Neoadjuvant FOLFOX Research Articles

FOxTROT: neoadjuvant FOLFOX chemotherapy with or without panitumumab (Pan) for patients (pts) with locally advanced colon cancer (CC).

4013 Background: FOxTROT has reported marked down-staging, reduced perioperative morbidity and a trend towards fewer recurrences with 6 wks of oxaliplatin-fluoropyrimidine neoadjuvant chemotherapy (NAC) in CC (Seymour, ASCO 2019 abstract 3504). Using updated data, we investigate the contribution of panitumumab (Pan) and tumour markers to efficacy of NAC. Methods: 1053 pts with radiologically-staged T3-4, N0-2, M0 CC were randomly allocated (2:1) to either 6 wks of NAC and 18 wks of postoperative adjuvant chemotherapy (AC) or 24 wks of AC. 279 pts with RAS-wt tumours were also randomised 1:1 to receive Pan or not with NAC. The primary endpoint was freedom from recurrence or residual disease at 2 years for NAC vs AC, and depth of extramural spread for the Pan randomisation; secondary endpoints include safety, histological downstaging, CC-specific survival and OS. Results: Of 699 allocated pre-and-postoperative chemotherapy, 674 (97%) started and 612 (88%) completed NAC. 684/699 (97.8%) pre-and-postoperative and 349/354 (98.6%) control patients underwent tumour resection. There was marked T- and N-down-staging and tumour regression with NAC (all p<0.001). There were fewer disease recurrences within 2 years in the NAC than AC group: 15.6% (109/698) vs 19.5% (69/354), RR=0.76 (95%CI 0.56-1.02), P=0.07. Response to NAC was significantly (p<0.001) less in MMR-deficient (dMMR) than MMR-proficient (pMMR) tumours: 7%(8/115) vs 23%(128/553) moderate or greater histological tumour regression. Reductions in 2-year recurrence were also seen only in pMMR tumours [RR=0.72 (0.52-1.00), p=0.05], with no apparent benefit in dMMR tumours: RR=0.94 (0.43 to 2.07), p=0.9]. Analyses of panitumumab will be presented. Conclusions: Six weeks of NAC for operable CC can be delivered safely, with marked histopathological down-staging, and may result in better disease control at 2 years in pMMR disease. Clinical trial information: 87163246 .

Outcomes of rectal cancer patients treated using Polish II neoadjuvant short course radiation therapy and chemotherapy approach in comprehensive cancer center.

e16088 Background: Neoadjuvant short-course (SC) radiation (RT) followed by fluoropyrimidine based chemotherapy prior to surgery (Polish II approach) is a less utilized treatment in the United States for rectal cancer. Based on data suggesting equivalent or improved outcomes at lower cost compared to the long course neoadjuvant chemoradiation, our team started utilizing this approach for rectal cancer management at Simmons Comprehensive Cancer Center. We aim to document our experience with Polish II approach at NCI-designated comprehensive cancer center program. Methods: A retrospective review of stage I-IV rectal cancer patients, seen at an academic center or the Dallas County safety net hospital and treated at Simmons Comprehensive Cancer Center from Nov 2017 to Dec 2019. Patients were treated with neoadjuvant SC-RT followed by 3 cycles of FOLFOX prior to surgery and followed by adjuvant FOLFOX. Descriptive data for demographic, radiation, chemotherapy and surgery, hospitalizations, 30 day post-surgery admission, time to relapse, and laboratory parameters was collected. Results: Thirty-nine patients met the inclusion criteria (average age 58 years; 74% men/26% women). Forty-six percent of patients were Hispanic, 28.2% White, 15.4% African American and 7.7% Asian. The majority of patients had stage IIIB (46.2%), followed by IIIC (17.9%), IIA (12.8%), IIIA (7.7%), while rest were stage I, IVA or unknown (5.1%). All patients received 5 x 5 SC-RT, 100% completed 3 cycles of planned neoadjuvant FOLFOX (12.8% received 4-8 cycles) and 36/39 (92%) of patients underwent planned surgery. Median duration from SC-RT to chemotherapy was 12 days, and from chemotherapy to surgery was 37 days. Hospitalization occurred in 3 patients (7.7%) during neoadjuvant therapy, and in 8 patients (20.5%) within 30 days post-surgery. Complete pathological response was seen in 6 patients (16.6%) and near-complete pathological response in 3 patients (8.3%). Relapse occurred in 10.3% patients at time of data acquisition. Grade 3 and 4 neutropenia, anemia, and thrombocytopenia in neoadjuvant phase was observed in 8.6%, 25.7%, and 2.8% patients, respectively. Conclusions: In rectal cancer patients treated at a comprehensive cancer center, neoadjuvant Polish-II approach was feasible and well tolerated. Pathological response rates were comparable to historical data. SC-RT based neo-adjuvant therapy approach should be favored due to lower pelvic radiation dose, tolerance and convenience to patients.

