Pathological CR Rate Research Articles

Preliminary efficacy and safety results from RC48-C017: A phase II study of neoadjuvant treatment with disitamab vedotin plus toripalimab in patients with muscle invasive bladder cancer (MIBC) with HER2 expression.

4568 Background: Disitamab vedotin (DV) is a novel humanized anti-HER2 antibody-drug conjugate. DV plus toripalimab (a recombinant humanized anti-PD-1 monoclonal antibody) showed promising antitumor activity in metastatic urothelial carcinoma (ASCO 2023). This study aimed to evaluate the safety and efficacy of DV plus toripalimab as neoadjuvant therapy in MIBC patients with HER2 expression. Methods: This is a prospective multicenter phase 2 trial which planned to enroll 40 pts. Primary endpoint is pathological CR (pCR) rate; secondary endpoints include pathologic response rate, safety and tolerability. Study enrolled pts who are previously untreated MIBC (cT2-T4aN0-1M0), medically fit for and agree to undergo curative intent RC+PLND. HER2 expression was required to be immunochemistry (IHC) ≥ 1+ tested locally. Pts received DV 2 mg/kg plus toripalimab 3 mg/kg every two weeks for 6 cycles, followed by RC+ PLND within 4 weeks. Here we present preliminary efficacy and safety results. Results: 44 pts were enrolled and clinical stage at diagnosis was: cT2N0 (38.6%), cT3N0 (29.5%), cT4aN0 (13.6%), cT2-4aN1 (18.2%). HER2 expression of IHC 1+, 2+ or 3+ was 11.4%, 56.8%, and 31.8%, respectively. By the data cut-off date (Feb-2024), 29 pts (65.9%) completed RC + PLND. The pCR rate was 62.1% (18/29). The pathologic response rate was 75.9% (22/29). Common treatment-related adverse events (TRAEs) were mostly Grade 1 or 2, including alopecia (36.4%), alanine aminotransferase increased (31.8%), aspartate aminotransferase increased (25.0%), rash (22.7%), gamma-glutamyl transferase increased (22.7%), peripheral sensory neuropathy (22.7%), and asthenia (20.5%). Grade 3-4 TRAEs were reported in 15.9% of pts. No deaths occurred. No surgery was cancelled due to TRAEs. Survival data are not yet mature. Conclusions: Neoadjuvant treatment with DV plus toripalimab showed promising efficacy results and was well tolerated in operable MIBC pts with HER2 expression. These results will support further investigation for DV plus toripalimab in this population. Clinical trial information: NCT05297552 .

612: Pathological CR rate with SIB for rectal cancer with short course preoperative Radiotherapy.

612: Pathological CR rate with SIB for rectal cancer with short course preoperative Radiotherapy.

Fruquintinib plus oxaliplatin combined with S-1 (SOX) as neoadjuvant therapy for locally advanced gastric adenocarcinoma (FRUTINEOGA): A multicenter, phase II study.

e16063 Background: Neoadjuvant chemotherapy (NCT) has become the standard treatment for patients (pts) with locally advanced GC, and SOX is the most common neoadjuvant regimen in China. Fruquintinib is a VEGFR inhibitor that blocks new blood vessel growth associated with tumor proliferation. It is a potent, highly selective small-molecule inhibitor of VEGFR-1,-2, and -3. The generally good tolerability in pts and fruquintinib’s low potential for drug-drug interaction suggest that it may be highly suitable for combinations with other antineoplastic therapies. We aimed to investigate the efficacy and toxicity of fruquintinib plus SOX as neoadjuvant treatment for locally advanced GC. Methods: It was a prospective, multicenter, phase II study in pts with stage III (cT3/4aN+M0) GC. Pts received 2 to 4 cycles of fruquintinib (5mg qd D1-14, Q3W) plus SOX (oxaliplatin 130mg/m2 D1, S-1 40-60mg bid D1-14 depending on body surface area (BSA), Q3W). Pts underwent D2 gastrectomy after neoadjuvant treatment. The primary endpoint was pathological response rate (pRR), and the secondary endpoints were disease-free survival (DFS), overall survival (OS), objective response rate (ORR), major pathological response rate (MPR), and R0 resection rate. Results: Up to February 3, 2023, 19 pts were eligible for the study. Median age was 62 years (29-73), 68.4% were male, and 21.1% were ECOG 1. Seven pts dropped out of clinical trial for AEs (2 pts), violation of treatment protocol (1 pt), staging error (2 pts), and refusal of surgery (2 pts). Twelve pts underwent surgery, 1 patient was found with peritoneal implantation, 11 patients underwent gastrectomy. Among the 11 pts, 9 pts achieved pRR (81.8%) and 3 pts achieved MPR (27.3%). The pathologic CR rate was 27.3% (3 of 11 pts). Moreover, 11 pts had curative intended operations and R0 resection rate was 90.9%. Among all the 19 pts, 16 pts received at least one dose of the combination treatment. A total of 2 pts had target lesions, 1 patient had complete response and 1 had partial response. Among the other 14 pts without target lesions, 1 (7.1%) had progressive disease with peritoneal implantation metastasis, and none had complete response. Furthermore, the most common TEAEs of grade ≥ 3 occurred in 19 pts were decreased appetite (21.1%), hypertension (21.1%), nausea (15.8%), vomiting (10.5%), oral mucositis (10.5%), fatigue (5.3%), diarrhea (5.3%) and respiratory infections (5.3%). There were neither new safety signals nor AEs inducing treatment deaths. Conclusions: The combination of fruquintinib and SOX as neoadjuvant treatment in patients with locally advanced GC is safe. The combination demonstrates promising evidence of anti-tumor efficacy in terms of pathological response. Clinical trial information: NCT05122091 .

