigalimab. The most common adverse events attributed to sotigalimab were nausea, fever/chills, fatigue, and cytokine release syndrome; most of these were grade 1 to 2. Grade ≥3 cytokine release syndrome was observed in 3 patients (9%). Twenty-five of the 29 efficacy-evaluable patients underwent an R0 resection (87.9%), with an overall path CR rate of 37.9% (11/29). Post-tumor samples demonstrated increased infiltration and activation of dendritic cells, monocytes, and cytotoxic T cells compared with baseline.</p>Conclusions:<p>Sotigalimab combined with NCRT for esophageal or GEJ cancers was generally well tolerated and achieved path CR rates that compare favorably with historical data and are promising for this treatment strategy. Clinical trial information: NCT03165994.</p>Significance:<p>The current study represents the first report to evaluate a CD40 agonist antibody in combination with concurrent chemoradiation in the neoadjuvant setting for patients with esophageal/GEJ cancers. This novel strategy was both safe and feasible, producing encouraging path CR rates that compare favorably with historical data. Our findings support the further evaluation of how immune-based therapies may be incorporated into perioperative treatment paradigms for upper gastrointestinal malignancies.</p></div>

The optimal timing of chemoradiotherapy (CRT) for patients with localized gastric cancer remains unclear. This study aimed to compare the survival outcomes between neoadjuvant and postoperative CRT for patients with gastric and gastroesophageal junction (GEJ) cancer. This retrospective study analyzed 152 patients with gastric (42%) or GEJ (58%) adenocarcinoma who underwent definitive surgical resection and received either neoadjuvant or postoperative CRT between 2005 and 2017 at the authors' institution. The primary end point of the study was overall survival (OS). The median follow-up period was 37.5months. Neoadjuvant CRT was performed for 102patients (67%) and postoperative CRT for 50 patients (33%). The patients who received neoadjuvant CRT were more likely to be male and to have a GEJ tumor, positive lymph nodes, and a higher clinical stage. The median radiotherapy (RT) dose was 50.4Gy for neoadjuvant RT and 45.0Gy for postoperative RT (p<0.001). The neoadjuvant CRT group had a pathologic complete response (pCR) rate of 26% and a greater rate of R0 resection than the postoperative CRT group (95% vs. 76%; p=0.002). Neoadjuvant versus postoperative CRT was associated with a lower rate of any grade 3+ toxicity (10% vs. 54%; p<0.001). The multivariable analysis of OS showed lower hazards of death to be independently associated neoadjuvant versus postoperative CRT (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.36-0.91; p=0.020) and R0 resection (HR 0.50; 95% CI 0.27-0.90; p=0.021). Neoadjuvant CRT was associated with a longer OS, a higher rate of R0 resection, and a lower treatment-related toxicity than postoperative CRT. The findings suggest that neoadjuvant CRT is superior to postoperative CRT in the treatment of gastric and GEJ cancer.