Does neoadjuvant FOLFOX chemotherapy improve the oncological prognosis of high-risk stage II and III colon cancers ? Three years’ follow-up results of the Prodige 22 phase II randomized multicenter trial.

4110 Background: Neoadjuvant chemotherapy in a perioperative setting has proven valuable in locally advanced resectable colon cancer (CC) in terms of toxicity, postoperative morbidity and downstaging, but its effect on oncological outcomes remains uncertain. Methods: Prodige 22 was a randomized multicenter phase II trial in patients with resectable high-risk T3, T4 and/or N2 CC on baseline CT-scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type (wt) patients a third arm testing perioperative FOLFOX-cetuximab was added. Primary endpoint was the Tumor Regression Grade. Secondary endpoints were 3-years overall (OS), disease-free survival (DFS) and time to recurrence (TTR). Results: 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients (control, n = 52; FOLFOX peri-op n = 52) represented our intention-to-treat population. In the FOLFOX peri-op group, 96% received the schedule 4 cycles prior to surgery and all but one underwent adjuvant FOLFOX for a total of 12 cycles. In the control arm, 38 patients received adjuvant FOLFOX (1 postoperative death and 13 low-risk stage II patients). Median follow-up was 54.3 months [48.5-57.2]. Nineteen deaths and 26 disease recurrences were observed leading to a 3 years-OS of 90.3% in both arms (p = 0.7) and to a 3-years DFS of 76.8% and 69.2% in the peri-op and control arm respectively (p = 0.6). A trend to a better TTR in the peri-op arm was observed with a 3-years TTR of 82% as compared to 72% in the control arm (p = 0.3). No benefit from adding Cetuximab was observed in the 16 RAS-wt treated patients. Conclusions: In this pilot randomized study, perioperative FOLFOX chemotherapy has no detrimental effect on long term oncological outcomes and may be an option for some patients with locally advanced CC. A pooled analysis of randomized trials testing peri-operative strategies in this setting is warranted. Clinical trial information: NCT01675999 .

Preliminary analysis of total neoadjuvant therapy for patients with locally advanced gastric (G) and gastroesophageal (GE) adenocarcinoma.

393 Background: Nearly half of patients with G/GE cancer do not receive or complete post-operative chemotherapy and/or chemoradiation (CRT). Total neoadjuvant therapy (TNT) is as an emerging alternate treatment strategy. We have previously reported a 28% pCR with FOLFIRINOX followed by CRT. However, TNT outcomes with FLOT or FOLFOX followed by CRT are lacking. Methods: We retrospectively analyzed patients after resection of locally advanced G/GE after receiving TNT. Patient received neoadjuvant FOLFOX or FLOT x 8 cycles, CRT (G 45 Gy, GE 50.4 Gy) with concurrent chemotherapy (5FU, carboplatin/paclitaxel). The primary aim was to explore TNT completion rates. Secondary aims included pCR and toxicity. We performed descriptive statistics, t-test, chi-squared, and Fisher’s exact tests as appropriate. Results: From 12/2015 to 8/2019, 57.1% (40/70) completed TNT and resection (15.7% active treatment, 15.7% progressive disease, 11% treated elsewhere). Median age was 66.0 (range:27-79) and 73% male. Tumor locations included 57.5% G, 30.0% GE, and 12.5% overlapping. Neoadjuvant chemotherapy included FLOT 22.5% (n = 9) or FOLFOX 77.5% (n = 31). Overall we found a 25% pCR without significant differences between type of neoadjuvant chemotherapy. Conclusions: TNT followed by resection is feasible with acceptable rates of treatment completion and toxicity. Notable limitations include the retrospective analysis, small sample size, and heterogenous treatment. The pCR rate is promising and warrants further prospective study to optimize TNT approaches. [Table: see text]