Results of phase II trial of intensified neoadjuvant treatment with interdigitating radiotherapy and chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid in patients with locally advanced rectal cancer (PROARCT trial)

Background and purposeThe chemotherapy exposure during chemoradiotherapy for rectal cancer is adequate for radiosensitization but suboptimal for treatment of distant micrometastasis. This study aimed to determine tolerability, dose intensity, response, and toxicity of a novel intensified neoadjuvant treatment approach. Materials and MethodsEligible patients were MRI-staged T3-4NxM0 rectal adenocarcinoma. Treatment consisted of FOLFOX chemotherapy given in weeks 1, 6, and 11 with pelvic radiotherapy (25.2 Gy in 3 weeks in 1.8 Gy/fraction with oxaliplatin and 5-FU continuous infusion) given in weeks 3–5, and weeks 8–10. Surgery was performed 4–6 weeks later. The primary endpoint was tolerability defined as the percentage of patients who were able to complete the planned treatment course. Survival rates were estimated using the Kaplan-Meier method. ResultsMedian age of the 40 patients was 61.5 years. Rectal MRI-stage was T3 in 88%. Overall, 95% completed the regimen. All patients received 50.4 Gy. Relative dose intensity (≥75%) was 92% and 98% for oxaliplatin and 5-FU, respectively. High grade toxicities included neutropenia (25% grade 3; 7.5% grade 4) and diarrhoea (10%). Pathologic CR rate was 20%. Median follow-up was 54 months. The 5-year overall survival, freedom from relapse, locoregional control, and freedom from distant metastasis of the cohort was 82%, 72%, 97% and 72%. ConclusionsDelivery of intensified neoadjuvant treatment with interdigitating chemotherapy and radiotherapy is feasible with no increase in acute perioperative complications. A larger prospective study is required to further evaluate the potential survival benefit of this design.

Abstract P2-16-25: Young age breast cancer who achieve pathologic complete response after neoadjuvant chemotherapy display excellent outcome than older age breast cancers

Abstract Introduction: Patients with pathologic complete response (pCR) after neoadjuvant chemotherapy (NCT) is known to have a good prognosis compared with patients with no residual disease necessitating additional adjuvant systemic therapy for some population. Also there are cases of recurrence and/or death among patients with pCR. We aimed to 1)analyze whether prognostic impact of pCR differ across subtypes and age groups and 2)investigate factors associated with outcome after achieving pCR. Methods: Among 1930 patients who underwent NCT at Asan Medical Center between 1890 to 2018, 1688 patients with clinico-pathological, follow-up data available were analyzed. 339 (20.1%) patients had pCR defined as ypT0/Tis with no residual nodes(N0) after NCT. Pathologic CR rate were 10.2% (102/1003), 40.0% (100/250) and 31.6% (137/434) in each HR positive, HRneg/HER2pos and triple negative tumors. Pathologic CR rate were 19.7% (232/1175) and 20.9% (107/513) in young age and old age group respectively. Results: Median follow up period was 62 months (6-129 months). Five-year disease free survival (5yr-DFS) of ‘total’ patients and patients with ‘no-pCR’ and ‘pCR’ were 81.7%, 79.1% and 92.4% respectively (p=<0.01). Pathologic complete response was significant favorable indicator across all subtypes and both in young/old age group (Cox regression analysis in each group, Table 1). Among patients with pCR, residual in-situ disease (p=<0.01, HR 3.889), tumor size>5cm (p=0.006, HR=1.45), and negative hormone receptor (p<0.01, HR=9.269) were independently associated with worse disease free survival. These prognostic factors were similar in patients with residual disease as well. Intriguingly, magnitude of impact affecting prognosis differed by age groups that younger patients (≤50) who achieved pCR displayed excellent outcome similar to older age group (HR=1.33, CI 0.57-3.12, p=0.51). On the other hand, young age patients who did not achieve pCR had the worst outcome with 5yr-DFS 77.3% indicating the necessity of additional systemic therapy. Also, while HR negative tumors are known to have worse outcome, HRneg/pCR group had longer 5yr-DFS than HRpos/no-pCR groups (90.6% vs 83.9%, p=0.009). The outcomes were similarly observed for overall survival analysis. Conclusion: Patients with pCR after NCT showed better DFS and OS across all subtypes. Achieving pathologic complete response was a good prognostic indicator especially in young age population. Younger patients with residual disease after NCT may be candidates for additional adjuvant systemic therapy after surgery. Table1. Cox regression analysis in each grouppCRNo-pCRHazard ratio (ref, pCR)95%CIP value5yr-DFS (%)5yr-DFS (%)SubtypesHR positive96.183.93.081.35-7.020.007HRneg/HER2pos89.672.02.431.13-5.220.023HRneg/HER2pos91.567.83.591.87-6.89<0.001AgeYoung age (≤50)93.377.34.502.53-8.08<0.001Old age (>50)90.183.42.251.06-4.750.033 Citation Format: Young Joo Lee, Yung Il Shin, Jisun Kim, Sae Byul Lee, Hee Jeoung Kim, Il Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Sei-Hyun Ahn. Young age breast cancer who achieve pathologic complete response after neoadjuvant chemotherapy display excellent outcome than older age breast cancers [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-25.