163 Background: In RTOG 85-01, patients with locally advanced esophageal and gastroesophageal junction (GEJ) cancer treated with concurrent chemoradiotherapy (CRT) had a median overall survival (OS) of 14 months and 5-year OS of 27%. Improving outcomes in these patients is an unmet need. We investigated the addition of oral metronomic chemotherapy (OMC) following definitive CRT. Methods: A randomized integrated phase II/III clinical trial (CTRI/2015/09/006204) in patients with squamous cell carcinoma of the esophagus or the GEJ who had completed definitive radical CRT within the past 12 weeks, had an ECOG PS 0-2 and no clinical or radiologic evidence of progressive disease. Patients were stratified based on whether or not they had received induction chemotherapy followed by CRT, and then randomized 1:1 to receive OMC (celecoxib 200 mg twice daily and methotrexate 15 mg/m2 weekly) for 12 months or observation. The primary efficacy endpoint for the phase II portion was progression free survival (PFS). The secondary endpoints were OS and toxicity. With a power of 70% and an alpha of 10%, we hypothesized a hazard ratio of 1.5, with a median follow-up of 6 months. The planned sample size for the phase II portion was 151 patients. The p-value for stopping the trial after the phase II part of the study was set at 0.2 for the PFS. Results: Between Jan 2016 and Dec 2019, we enrolled 151 patients, 75 to the OMC arm and 76 to observation. The median age was 57 years, 59% were male. The tumor originated in the upper thoracic esophagus in 79% patients, with median tumor length 6 cm. Induction chemotherapy was received by 14% of the patients. Concurrent CRT consisted of median 63 Gy in median 35 fractions; 91% patients received concurrent weekly paclitaxel and carboplatin with radiation. OMC was started at a median of 11 weeks (IQR, 9 to 12) from the start of CRT. Grade 3 or higher toxicities (regardless of relatedness to study intervention) were noted in 27 patients (17.9%), 18 in the OMC arm and 9 in the observation arm; P=0.071. The median time to disease progression or death was 23 months (95% CI, 7.9-38.1) in the OMC arm and not reached in the observation arm; HR, 1.33, 95% CI, 0.83-2.14; P=0.23. The 1-year PFS was 67% in both the arms; the 2-year PFS were 48% and 61% in the OMC and observation arms respectively. The median OS was 36 months (95% CI, 17.9-54) in the OMC arm and not reached in the observation arm; HR, 1.75; 95% CI, 1.02-2.99; P, 0.037. The 1-year OS was 74.7% in the OMC arm and 88% in the observation arm; the 2-year OS was 53.9% in the OMC arm and 75% in the observation arm. Conclusion: Adjuvant oral metronomic chemotherapy after radical CRT does not improve outcomes in patients with locally advanced esophageal or GEJ squamous cell carcinoma. Clinical trial information: CTRI/2015/09/006204.

Prognostic Factors After Combined Modality Treatment of Squamous Cell Carcinoma of the Esophagus

Background: The ability of pretreatment laboratory markers of acute-phase inflammatory reactions like serum albumin level (SAL), hemoglobin (Hb), and absolute blood cell counts to predict complete pathological response (CPR) to neoadjuvant chemoradiotherapy (NACRT) in patients with locally advanced rectal cancer (LARC) has not yet been fully studied. Methods: We retrospectively examined the relation between SAL, Hb and absolute blood cell counts, and CPR rates in 140 LARC patients treated with NACRT. Results: Univariate analysis showed a significantly higher probability of CPR to NACRT in patients with clinical stage (CS) III LARC who had SAL >3.5 mg/dl (OR = 2.39; p = 0.04) and a neutrophil-to-lymphocyte ratio (NLR) value <5 (OR = 2.86; p = 0.03). The relation of CPR with SAL (OR = 2.11; p = 0.048) and NLR (OR = 2.54; p = 0.04) was confirmed by multivariate analysis in the same subset of patients. None of the parameters studied predicted CPR in patients with CS II disease. Patients who achieved CPR to NACRT had a higher probability of 5-year overall survival (HR 0.48; p = 0.01) and 5-year disease-free survival (HR 0.33; p = 0.003). Conclusions: Our data indicate that SAL >3.5 mg/dl and NLR <5 may be positively related to CPR after NACRT in patients with CS III LARC. Hypoalbuminemia and a high NLR may be considered an indication for a more aggressive approach to NACRT and postoperative adjuvant chemotherapy in this subset of patients. This hypothesis requires confirmation in a randomized study.

Esophagectomy postallogenic hematopoietic stem cell transplantation for hematologic malignancy: A case series