2783 The Extreme of Morning Sickness: A Case of Gastric Adenocarcinoma in Pregnancy

INTRODUCTION: Gastric adenocarcinoma usually presents in advanced stages and after 40 years of age. Presentation in pregnancy is rare, occurring in less than 0.1% of all pregnancies, and it presses additional challenges as the symptoms are usually overlooked. Reports of gastric adenocarcinoma in pregnancy undergoing different mainstays of therapy have been described. Here, we present a case of poorly differentiated gastric adenocarcinoma diagnosed at 26 weeks gestation, who had to undergo an individualized and multi-disciplinary approach, with a favorable outcome thus far. CASE DESCRIPTION/METHODS: A 24-year-old woman with no significant history, gravida 2, para 1 at 26 weeks gestation presented with hyperemesis, dehydration and anorexia requiring inpatient management. She had lost 19 Kgs during the second trimester. Lab work revealed hypokalemia of 2.8 mEq/L, and transaminitis: AST 206 U/L, ALT 354 U/L. MRI abdomen without contrast showed mild distention of the proximal stomach of unclear significance. Ultrasound of the liver, kidneys and appendix were non-revealing. Symptoms progressed; therefore, she underwent upper endoscopy, which revealed inflamed antral mucosa with nodularity. Biopsy did not show H. pylori, but rather poorly differentiated adenocarcinoma with signet ring features. This was further classified as IHC positive for CDX-2 and E-cadherin, HER-2+ (IHC 2+, FISH amplified). The patient was initially treated with neoadjuvant FOLFOX for 4 cycles given concurrent pregnancy, followed by induction of pregnancy at 36 weeks gestation. She then underwent surgical resection with total gastrectomy, omentectomy and lymphadenectomy. Surgical biopsy showed metastatic disease stage ypT3N1. Currently, 7 months after diagnosis, the patient is tolerating adjuvant chemotherapy with FLOT (5-FU, oxaliplain, docetaxel). Radiation therapy is planned following chemotherapy. The patient’s baby is alive and thriving. DISCUSSION: Gastric adenocarcinoma rarely presents in pregnancy and is often overshadowed by pregnancy-related symptoms as these may overlap. Thus, red flags such as extreme weight loss in pregnancy should raise suspicion for underlying pathology. Diagnosis and treatment pose challenges as these can encompass risks for the fetus, especially early on gestation. Nevertheless, gastric adenocarcinoma often presents as poorly differentiated disease in pregnancy warranting prompt diagnosis, staging and expeditious intervention with chemotherapy and surgical resection.

NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—First experimental arm (EA) initial results.

3505 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of hypotheses in a consistent high-risk pt population with correlative biomarkers. Primary endpoint (EP) and available secondary EPs from the first EA using veliparib (a PARPi) are reported. NCT02921256. Methods: Stage II/III pts with LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX (x 4mo) → chemoRT (cape with 50.4Gy +/- veliparib 400mg PO BID) → surgery 8-12 wks later. Primary EP: 4 point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α = 0.10 and 80% power. NAR compared by linear model controlling for stratification and possibly other factors. Secondary EPs: OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, and SSS. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 10/2016 - 2/2018, 178 pts were randomized (88 control, 90 veliparib). Baseline characteristics were balanced except for candidate for SSS at entry (39% control, 61% veliparib). 140 pts were evaluable for NAR (72 control, 68 veliparib). Mean NAR was 12.6 control (95% CI: 9.8–15.3) vs 13.7 for veliparib (CI: 10.2–17.2). Controlling for stratification (p = 0.69) or stratification and candidate for SSS (p = 0.78), NAR difference was not significant. pCR = 21.6% vs 33.8% (p = 0.14); cCR = 28.2% vs 33.3% (p = 0.60); and SSS = 52.5% vs 59.3% (p = 0.43). Most common grade 3/4 AEs were diarrhea and cytopenias. The EA had two deaths (cardiac arrest [FOLFOX]; enterocolitis [chemoRT]). Conclusions: Veliparib added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie. Clinical trial information: NCT02921256.