Clinical Outcomes and Prognostic Factors in Locally Advanced Breast Cancer Patients with Estrogen Receptor-Positive, HER2-Negative Subtype Treated with Neoadjuvant Chemotherapy and Surgery Followed by Postmastectomy Radiation Therapy

The aim of this study was to determine clinical outcomes and identify reliable prognostic factors in patients with locally advanced breast cancer who had estrogen receptor (ER) positive and HER2 negative subtype treated with neoadjuvant chemotherapy (NAC) followed by mastectomy and PMRT in the modern treatment era. We retrospectively evaluated the relationship between clinicopathological factors and clinical outcomes in 216 patients with ER positive and HER2 negative, stage II or III breast cancer who underwent NAC followed by radical mastectomy and PMRT between March 2005 and December 2013. Locoregional recurrence free survival rate (LRFS), distant metastasis free survival rate (DMFS), and overall survival rate (OS) were calculated as clinical outcomes. All patients received a radical modified mastectomy. Patients were typically treated with anthracycline and taxane-based chemotherapy before surgery. The indications for PMRT were a diagnosis of ≥4 positive axillary lymph nodes by clinical evaluation including ultrasonography before treatment, diagnosis of a positive ipsilateral supraclavicular lymph node, or internal mammary region and a T4 or positive surgical margin of the chest wall. PMRT was performed with up to 50 Gy with photon beams using the partially wide tangential technique to the CW and anterior supraclavicular region. If the surgical margin was positive, an electron boost of 10 Gy to16 Gy was added for the involved area of the CW. Between 2005 and 2007, the IMN (intercostal space 1-3) was prophylactically irradiated if a patient had ≥10 positive lymph nodes or if ≥4 positive lymph nodes and the tumor were located on the inner part of the breast. Between 2007 and 2013, we included the IMNs in the clinical target volumes for all patients. The median follow-up duration was 81 months (range, 12–156 months). Fourteen patients experienced locoregional recurrence, 83 patients experienced distant failure, and 59 patients died of cancer. For all patients, the 5-year LRFS, DMFS, and OS were 94.1%, 69.4 %, and 85.1 %, respectively. Pathological CR rate was 1.4 %. On multivariate analysis, nuclear grade (NG), fat infiltration and nodal ratio (NR; number of positive axillary node/removed node) were significant prognostic factors of DMFS and OS. The patients with low NG (NG1/2) had significantly better 5-year OS than patients with high NG (NG3) (89.3 % vs. 65.0 %, p = 0.001), and patients with low NR (NR<30) had significantly better 5-year OS than patients with high NR (NR≧30) (93.6 % vs. 76.1 %, p=0.0003). The 5-year OS was significantly better in patients with low fat infiltration than those with high fat infiltration (95.6 % vs. 80.2 %, p=0.02). pCR and ypN0 were not significantly related to clinical outcomes. We identified several prognostic factors; in particular, NG, NR, and fat infiltration were significantly related to OS.

Abstract CT182: Neoadjuvant immuno-radiotherapy (NIRT) in head and neck cancer: Phase I/Ib study of combined PD-1/SBRT prior to surgical resection

Abstract Background: Standard treatment of locally advanced HPV-associated oropharyngeal HNSCC includes definitive chemoRT or surgery followed by risk-adapted adjuvant RT +/- chemo. These approaches provide high rates of long term survival, but are associated with significant subacute as well as long term morbidity. Therefore, increasing efforts have been directed at exploring alternative approaches. Combined SBRT and PD-1 blockade may have particularly favorable properties for anti-tumor immune response in HNSCC (Gough 2009). We present phase I safety &amp; efficacy data from the NIRT trial of neoadjuvant nivolumab/SBRT in oropharyngeal p16+ HNSCC (NCT03247712). Methods: Patients with p16+ oropharyngeal or unknown primary HNSCC, with clinical indications for adjuvant RT, or upfront TORS ineligible due to tumor size, could enroll. Patients received Nivo 240mg IV q2wks x3 prior to surgery, with SBRT to GTV+3mm delivered between Nivo doses 1 &amp; 2, in two dose finding cohorts (n=5 each): 8Gy x5 daily (M-F) and de-escalated 8Gy x3 (M,W,F). Surgery was performed 5 weeks post-SBRT followed by adjuvant Nivo 480mg IV q4wks x3, starting 4 weeks post-op. The primary endpoint was &amp;lt; 33% unplanned surgical delay; the secondary endpoint was pathologic response by irPRC (Cottrell 2018). Results: There were no unplanned surgical delays. All patients had radiologic evidence of decreased tumor size prior to surgery, but none showed a CR by RECIST. Remarkably, the pathologic CR rate was 100% in the 8Gy x 5 cohort (5/5) and 80% In the 8 Gy x 3 cohort (4/5), with the remaining patient achieving MPR (major pathologic response; &amp;lt;10% residual viable tumor). G3 toxicity was observed after surgery in both cohorts but was higher in the 8 Gy x 5 cohort. No G4 or higher toxicity was observed. Interestingly, G2 adrenal insufficiency was observed in 50% (5/10), a higher rate than previously reported with PD-1 blockade for recurrent/metastatic HNSCC. Notably, patients did not experience xerostomia or ageusia rates associated with standard adjuvant radiation in HNSCC. Tissue responses were characterized by robust inflammatory infiltrates into the regression bed and cholesterol clefts, as previously described. Circulating immune cells, baseline tissue, end of RT biopsy and surgical specimen were analyzed using flow cytometry and RNAseq to characterize of immunologic changes over time. There have been no local or distant failures, but median follow up remains &amp;lt; 1 year. Conclusions: Neoadjuvant combined PD-1/SBRT to GTV+3mm dosed at either 8Gy x5 (M-F) or 8Gy x3 (M,W,F) did not delay HNSCC surgery in this Phase I trial (n=10; five per dose). Potent anti-tumor response was observed in all cases (CR=9 + MPR=1). A high response rate and lower toxicity profile favors the 8Gy x3 cohort for development. This study represents a major paradigm shift in the approach to treatment of locally advanced p16+ oropharyngeal cancers. Citation Format: Rom Leidner, R. Bryan Bell, Kristina Young, Brendan Curti, Marcus Couey, Ashish Patel, Amber Watters, Hong Xiao, Carlo Bifulco, Brian Piening, George Morris, Lessli Rushforth, Dawn Brucker, Shorin Nemeth, Michael Gough, Marka Crittenden. Neoadjuvant immuno-radiotherapy (NIRT) in head and neck cancer: Phase I/Ib study of combined PD-1/SBRT prior to surgical resection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT182.