BackgroundSquamous cell carcinoma of the esophagus ranks as the most common cause of cancer incidence and mortality in males and the second most common in females. Surgery alone is associated with poor long-term survival. Neoadjuvant chemoradiation and perioperative chemotherapy without radiation have been tried to improve survival rates.MethodsWe retrospectively evaluated the neoadjuvant chemotherapy in forty-eight patients with non-metastatic, non-cervical squamous cell carcinoma of the esophagus with a docetaxel-based three-drug regimen to improve complete pathological response rates.ResultsThe median age of presentation was 52 years, with male preponderance. All the patients received three cycles of docetaxel-cisplatin-fluorouracil-based chemotherapy. A complete pathological response to neoadjuvant chemotherapy was seen in 8 patients (17%). Rates of grade 3 hematological toxicities were seen in 12% of patients, with no observed grade 4 toxicity. The most common non-hematological toxicity was grade 3 alopecia (seen in 40%) and grade 2 nausea/vomiting in 8% of patients. At a median follow-up of 26.5 months, 2-year survival for the patients receiving chemotherapy and surgery is 66%.ConclusionsPreoperative chemotherapy with a taxane-based triple-drug regimen is a reasonable approach in squamous cell carcinoma of the esophagus, associated with improvement in complete pathological response rates, increases complete resection rates, with manageable toxicity.

Since the prognosis of patients with T4 squamous cell carcinoma (SCC) of the esophagus is extremely poor, an effective multimodal treatment needs to be established. Forty-five patients with SCC of the esophagus at the T4 classification of the disease but no hematogenous metastasis were treated with concurrent chemoradiation therapy followed by surgical resection. Twenty-eight patients were treated with a regimen (protocol A) of 5-fluorouracil 750 mg/m2 on days 1-5 and 22-26, and cisplatin 70 mg/m2 on days 1 and 22. The remaining 17 patients were treated with a modified regimen (protocol B) of 5-fluorouracil 400 mg/m2 and cisplatin 10 mg/m2 on days 1-5, 8-12, 15-19, and 22-26. Radiation was delivered daily for 5 days/week for 4 weeks at the rate of 2 Gy/day to a total dose of 40 Gy in both protocols. A major clinical response was observed in 29 [3 complete response (CR) and 26 partial response (PR)] patients (64.4%). Twenty-eight patients (62.2%) underwent esophagectomy with no postoperative death. The median survival time of the resected patients (959 days) was significantly longer than that of the non-resected patients (178 days). Protocol B showed significantly higher pathologic effectiveness than protocol A. The pathologic CR rate for the main tumors was 1 (6.3%) of 16 patients for protocol A and 7 (58.3%) of 12 patients for protocol B. The pathologic CR rate for metastasized lymph nodes was 4/11 (36.4%) for protocol A and 5/5 (100%) for protocol B. Good histological response of the main tumors correlated well with long survival. The treatments were well tolerated except for one treatment-related death. Concurrent chemoradiation therapy followed by surgery is an effective and safe multimodal therapy for patients with primary inoperable T4 SCC of the esophagus.

To compare the outcomes of two neoadjuvant radiochemotherapy (N-RCT) regimens for squamous cell carcinoma of the esophagus (ESCC). The standard N-RCT regimen for ESCC at our institution between 2002 and 2011 was a total dose of 45 Gy (1.8-Gy fractions) with concomitant cisplatin (20 mg/m(2), days 1-5 and 29-33) and 5-fluorouracil (5-FU; 225 mg/m(2), 24 h continuous infusion on days 1-33). During the same period, a phase I/II study comparing the standard ESCC N-RCT protocol with a regimen identical except for the replacement of cisplatin with weekly oxaliplatin (40-50 mg/m(2)) was performed at our center. The standard regimen was used to treat 40 patients; 37 received the oxaliplatin regimen. All patients subsequently underwent radical resection with reconstruction according to tumor location and two-field lymph node dissection. Median follow-up time from the start of N-RCT was 74 months (range 3-116 months). The two patient groups were comparable in terms of demographic and baseline tumor characteristics. R0 resection was achieved in 37/39 patients (95 %) in the cisplatin-based N-RCT group, compared to 24/37 (65 %) in the oxaliplatin-based group (p = 0.002). A pathological complete response (pCR) was seen in the resection specimens from 18/39 patients (46 %) in the cisplatin-based N-RCT group and in 8/37 (22 %) oxaliplatin-group patients. In the cisplatin group, 2- and 5-year overall survival (OS) rates were 67 ± 8 % and 60 ± 8 %, respectively (median OS 103 months), compared to 38 ± 8 % and 32 ± 8 %, respectively, for the oxaliplatin group (median OS 17 months; hazard ratio, HR 0.452; 95 % confidence interval, CI 0.244-0.839; p = 0.012). Oxaliplatin-based N-RCT resulted in poorer outcomes in ESCC patients and should not routinely replace cisplatin-based N-RCT.