Clinical downstaging and quality of life after neoadjuvant chemotherapy in patients with locally advanced rectal cancer: Interim analysis from a phase II clinical trial.

e15178 Background: The role of neoadjuvant FOLFOX in achieving clinical downstaging and improvement in quality of life (QOL) in patients with locally advanced rectal cancer (LARC) remains to be established. We are conducting a phase II prospective clinical trial to evaluate the use of six cycles of FOLFOX as neoadjuvant chemotherapy in patients with T2-T3/N0-N+ rectal cancer. We now report tumor clinical downstaging and patient-reported QOL in our first patient cohort. Methods: Eleven Patients enrolled in our phase II prospective trial. Patients received three months of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) administered every two weeks. After three weeks of recovery, each patient was treated with conventional chemo-radiotherapy (5FU or capecitabine) All patients had an MRI and endorectal ultrasound at baseline and after completion of FOLFOX. A compilation of validated QOL questionnaires were also administered before and after FOLFOX. Results: A total of 11 patients completed the chemotherapy regimen. Based on pelvic MRI, complete clinical response (T0N0) was achieved by seven patients (64%), one patient (9%) was clinically downstaged but three (27%) didn’t have any changes following FOLFOX. Importantly, we found no disease progression during the FOLFOX course. QOL assessment after FOLFOX regimen showed trend towards improvement in general health, mobility, bladder control and psychological health. These changes in QOL were not statistically significant due to the small sample size. Patients self-grading of their general health before starting FOLFOX was 50% compared to 75% after. Of the five patients with pain at time of diagnosis, four reported complete pain relief while the fifth reported improvement from extreme to moderate pain. Three patients reported improvement in their anxiety/depression. In terms of bowel function, although there was trend towards improvement in the urgency subscale, other bowel functions subscales were unchanged. In general, scores for mobility, selfcare, and bladder function were slightly better after FOLFOX. Conclusions: This study suggests that adding only six cycles of neoadjuvant FOLFOX before CRT not only resulted in clinical downstaging of (LARC) but showed a trend toward improved QOL. This result provides some reassurance for oncologists that this approach does not diminish QOL with no risk of disease progression during the time of neoadjuvant chemotherapy. These findings need to be validated in a larger phase III trial.

CLO19-023: Induction Chemotherapy Followed by Chemoradiation and Trans-Anal Full Thickness Local Excision or Total Mesorectal Resection in Patients With T2-T3/NO-N+ Adenocarcinoma of the Rectum; Preliminary Results of Phase 2 Prospective Clinical Trial

Background: The National Comprehensive Cancer Network (NCCN) Guidelines recently recognized total neoadjuvant therapy (TNT) as an acceptable option in patients with T3 and any N rectal cancer. Previous studies suggested that patients who received chemotherapy prior to conventional preoperative chemoradiation (CRT) and surgery allowed patients to receive more of their planned treatment with a better toxicity profile and increase in pathological response. However, those studies used a long course of FOLFOX or used capecitabine and oxaliplatin as an induction regimen. We are conducting a phase 2 prospective clinical trial to evaluate the use of 6 cycles of FOLFOX as TNT in patients with T2-T3/N0-N+. Patients and Methods: Patients with T2-T3/N0-N+ enrolled on our phase 2 prospective trial were included for this analysis. Patients received 6 cycles of FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin), which was administered every 2 weeks. After 3 weeks of recovery period, patients then received conventional CRT with 5FU or capecitabine. All patients got MRI and endorectal ultrasound (ERUS) at baseline, after completing FOLFOX 3-months regimen and after finishing conventional CRT. Patients underwent either full-thickness local excision or total mesorectal resection depending on their tumor response to neoadjuvant therapy. The time interval between completion of radiation therapy and surgery ranged between 7and 12 weeks. Results: A total of 10 patients completed the chemotherapy and CRT treatment regimen. 9 patients proceeded to surgery and the 10th patient is scheduled for surgery. Clinical downstaging by MRI or ERUS was shown in 9 of 10 patients with only 6 cycles of FOLFOX. Complete clinical response was achieved in 6 patients as evident by ERUS/MRI of the pelvis after 3 months of FOLFOX before CRT. Complete pathological response was found in 4 of 9 patients (44%). In addition, 4 other patients had significant albeit not complete pathological response. Conclusions: This study suggests that adding only 6 cycles of neoadjuvant FOLFOX before CRT improved clinical and pathological downstaging of T2-T3/N0-N+ rectal adenocarcinoma and may facilitate organ preservation surgery. This is strategy needs to be investigated in larger phase III trials to validate these findings.