One-year (yr) recurrence-free survival (RFS) from a randomized, open label phase II study of neoadjuvant (neo) talimogene laherparepvec (T-VEC) plus surgery (surgx) versus surgx for resectable stage IIIB-IVM1a melanoma (MEL).

9520 Background: We previously reported that neo T-VEC + surgx resulted in a pathologic CR rate of 21% and an OR rate of 14.7% in a randomized trial of neo T-VEC + surgx vs upfront surgx in pts with resectable stage IIIB/C/IVM1a MEL (Andtbacka et al, ASCO 2018; NCT02211131). Here, we present results from an interim 1-yr analysis of RFS. Methods: Patients (pts) with resectable stage IIIB/C/IVM1a MEL, ≥ 1 injectable cutaneous, subcutaneous, or nodal lesions ≥ 10 mm, and no systemic tx 3 mos prior were randomized 1:1 to 6 doses/12 wks of T-VEC followed by surgx during wks 13-18 (Arm 1) vs upfront surgx during wks 1-6 (Arm 2). T-VEC was given at standard dosing until surgx, no injectable tumors, or intolerance. This analysis conducted on the ITT set estimated a between-group difference in 1-yr RFS per protocol. An RFS event was defined as the first of local, regional or distant recurrence or death due to any cause after surgx. Pts without a R0 surgical outcome or withdrew prior to surgx were considered an event at randomization for RFS. In a sensitivity analysis, RFS was calculated from randomization to the date of the first post-surgx event regardless of surgical outcome. Results: 150 pts were randomized (76 Arm 1, 74 Arm 2). Median (range) follow-up time was 20.6 (0.1, 38.5) mos in Arm 1 and 20.0 (0.1, 35.3) mos in Arm 2. 75% in Arm 1 and 93% in Arm 2 had surgx as planned. R0, R1, and R2 rates, respectively, for Arm 1 were 42.1%, 31.6%, and 1.3% and for Arm 2 were 37.8%, 51.4%, and 4.1%. At 1 yr, 33.5% of pts in Arm 1 and 21.9% of pts in Arm 2 remained recurrence free (HR 0.73, P= 0.048). From the sensitivity analysis, 55.8% of pts in Arm 1 and 39.3 % in Arm 2 remain recurrence free at 1 yr (HR 0.63, P= 0.024). OS rates at 1 yr were 95.9% in Arm 1 and 85.8% in Arm 2 (HR 0.47, P= 0.076). Pts receiving subsequent adjuvant tx was 8 (11%) in Arm 1 and 20 (29%) in Arm 2- most common was immunotherapy 6 (8.2%) and 8 (11.6%), respectively. Conclusions: In the largest randomized neo trial to date in resectable stage IIIB-IVM1a MEL, the following outcomes were improved with neo T-VEC monotherapy vs surgx: R0 surgical resections, 1-yr RFS, and OS. Primary analysis of RFS at 2 yrs is expected. Clinical trial information: NCT02211131.

Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin

BackgroundIntraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). MethodsBoth trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. Results81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36–76) and 55 (range, 19–69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3–4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2–35.3) and 25 (95%CI 16.4–42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0–79.7) months, respectively for Trial A and B. ConclusionsWeekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

Preoperative Conformal Radiotherapy Concurrently with Paclitaxel/Carboplatin in Gastric Cancer

Background and objectives: Surgery is the primary therapy for localized gastric cancer, but even with the best results only 40% 5-year survival can be achieved with the use of postoperative adjuvant chemoradiotherapy. Preoperative therapy might help increase the R0 resection rate, which is an independent predictor of 5-year OS. Our study hypothesized that the concurrent combination of carboplatin-paclitaxel with radiation therapy would result in a pathological CR rate, which will be in turn associated with OAS and DFS benefits. Patients and methods: prospective phase II study included 32 patients with locally advanced gastric adenocarcinoma including gastroesophageal junction who received a combination of neoadjuvant conformal radiotherapy concurrently with carboplatin-paclitaxel followed by surgery. Results: Pathological CR and R0 resection rates were 18.8% and 75% respectively. With a median follow up of 24 months, 2 years disease-free survival was 28.1% and overall survival was 51.3%. The regimen was tolerated with neither grade 4 toxicities nor deaths. Conclusion: Neoadjuvant radiotherapy concomitant with carboplatin-paclitaxel chemotherapy is a well-tolerated approach for patients with locally advanced gastric adenocarcinoma resulting in significant pathological CR and R0 resection margins as reflected by the good DFS and OS.

Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): Preliminary results from KEYNOTE-173.

556 Background: Pembro has shown efficacy and acceptable safety in pts with previously treated metastatic TNBC. The phase Ib KEYNOTE-173 study (NCT02622074) evaluated pembro + chemo as neoadjuvant therapy for locally advanced TNBC. We present cohorts A and B. Methods: Women aged ≥18 y with locally advanced, nonmetastatic TNBC; ECOG PS 0/1; and no prior chemo, targeted therapy, or immunotherapy within 12 mo were eligible. Dosing in A was single-dose pembro followed by 4 cycles of pembro Q3W + nab-paclitaxel (Np) weekly followed by 4 cycles of pembro + doxorubicin + cyclophosphamide Q3W. Dosing in B was the same as in A but with carboplatin Q3W added to pembro + Np. Concentrations were pembro 200 mg; doxorubicin 60 mg/m2; cyclophosphamide 600 mg/m2; Np 125 mg/m2 in A, 100 mg/m2 in B; and carboplatin AUC 6 (1 cycle = 21 d). DLTs were assessed at cycles 1-3 and 6-7. Dose levels were deemed toxic if ≥3 of the first 6 pts or ≥4 of 10 pts had DLTs. Surgery was 3-6 wk after treatment completion/discontinuation. Primary end points were safety and recommended phase 2 dose of pembro combined with chemo. Key efficacy end points were pathological CR (pCR) rate, defined as ypT0/Tis, ypN0, and ypT0 ypN0, and ORR (RECIST v1.1, investigator). pCR analyses included all pts. Results: By Jan 6, 2017, 10 pts were in each cohort. Median age was 53 y (range 32-71); most pts had invasive ductal histology (90%), primary tumor stage ≥T2 (90%), and nodal involvement (75%). DLTs (myelosuppression) occurred in 7 pts (3 in A, 4 in B) and were unrelated to pembro. Gr 3-4 treatment-related AEs (TRAEs) occurred in 8 pts in A and 10 pts in B; none were fatal. One pt in A and 2 pts in B discontinued for a TRAE (2 ALT elevations with pembro; 1 DVT with chemo). Overall ORR (CR+PR) before surgery was 80% (90% CI, 49-96) in A and 100% (90% CI, 74-100) in B. ypT0/Tis pCR rate was 70% (90% CI, 39-91) in A and 100% (90% CI, 74-100) in B; ypT0 ypN0 pCR rate was 50% (90% CI, 22-78) in A and 90% (90% CI, 61-100) in B; and yT0/Tis ypN0 pCR rate was 60% (90% CI, 30-85) in A and 90% (90% CI, 61-100) in B. Conclusions: Preliminary data suggest that pembro + chemo as neoadjuvant therapy for TNBC results in manageable toxicity and promising antitumor activity. Clinical trial information: NCT02622074.

Radiological-pathological correlation study of hepatocellular carcinoma undergoing local chemoradiotherapy and surgery.

Optimal response criteria and assessment timing were investigated through radiologic-pathologic correlation in hepatocellular carcinoma (HCC) treated with localized chemoradiotherapy (CRT). We reviewed 19 consecutive HCC patients who underwent surgical resection after radiotherapy and concurrent hepatic arterial infusion chemotherapy. Patients who received transarterial chemoembolization before RT or surgery were excluded from evaluation. Tumor diameters and total and enhancing tumor volumes were measured from CT images obtained 1, 3, 6, and 9 months after CRT. Percent changes calculated using size (RECIST and WHO) and enhancement criteria (mRECIST and EASL) were correlated with percent changes in total and enhancing tumor volumes, and with percent viable tumor in surgical specimens. Median time between CRT and resection was 4.1 months (range, 1.5-15.4 months). CR and PR rates were 0 and 68% by RECIST, 0 and 63% by WHO, 53% and 37% by mRECIST, and 53% and 42% by EASL. Pathologic CR (pCR) rate was 52.6%. Radiologic criteria showed strong correlation with tumor volumes at 1 and 3 months after CRT; at 6 months, however, size and enhancement criteria showed strong correlation only with total and enhancing tumor volumes, respectively. Enhancement criteria were better predictors of pathologic response at all times including preoperative evaluation (RECIST: R(2) = 0.303, P = 0.015 and WHO: R(2) = 0.366, P = 0.006 vs. mRECIST: R(2) = 0.760, P < 0.0001 and EASL: R(2) = 0.768, P < 0.0001). Time interval >6 months before resection showed significant correlation with pCR (P = 0.013). We recommend using enhancement criteria in assessing tumor viability, especially if the tumor was to be resected <6 months after CRT.