With or without consolidation chemotherapy using cisplatin/5-FU after concurrent chemoradiotherapy in stage II–III squamous cell carcinoma of the esophagus: A propensity score-matched analysis

Aim: Objective of this study was to evaluate the hemoglobin level (Hb) as potential prognostic factor in uniformly staged patients (pts) undergoing primary chemoradiotherapy (ChRT) for locally advanced squamous cell carcinoma (SCC) of the esophagus. Patients and Methods: Pts with histologically proven SCC of the esophagus (uT3/4 Nx or uTx N+) were included in the analysis. Staging procedures comprised endoscopic ultrasound, barium swallow and computed tomography. All pts received radiotherapy (≧40 Gy) and ≧2 courses of fluorouracil / folinic acid, and cisplatin (5 days/month). In selected pts surgical resection after neoadjuvant ChRT was carried out. Clinical parameters, especially Hb were retrospectively evaluated for their impact on survival. Results: 46 pts were treated between 1996 and 2001. Median survival was 16 months. Survival for pts treated with definitive ChRT (n = 28) was 14 months, whereas pts treated surgically after neoadjuvant ChRT (n = 18) survived 19 months (p = 0.79). Pts with low Hb levels at baseline did not show a worse outcome in comparison with pts with normal Hb levels (16 months), whereas a significant decrease in Hb level within the time period of ChRT was associated with a significantly inferior outcome (11 vs. 31 months; p = 0.046). Pts requiring blood transfusion tended to have inferior survival (11 vs. 24 months; p = 0.07). Conclusion: In this retrospective analysis a significant decrease of Hb level during ChRT was identified as prognostic factor for pts undergoing ChRT of SCC of the esophagus.

Definitive concurrent chemoradiotherapy (ccrt) is currently a therapeutic option for locally advanced esophageal cancer. However, clinical practice differs with respect to the target volume for irradiation. The purpose of the present study was to analyze failure patterns and survival, and to determine the feasibility of using involved-field irradiation (ifi) with concurrent chemotherapy for T4 squamous cell carcinoma (scc) of the esophagus. Between January 2003 and January 2013, 56 patients with clinical T4M0 scc of the esophagus received ccrt using ifi. The radiation field included the primary tumour and clinically involved lymph nodes. Target volumes and sites of failure were analyzed, as were treatment-related toxicity and survival time. In this 56-patient cohort, 13 patients (23.2%) achieved a complete response, and 21 (37.5%) achieved a partial response, for a total response rate of 60.7%. The major toxicities experienced were leucocytopenia and esophagitis, with 14 patients (25.0%) experiencing grade 3 toxicities. At a median follow-up of 34 months, 48 patients (85.7%) had experienced failure: 39 (69.6%) in-field, 7 (12.5%) elective nodal, and 19 (33.9%) distant. Only 1 patient (1.8%) experienced isolated elective nodal failure. The 1-, 2-, and 3-year survival rates were 39.3%, 21.4%, and 12.5% respectively. For patients with T4M0 scc of the esophagus, definitive ccrt using ifi resulted in an acceptable rate of isolated elective nodal failure and an overall survival comparable to that achieved with elective nodal irradiation. A limited radiation therapy target volume, including only clinically involved lesions, would therefore be a feasible choice for this patient subgroup.