A phase II clinical trial platform for sensitization testing using total neoadjuvant therapy (TNT) in rectal cancer: Nrg-GI002.

TPS721 Background: Locally advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers is needed to advance treatment outcomes. This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EA) in LARC. The EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk patient (pt) population with correlative biomarkers. Success of any EA will be determined by achievement of pathologic endpoints compared to a control arm. Methods: The NRG-GI002 trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC with any ONE of the following: distal location (cT3-4 ≤ 5 cm from anal verge, any N); bulky (any cT4 or tumor within 3 mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, pts receive neoadjuvant FOLFOX x 4 mo→chemoRT (capecitabine with 50.4 Gy)→surgical resection 8-12 wks later. The first EA will assess activity of veliparib with standard chemoRT. Enrollment to this EA is complete (results anticipated late 2019). The second EA, testing pembrolizumab concurrently with and following chemoRT, is currently active, with several other EAs in development. Primary endpoint is demonstrated improvement in Neoadjuvant Rectal Cancer score for the EA v control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including QOL, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts/arm with additional EAs added through protocol amendments. NCT02921256. Support: U10CA180868, -180822, UG1-189867, U24-196067; AbbVie, Merck. Clinical trial information: NCT02921256.

Treatment of advanced rectal cancers: Cylindrical abdominoperineal excision of rectum

Introduction: Treatment for patients with locally advanced low lying rectal cancer differs significantly from patients with rectal cancer restricted to the mesorectum. They require multimodality treatment, including preoperative chemo-radiation and extended surgical resection. Cylindrical abdominoperineal excision of rectum (C-APER) along with possible composite pelvic organ resection is a surgical method to remove an adequate circumferential margin.
 Method: Patients with the diagnosis of advanced rectal cancers over a period of 9 months are included in this study. Therapeutic approach of C-APER is taken for these patients with focus on multimodality treatment protocols to downstage the tumours and extended resections to enable complete removal of all tumour tissue with clear surgical margins. Consecutive review of cases of advanced rectal cancer to their immediate surgical outcome were done.
 Results: Five patients with compromised CRM in MRI of rectum, 4 were treated with Neoadjuvant FOLFOX 6 regimen chemotherapy 3 cycles and Short course Radiotherapy. All underwent surgery 6-8 weeks after treatment. The pelvic floor was repaired with biological mesh in 1 and synthetic mesh in 4. The pathological stage of disease remained T3 and above despite neoadjuvant treatment in majority of patients but none of them had positive CRM. The wound complication rates were high in the perineum with serous discharge in almost every patient and one patient needing long term vacuum assisted dressing in the community.
 Conclusion: The surgery is technically feasible with acceptable morbidity in short term with possible long term outcome of reduced loco-regional failure.

Oxaliplatin, 5-Fluorouracil and Nab-paclitaxel as perioperative regimen in patients with resectable gastric adenocarcinoma: A GERCOR phase II study (FOXAGAST)

Background5-Fluorouracil (5-FU) and platinum-based perioperative chemotherapy is standard of care for resectable gastric adenocarcinoma (RGA). Nanoparticle albumin-bound (Nab-) paclitaxel is active in advanced disease but has never been evaluated in the perioperative setting. The objective was to evaluate the efficacy of Nab-paclitaxel in combination with FOLFOX for RGA patients. MethodsWe performed a non-randomised, open-label, phase II study. RGA patients were assigned to receive neoadjuvant Nab-paclitaxel (150 mg/m2) and FOLFOX q2w for six cycles. Six additional post-operative cycles were kept at the investigator's discretion. The primary end-point was complete pathological response (tumour regression grade [TRG1]) rate. According to Fleming design, 49 patients were required to test H0 (10% TRG1) and H1 (25% TRG1). To reject H0, TRG1 had to be achieved in 8 patients. ResultsForty-nine patients were included. Median number of neoadjuvant chemotherapy cycles was 6 (range, 3–6). Median dose intensity for Nab-paclitaxel, oxaliplatin and 5-FU was 96% (38–103%), 97% (47–103%) and 99% (50–112%), respectively. Surgery could not be performed in 5 (10.2%) patients. Tumour resection was R0 for 42 of 44 (95.5%) patients. Pathological review classified tumours as TRG1 to TRG5 for 8 (16.3%), 11 (22.5%), 4 (8.2%), 18 (36.7%) and 3 (6.1%) patients, respectively. Grade 3 or worse toxicities during neoadjuvant chemotherapy were non-febrile neutropenia (20.4%), nausea (8.2%), diarrhoea (8.2%) and neuropathy (6.1%). Of 44 patients, 14 (31.8%) experienced surgery-related complications and three (6.8%) died of surgical complications. ConclusionThis regimen shows promising activity. Toxicity is manageable but a meaningful rate of surgical complications was observed. This strategy deserves investigation in phase III studies.