O1-15-2 - Tp53 Signature Predicts the Efficacy of Neoadjuvant Chemotherapy (Nac) of Breast Cancers

Background: We have reported that status of the TP53 mutation is predictable by expression profile of 33 genes (TP53 signature) in breast cancer and that the TP53 signature can predict overall survival and recurrent free survival of early breast cancer (Cancer Sci. 99: 324-32, 2008). The aim of this study is to determine whether the TP53 signature can also predict both the efficacy of NAC and the recurrence after surgery in breast cancer.Methods: An NAC cohort (E-GEOD-25066) that contains 508 patients with HER2 negative breast cancer is used. Among the genes previously used TP53 signature, 20 up-regulated and 5 down-regulated genes in breast cancer with TP53 mutation were selected and the TP53 status was determined by the ratio of the sum of expression values of 20 up-regulated genes to that of the 5 down-regulated genes. If the ratio (down / up) was less than 0.325, the tumor was determined as aTP53 mutant. If it was greater than or equal to 0.325, the tumor was determined aTP53 wild.Results: Fifty percent (255 of 508) of tumors was determined as a TP53 mutant. The pathological CR (pCR) rate is significantly higher in TP53 mutant tumor than in TP53 wild-type tumor (34.7% vs 5.4%). In Stage I and II patients (n = 280), recurrence free survival (RFS) was significantly better in patients with TP53 wild type tumor (P = 0.0018). Patients with TP53 mutant tumor not leading to pCR (mt / non-pCR) showed significantly worse RFS than the other patients (P < 0.001). In ER positive and triple negative subgroup, RFS were also worse in patients with mt / non-pCR.Conclusions: TP53 signature has the ability to predict the efficacy of NAC and recurrence after surgery in breast cancer. The TP53 signature was especially useful to predict the recurrence in combination with pCR status. Our data suggests that patients with TP53 mutant tumor not leading to pCR after NAC may need adjuvant chemotherapy after surgery to improve prognosis of these patients.

The efficacy of superselective intra-arterial chemo-radiotherapy for cervical neck lymph node metastases

We report herein on 32 cases of head and neck carcinoma with cervical lymph node metastases treated by radiotherapy and concomitant intraarterial cisplatin (RADPLAT) from April 2009 to May 2013. N3 cases revealed residual disease of the cervical lymph nodes in 7/9 cases. Among the 22 patients excluding N1 and N3 cases, the pathological CR rate was 63.6%. Among the 13 patients in whom the anticancer drug was directly infused into the cervical lymph nodes, the pathological CR rate was 76.9%, whereas in the 9 patients without direct infusion of the cervical lymph nodes, the pathological CR rate was 44.4%. Therefore, we recommend the direct infusion into cervical lymph node metastases for not only N3 cases but also N2 cases if a feeding artery is identified easily. When clinical examination after RADPLAT leads to suspected residual disease, neck dissection should be adapted. If the clinical examination leads to a diagnosis of CR, we recommend a biopsy of the original cervical lymph nodes because the cases which we diagnosed as CR revealed residual disease of the cervical lymph nodes in 4/16.

Abstract P1-08-05: The prognostic significance of Ki-67 expression before and after neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes

Abstract Purpose This study was conducted to analyze the Ki-67 expression before and after neoadjuvant chemotherapy and clinical pathology characteristics of different biological breast cancer phenotypes at our center. A correlation study was performed between Ki-67 index change and the prognosis of different biological breast cancer phenotypes and prognosis in Northern China. Methods A regression analysis was performed on 213 patients with invasive breast carcinoma accepted NAC admitted to Tianjin Medical University Cancer Institute and Hospital of Breast Surgery from January 2007 to April 2008. These patients were subtyped by hormone receptor status and HER2 status.The Ki67 index (percentage of Ki67-positive cancer nuclei) were determined immunohistochemically. The prognostic value of the Ki-67 index for different biological breast cancer phenotypes disease-free survival (DFS) and overall survival (OS) was investigated by use of Kaplan–Meier curves and multivariable Cox regression. Results The overall pathologic CR (pCR) rate, defined as no invasive residuals in breast and axilla, was 17.8%. The highest pCR rate of 32.1% was observed in patients with HR-/HER2+ tumors, which is 11.4%, 20.0% and 26.2% in HR+/HER2- HR+/HER2-,HR+/HER2+and HR-/HER2- tumor respectively(P = 0.024).The Ki-67 expression of pre-NAC and post-NAC have prognostic significance in HER2- breast cancer, which have not significance different in HER2+ breast cancer:The best Ki-67 idex cut point of pre-NAC and post-NAC to predict long-term survival was respectively 20% and 10% in HR+/HER2- breast cancer. Moreover, patients with a higher Ki-67 index (&amp;gt; cut-off point) showed significantly lower 5year-DFS/OS rates compared with those whose Ki-67 index were below cut-off point. In addition, Ki-67 index of post-NAC were independent prognostic factors for 5 year disease-free survival of patients with HR+/HER2- breast cancer. Ki-67 change between pre- and post-NAC as an independent prognostic factor independently predict prognosis in the patients who have not achieved pCR, while the best cut-off point was 18%. Conclusion The Ki-67 index of pre- and post-NAC could predict the prognosis in the patients with HER2- breast cancer. Moreover, the Ki-67 change between pre- and post-NAC was an independent prognostic factor in the patients who have not achieved pCR. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-05.

Neoadjuvant DCF in resectable esophageal cancer: Single-center experience.