Recently, attention has been directed to concurrent chemoradiotherapy (CRT) for the treatment of squamous cell carcinoma of the esophagus with regard to efficacy, quality of life and functional preservation, and survival periods comparable to those after standard surgical therapy have been reported in responders to CRT. However, there are some non-responders to CRT, and the prediction of the outcome after CRT is an important subject for future studies. In this study, using biopsy specimens obtained before CRT, we evaluated the relationships between biological markers and the outcome after CRT in order to determine the prognostic factors of CRT. The subjects were 51 patients (42 males and nine females: median age 68 years). who were histologically confirmed to have squamous cell carcinoma of the esophagus at stage II or III (UICC). Concurrent CRT consisting of chemotherapy using 5FU and CDDP and radiation therapy (60 Gy) was performed as the initial treatment, and the relationships of overexpression of EGFR, p53, VEGF, PCNA and CyclinD1 were examined immunohistochemically in biopsy specimens collected before treatment. Overall survival was estimated by multivariate analysis. The percentages of patients overexpressing p53, VEGF, PCNA, CyclinD1, and EGFR were 33, 31, 37, 31 and 29%, respectively. On multivariate analysis, T stage (P = 0.0393) and PCNA (P = 0.0302) were found to be significant prognostic factors. PCNA overexpression appears to be a prognostic factor for squamous cell carcinoma of the esophagus after CRT.

This study investigates the feasibility of using (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) to predict the pCR (pathologic complete response) rate after neoadjuvant chemoradiotherapy (NCRT) in patients with locally advanced rectal cancer. A total of 88 patients with locally advanced rectal cancer were retrospectively analyzed. All patients were treated with NCRT, followed by radical surgery, and (18)F-FDG PET/CT was performed before and after NCRT. For a semiquantitative assessment, a volume of interest was drawn, including the whole tumor region, and the maximum SUV (SUVmax), SUVmax normalized to liver uptake (SLR), SUVmax normalized to blood pool uptake (SBR), the metabolic tumor volume at SUV 2.0 (MTV[2.0]), SUV 2.5 (MTV[2.5]), and SUV 3.0 (MTV[3.0]) were measured. In addition, their percentage changes after NCRT were assessed. The pCR was verified through a histologic examination of postsurgical specimens. A receiver operating characteristic curve analysis was conducted to predict the pCR by using these PET parameters. The pCR was predicted in 17 patients (19%). The values of the area under the curve (AUC) for predicting the pCR were 0.774 for SUVmax after NCRT, 0.826 for SLR after NCRT, 0.815 for SBR after NCRT, 0.724 for MTV(2.5) after NCRT, 0.729 for the percentage change in SUVmax, 0.700 for the percentage change in SLR, and 0.749 for the percentage change in MTV (2.5). Among these PET parameters, SLR after NCRT showed the highest AUC value. The optimal criterion, sensitivity, specificity, and accuracy of SLR after NCRT for predicting the pCR were ≤1.41, 88%, 65%, and 68%, respectively. F-FDG PET was found to be useful for predicting the pCR after NCRT in patients with locally advanced rectal cancer. Among various PET parameters, SUVmax normalized to liver uptake after NCRT was the best predictor of the pCR.

We investigated nimotuzumab (h-R3), a humanized monoclonal antibody against epidermal growth factor receptor, when combined with irradiation or chemoradiation for squamous cell carcinoma (SCC) of the esophagus. The aim of this study was to evaluate its safety and efficacy. We retrospectively analyzed 66 patients with esophageal SCC treated with a combination of h-R3 and radiation or chemoradiation between December 2008 and September 2011 at Fudan University Shanghai Cancer Center. Fifty-two of the 66 patients received h-R3 combined with chemoradiation and 14 received h-R3 plus radiation. The median total irradiation dose was 61 Gy given by conventional fractionation. The h-R3 weekly dosage was 100 mg (6/66), 200 mg (54/66), or 400 mg (6/66) given concurrently during the irradiation period. Patients tolerated the treatment well. Grade 3-4 adverse events and toxicities occurred in 50 % of the patients. h-R3-related toxicities manifested as Grade 1 skin rash in 1 case and Grade 2 infusion-related reaction in 2 cases. The median overall survival (OS) and progression-free survival (PFS) were 26.0 months and 16.7 months, respectively. OS, PFS and locoregional control (LC) at 2 years were 54, 37 and 80 %, respectively. h-R3 in combination with irradiation or chemoradiation was safe and tolerable, and yielded encouraging OS, PFS and LC.