Complete pathological response following neoadjuvant FOLFOX\xa0chemotherapy in BRCA2-mutant locally advanced rectal cancer: a case report

BackgroundPatients with locally advanced rectal cancer (LARC) achieving a pathological complete response (pCR) to neoadjuvant treatment usually have a good prognosis, but only accounted for less than 20%.Case presentationWe report a case of a 25-year-old male with LARC treated with neoadjuvant FOLFOX chemotherapy, and experienced a pCR. The next-generation sequencing analysis revealed the presence of breast cancer gene 2 (BRCA2) somatic mutation and an increased somatic mutational load without microsatellite instability (MSI). To our knowledge, this is the first report of BRCA2 mutant LARC that demonstrated significant benefit from FOLFOX neoadjuvant treatment.ConclusionsThis case indicated an association of BRCA2 mutation with high mutation loads and an excellent response of oxaliplatin-based chemotherapy regimen for LARC. Our findings encourage further studies to analyze BRCA mutations in patients with LARC, especially for those patients unable or unwilling to receive radiotherapy.

Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study)

BackgroundAt time of diagnosis, less than 10% of patients with pancreatic adenocarcinomas (PDAC) are considered to be immediately operable (i.e. resectable). Considering their poor overall survival (OS), only tumours without vascular invasion (NCCN 2017) should be considered for resection, i.e. those for which resection with disease-free margins (R0) is theoretically possible in absence of presurgery treatment. With regard to high R1 rates and undetectable locoregional and/or metastatic spreading prior to surgery explain (at least in part) the observed 1-year relapse and mortality rates of 50 and 25%, respectively. Today, upfront surgery followed by adjuvant chemotherapy is the reference treatment in Europe. The main limitation of the adjuvant approach is the low rate of completion of the full therapeutic sequence. Indeed, only 47 to 60% patients received any adjuvant therapy after resection compared to more than 75% for neoadjuvant therapy. No previous prospective study has compared this approach to a neoadjuvant FOLFIRINOX or FOLFOX chemotherapy for resectable PDAC.MethodsPANACHE01-PRODIGE48 is a prospective multicentre controlled randomized non comparative Phase II trial, evaluating the safety and efficacy of two regimens of neo-adjuvant chemotherapy (4 cycles of mFOLFIRINOX or FOLFOX) relative to the current reference treatment (surgery and then adjuvant chemotherapy) in patients with resectable PDAC. The main co-primary endpoints are OS rate at 12 months and the rate of patients undergoing the full therapeutic sequence.DiscussionThe “ideal” cancer treatment for resectable PDAC would have the following characteristics: administration to the highest possible proportion of patients, ability to identify fast-progressing patients (i.e. poor candidates for surgery), a low rate of R1 resections (through optimisation of local disease control), and an acceptable toxicity profile. The neoadjuvant approach may meet all these criteria. With respect to published data on the efficacy of FOLFOX and mFOLFIRINOX, these two regimens are potential candidates for neoadjuvant use in the aim to optimising oncological outcomes in resectable PDAC.Trial registrationClinicalTrials.gov, NCT02959879. Trial registration date: November 9, 2016.