124 Background: Despite improvement in surgical techniques and peri-operative care, the 5 yr OS in esophageal cancer is 10%. RCTs comparing NACT to surgery alone have demonstrated a significant increase in median survival from 13 months to 17 months. We aimed at studying impact of DCF NACT. Methods: Retrospective analysis of prospective database of patients with locally advanced esophageal cancer. All patients had ECOG performance status of 0 to 1, with no uncontrolled comorbidities. Chemotherapy consisted of 3 cycles of standard DCF (Docetaxel 75 mg/m2 on day1, Cisplatin 75 mg/m2 on day 1 and 5 fluorouracil 750mg/m2 as a continuous intravenous infusion for 5 days) with growth factors and prophylactic antibiotics were administered. Following chemotherapy, a restaging scan was performed. If disease was deemed resectable, surgery was performed. Patients were followed up after surgery and then 3-monthly. Toxicity was graded according to CTCAE v.4.03, response was calculated as per RECIST 1.1 and statistics were by simple percentages. OS and PFS calculated by Kaplan–Meier method. Results: Between February 2010 and April 2012, there were 22 patients who received neoadjuvant DCF chemotherapy. Male to female ratio 1.2. Median age 44.5 years (range: 32- 63 yrs). 20 patients had squamous histology and 2 had adenocarcinoma. Middle one third of esophagus was the primary site in 54.5%. Response rate: CR-32%, PR-55%, SD-9% and PD-4.5%. 16 (73%) patients underwent R0 resections, 1-R1 resection, 3-R2 resection, 1 was deemed unresectable preoperatively and treated with chemo-radiotherapy and 1 had CR but surgery was postponed due to hyperthyroidism. 7 patients (31.8%) had pathologic complete remission. Toxicities grade (3/ 4) included neutropenia (77.3%), febrile neutropenia (86.4%), diarrhea (45.5%), hyponatremia (45.5%), fatigue (18.2%), and mucositis (13.5%). Dose reduction due to toxicities was done in 50% patients. At a median follow up period of 13 months (range 4-31 months), the PFS is 81.8% and OS is 90.9%. Conclusions: Response rate to DCF is 87%, with a pathologic CR rate of 32%. The complete responders appear to have a durable benefit; all remain disease free at the last date of follow up. Our initial data looks promising but follow up period is short.

377 - Clinical, Molecular Profiles and Response to Neoadjuvant Chemotherapy in Patients with Locally Advanced Breast Cancer: An Indian Experience

ABSTRACT Background Breast cancer is now the most common cancer in many parts of India and Locally advanced breast cancer (LABC) accounts for nearly one thirds of cases. Advanced stages at presentation are attributed to late diagnosis and biologically aggressive disease in Indian women. Materials and methods Patients diagnosed with inoperable LABC at the Gujarat Cancer and Research Institute, Ahmedabad, India were included in the study. Baseline evaluation included clinical assessment, testing for Estrogen Receptor(ER), Progesterone Receptor (PgR), Her2Neu and serum Vascular Endothelial Growth Factor (S. VEGF). First line NACT was FAC or FEC. Patients were assessed clinically and radiologically at the end of 3 cycles for response evaluation (mammography or ultrasonography of breast). S. VEGF levels were repeated at the end of 3 cycles of NACT or before surgery. All resectable patients underwent a Modified Radical Mastectomy. Unresectable patients were offered taxanes based chemotherapy or supportive care. Results Fifty seven patients with LABC were included. Fifty Four patients (95%) received NACT. Mean age at diagnosis was 49 years. ER was positive in 51%, PgR in 35% and Her2Neu in 47%. Mean baseline S. VEGF was 463.4pg/ml. Baseline S. VEGF was higher in patients who were hormone receptor or Her2Neu positive. The overall clinical response rate [complete response (cCR) + partial response (cPR)] to the initial anthracycline based chemotherapy was 63%, cCR was 0%. Resectability rate after 1st line NACT was 77%. Pathological CR (pCR) rate was 4%. There was no significant reduction in S. VEGF levels after NACT, irrespective of clinical or pathological responses. Nearly 17% of patients were lost to follow up at various stages of treatment including three patients who refused any kind of treatment. Conclusions This study analyzes clinical and molecular profile of patients with LABC in India which differs from that seen in developed nations. High treatment drop-out rates may reflect treatment related toxicities, socio-cultural and logistical issues in a big developing country. Responses to anthracycline based NACT are comparable to the results reported from similar centers. Disclosure All authors have declared no conflicts of interest.

Customization of treatment for patients with esophageal adenocarcinoma (EAC) who achieve clinical complete response (cCR) after chemoradiation using initial standardized uptake value (iSUV) of 18f-fluorodeoxyglucose PET.

4069 Background: Patients with localized esophageal adenocarcinoma (EAC) receive preoperative chemoradiation followed by surgery (trimodality [TM] therapy) or definitive chemoradiotherapy (bimodality [BM] therapy) based on comorbidities and tumor geography. However, we cannot individualize recommendations beyond these parameters. We hypothesized that iSUV could customize therapy. Methods: Data source was our prospective database of fully staged EAC patients (2002-2010). All patients had a cCR (post-chemoradiation negative biopsy and post-chemoradiation physiologic uptake on PET). iSUV cut-point was derived by recursive partitioning. Results: For 323 cCR patients, the median follow-up was 40.8 months. 206 (63.8%) patients had TM and 117 (36.2%) had BM therapy. Median OS of TM patients and BM patients were 94.8 months (95 % CI; NA-NA) and 36.5 months (95% CI; 30.5-42.4; p&lt;0.001), respectively. Similar differences were observed in RFS (p&lt;0.001). The median iSUV was 9.4 (range, 0-58.0). Intriguingly, TM patients with iSUV of &gt;6 had a better OS (94.8 months; 95% CI; 39.1-150.5) and RFS (94.8 months; 95% CI; 18.2-171.4) compared to BM patients with iSUV of &gt;6 OS (31.4 months; 95% CI; 21.0-41.9; p=&lt;0.001) and RFS (17.2 months; 95% CI; 14.5-19.8; p&lt;0.001). However, the prognosis of TM and BM cCR patients with iSUV &lt;6 was similar (OS, p=0.62 and RFS, p=0.46). The pathological CR (pathCR) rate in TM patients was similar irrespective of iSUV of ≥6 (27.1%) vs. iSUV &lt;6 (28.6%; p=0.85). Conclusions: Our unique data provide an insight into the fate of cCR EAC patients by iSUV. Patient with iSUV ≥6 dramatically benefit from surgery and TM therapy is encouraged. iSUV and pathCR do not correlate. iSUV can customize therapy of localized EAC patients.