Abstract CT123: A phase I study assessing the safety and clinical activity of multiple doses of a NKG2D-based CAR-T therapy, CYAD-01, administered concurrently with the neoadjuvant FOLFOX treatment in patients with potentially resectable liver metastases from colorectal cancer

Abstract We recently developed a novel chimeric antigen receptor (CAR) T-cell therapy, called CYAD-01 (a.k.a. NKR-2), incorporating the full-length human natural killer receptor NKG2D fused with the human CD3 zeta signaling domain, which associates with the adaptor molecule DAP10 to provide co-stimulatory signal upon ligand binding. CYAD-01 is currently evaluated in the ongoing THINK study (NCT03018405) without preconditioning therapy in both hematological and solid indications. Classical CAR-Ts has yet to demonstrate positive results in the context of solid tumors. Underlying reasons for this reduced clinical activity include the need to extravasate from the peripheral circulation, infiltrate into the tumor and overcome the hostile immune suppressive tumor microenvironment (TME) to deliver anti-tumor effector responses. To address the challenge related to the immunosuppressive TME, the SHRINK trial (Standard cHemotherapy Regimen and Immunotherapy with NKR-2) has been developed to assess the safety and clinical activity of multiple infusion CYAD-01 treatment (every 2 weeks x 3 infusions) in patients undergoing standard-of-care FOLFOX (Folinic acid, Fluorouracil (5-FU) and Oxaliplatin) chemotherapy, as neoadjuvant treatment, for the treatment of colorectal metastatic disease with potentially resectable metastases (NCT03310008). The FOLFOX treatment is given every two weeks for six cycles and CYAD-01 cells are infused shortly after chemotherapy on cycles 3, 4 and 5. This concurrent administration of chemotherapy and CYAD-01 treatments would not only (i) favor infiltration into the immunosuppressive TME due to the effect of chemotherapy on TME and cancer cells but also (ii) provide an opportunity for the CYAD-01 cells to better engraft due to the lymphodepletion induced by the standard chemotherapy administration, and likely (iii) increase the NKG2D ligand expression in tumor tissues targeted by CYAD-01, even in patients presenting heterogeneity and/or low ligand expression. The study contains two consecutive segments. The dose escalation segment will enroll 9 patients and will evaluate 3 dose levels of CYAD-01 (1x108, 3x108 and 1x109 CYAD-01 per injection) following a 3+3 design. The expansion segment will then enroll 21 additional patients to further evaluate the safety and potential signs of activity of the CYAD-01 therapy when administered concurrently with chemotherapy. Peripheral blood samples, as well as tumor biopsies from patients at baseline and at resection, will be collected to determine, among others, CYAD-01 persistence, NKG2D ligand expression and systemic cytokine levels in peripheral blood post-infusion. Citation Format: Caroline Lonez, Alain Hendlisz, Leila Shaza, Philippe Aftimos, Ahmad Awada, Jean-Pascal H. Machiels, Marc Van Den Eynde, Jean-Luc Canon, Javier Carrasco, Bikash Verma, David E. Gilham, Frédéric F. Lehmann. A phase I study assessing the safety and clinical activity of multiple doses of a NKG2D-based CAR-T therapy, CYAD-01, administered concurrently with the neoadjuvant FOLFOX treatment in patients with potentially resectable liver metastases from colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT123.

Predictive value of ERCC1, ERCC2, and XRCC expression for patients with locally advanced or metastatic gastric cancer treated with neoadjuvant FOLFOX chemotherapy

Background: The dismal outcome in patients with locally advanced or metastatic gastric cancer highlights the need for effective systemic neoadjuvant chemotherapy to improve clinical results. This study evaluated the correlation between the expression of three DNA repair genes, namely the excision repair cross-complementing group 1 (ERCC1), excision repair cross-complementing group 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1), and the clinical outcome of patients with locally advanced or metastatic gastric cancer treated with FOLFOX-4 neoadjuvant chemotherapy.

NRG-GI002: A phase II clinical trial platform for sensitization testing using total neoadjuvant therapy (TNT) in rectal cancer.

TPS876 Background: Locally-advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (TNT) with parallel experimental arms (EA) in LARC. The EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk patient (pt) population with correlative biomarkers. Success of any EA will be determined by achievement of pathologic endpoints compared to a control arm. Methods: This NCTN multi-arm randomized phase II trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC with any ONE of the following criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, all pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. The first EA will assess the activity of veliparib with standard chemoRT. A second EA, testing pembrolizumab concurrently with and following chemoRT, is in development. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score for the EA vs control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional EAs added through protocol amendments. NCT02921256. Support: U10 CA-180868, -180822, UG-189867, U24CA196067; AbbVie Clinical trial information: NCT02921256..

Feasibility of Neoadjuvant FOLFOX Therapy Without Radiotherapy for Baseline Resectable Rectal Cancer.

The combination of oxaliplatin, leucovorin and fluorouracil (FOLFOX) has been established as postoperative adjuvant chemotherapy for stage III colon cancer. However, the safety and efficacy of neoadjuvant FOLFOX in patients with rectal cancer are still controversial. This prospective pilot study aimed to evaluate the feasibility of neoadjuvant FOLFOX therapy without radiation for baseline resectable rectal cancer (RC). The study included 30 patients with clinical stage II/III RC between February 2012 and December 2015. The patients were treated with six cycles of FOLFOX followed by elective surgery. The primary endpoint was the R0 resection rate. The secondary endpoints were the scheduled treatment completion rate, adverse events, pathological response and the disease-free survival (DFS) rate. All the patients underwent elective R0 resection after neoadjuvant FOLFOX therapy. The completion rate of the 6-cycle regimen was 93.3% (28/30 patients). Grade 3-4 adverse events occurred in seven patients (23.3%). Pathological complete response was noted in two patients (6.7%). The 3-year DFS rate was 77.5% (95% confidence interval, 61.4%-93.7%). Neoadjuvant FOLFOX therapy without radiation is a feasible therapeutic strategy for baseline resectable RC.

Predictive value of ERCC1, ERCC2, and XRCC expression for patients with locally advanced or metastatic gastric cancer treated with neoadjuvant FOLFOX chemotherapy

Predictive value of ERCC1, ERCC2, and XRCC expression for patients with locally advanced or metastatic gastric cancer treated with neoadjuvant FOLFOX chemotherapy

Prognostic Significance of Surgical Margin Size After Neoadjuvant FOLFOX and/or FOLFIRI for Colorectal Liver Metastases

PurposeOptimal margin size when resecting colorectal liver metastases (CRLM) remains unclear, particularly in the setting of perioperative chemotherapy. We evaluated the prognostic significance of margin size in patients who received neoadjuvant FOLFOX and/or FOLFIRI prior to resection of CRLM. MethodsClinicopathologic factors were collected for patients who underwent curative liver resections for CRLM between 4/2004–1/2016 and received neoadjuvant oxaliplatin and/or irinotecan and 5-FU (FOLFOX, FOLFIRI). Margins were categorized as < 1, ≥ 1–< 5, ≥ 5–< 10, or ≥ 10 mm and evaluated for association with overall survival (OS) and disease-free survival (DFS) by Cox multiple regression analysis. Margin status was classified as positive (< 1 mm) or negative (≥ 1 mm) and similarly evaluated. ResultsOf 227 patients, the median age was 58 years and most had synchronous (80%) lesions. The majority had colon cancers (75%). Margin sizes were 13% < 1 mm, 27% ≥ 1–< 5 mm, 23% ≥ 5–< 10 mm, 36% ≥ 10 mm. Most (63%) received chemotherapy post-liver resection. Five-year OS and DFS were 54% (95% CI 46–62%) and 22% (95% CI 16–28%), respectively. Positive margins significantly increased the risk of death without post-liver resection chemotherapy (HR = 3.32, p = 0.0077), but not with post-liver resection chemotherapy (HR = 1.00, p = 0.99). Negative margin sizes of ≥ 1–< 5, ≥ 5–< 10, and ≥ 10 mm were not significant predictors of OS (p > 0.05). ConclusionPatients undergoing liver resection for CRLM should receive post-resection chemotherapy if negative margins (≥ 1 mm) cannot be achieved. For patients receiving FOLFOX and/or FOLFIRI chemotherapy, wider margins did not improve OS.

476O - Neoadjuvant FOLFOX 4 versus FOLFOX 4 plus cetuximab versus immediate surgery for high-risk stage II and III colon cancers: A phase II multicentre randomised controlled trial (PRODIGE 22)

476O - Neoadjuvant FOLFOX 4 versus FOLFOX 4 plus cetuximab versus immediate surgery for high-risk stage II and III colon cancers: A phase II multicentre randomised controlled trial (PRODIGE 22)