Chemoradiation with FOLFOX plus cetuximab in locally advanced cardia or esophageal cancer: Final results of a GERCOR phase II trial (ERaFOX).

4072 Background: Chemoradiotherapy (CRT) for locally advanced cardia and esophageal cancer is based on 5-FU combined with cisplatin, which could be favourably replaced by oxaliplatin (Ox). Cetuximab (C) has demonstrated synergism with both radiotherapy (RT) and platinum-based chemotherapy. ERaFOX trial was evaluating the safety and efficacy of the addition of C to CRT with FOLFOX. Methods: Main inclusion criteria were: stage III squamous cell or adenocarcinoma of the esophagus or gastroesophageal junction; WHO PS 0-1; age 18-80 years; weight loss <15% in the last 6 months. Patients (pts) received 2 cycles of FOLFOX induction therapy (Ox 85 mg/m2/d1, folinic acid 400 mg/m2/d1, 5-FU 2,400 mg/m2/d1-2, q2w) plus C (first infusion 400 mg/m2 then 250 mg/m2, q1w), then RT 50.4 Gy (1.8Gy/d x 28 fractions) with FOLFOX plus C (same doses, except 5-FU 1,800mg/m2/d1-2). Tumor evaluation was performed at the end of CRT (RECIST and endoscopic ultrasonography). The primary endpoint was overall response rate (ORR), with a 50.0% threshold for efficacy (Simon Minimax two-stage design). Results: From Nov 2007 to Feb 2010, 80 pts were enrolled in 12 centers. The characteristics of the 79 eligible pts were (1 ineligible pt for stage IV disease): male/female 60/19, median age 63 (23-79), PS 0/1/ND 47/31/1, squamous/adenocarcinoma/undifferentiated 53/25/1; esophagus/cardia 74/5; median daily caloric intake 1720 Kcal (550-3160). 74 pts were treated by CRT (5 pts experienced anaphylaxis during the first cetuximab infusion). ORR (ITT) was achieved in 61 pts (77.2%; 95% CI 67.9-86.5). After a median follow-up of 19.4 months, median PFS/OS were 13.8/21.6 months. Nineteen (24.0%) pts experienced primitive resection. Pathological CR rate will be presented at the meeting. Most frequent grade 3-4 toxicities were: neutropenia (28.4%), dysphagia-esophagitis (13.5%), rash (10.8%) and allergy (8.9%). One toxic death (1.3%) occurred after CRT related to esophagitis with GI bleeding. Conclusions: Threshold for efficacy was reached with an ORR of 77.2%. Chemoradiotherapy with FOLFOX plus cetuximab should be compared to the same strategy without cetuximab in pts with locally advanced cardia or esophageal cancer.

A pilot study of FOLFOX with or without radiation in treating patients with locally advanced rectal cancer.

e14147 Background: Preoperative 5FU-based chemo plus radiation therapy is standard for patients (pts) with locally advanced rectal cancer (RC). We conducted a pilot feasibility trial of adding the third generation drug oxaliplatin to the standard treatment to see whether the treatment outcome can be improved and the place of RT can be replaced. Methods: Pts with clinical stage II-III resectable RC were treated with 4 cycles of FOLFOX (CT) or 5 cycles of FOLFOX with radiation (2Gy/fraction, total 46Gy, CRT). Pts then were re-imaged and had repeat colonoscopy with MRI to assess the primary tumor response. Those with progressive disease in FOLFOX group were to be referred for pre-op 5FU plus RT, followed by surgery, and those with clinical regression/stable disease were to have surgery without pre-op RT. Post-op 5FU plus RT was planned for any pts who did not have an R0 resection. 7-8 cycles of FOLFOX were recommended in Post-op chemo. The primary endpoint was the objective response rate. Secondary outcomes were the pathologic CR rate, the 3-year disease free survival and local recurrence (LR) rate. Results: Of 51 pts were accrued since April 2007, 25 have completed pre-op RCT, 26 who have completed pre-op CT, 7 of 25 RCT pts (28%) had a path CR, however no pts with CT had path CR, the difference was significant. ORR was 92%, 80.8% and disease control rate (DCR) 96%, 96.2% respectively, there was no difference between the two groups. The quality of life was better and the in-hospital time was shorter the CT alone group. Local and distant recurrence rate data are immature. But so far, no recurrence was found in the CT group, which indicated the potential benefit of CT alone in the adjuvant setting. Conclusions: Preliminary results of this pilot trial depicts that preoperative FOLFOX alone without RT achieves a high rate of DCR. And FOLFOX with RT achieves a high rate of CR. Further phase III trials are warranted.