Background

Neoadjuvant chemoradiotherapy (CRT) is the standard of treatment for locally advanced rectal cancer, but it delays administration of systemic chemotherapy, leading to high incidence of distant metastases. To enhance systemic chemotherapy and avoid the damage of radiation, full dose of neoadjuvant chemotherapy regimens with mFOLFOXIRI or mFOLFOX6 were both under investigation. Here, we aimed to compare the efficacy of preoperative chemotherapy with mFOLFOXIRI versus mFOLFOX6 in locally advanced rectal cancer.

Methods

Prospectively maintained databases of patients from two clinical trials (NCT01211210 and NCT02217020) underwent preoperative treatment for locally advanced rectal cancer in a single center were included. Those had received mFOLFOXIRI or mFOLFOX6 chemotherapy alone preoperatively was selected for this study, including 90 patients with mFOLFOXIRI and 119 patients with mFOLFOX6. All patients had undergone total mesorectal excision. A comparative analysis was performed after the implementation of propensity score matching on the 2 main cohorts (mFOLFOXIRI and mFOLFOX6).

Results

A total of 209 patients were enrolled in the study. After propensity score matching, 180 patients were selected. 90 patients were comparable in the two groups. Higher pathologic complete response rate was observed in mFOLFOXIRI group than that of mFOLFOX6 group (16.7% vs. 5.6%, p=0.03). However, the tumor downstaging rate was comparable in this two group (41.1% vs. 37.8%, P=0.76). The anal preservation rate was similar between the two groups (87.8% vs. 89.2%). But higher incidence of grade 3/4neutropenia (42.2% vs. 10%, P<0.001) was shown in mFOLFOXIRI alone group than that of mFOLFOX6 group.

Conclusions

Preoperative mFOLFOXIRI alone showed higher pCR rate than that of mFOLFOX6. The tumor downstaging rate was comparable between the two regimens. But the adverse events were more common in mFOLFOXIRI group. The intensive regimen might only fit for some highly selected patients. Whether the intensive regimen would improve the survival is unknown. Further follow-up is needed.

Clinical trial identification

The study cohorts were from two clinical trials (NCT01211210 and NCT02217020) .

Background

Modified XELIRI (irinotecan 200 mg/m² on day 1, capecitabine 1600 mg/m² on days 1–14 every 3 weeks) has shown non-inferiority of overall survival compared with FOLFIRI based on “Asian XELIRI ProjecT” (AXEPT) as second-line chemotherapy for patients with mCRC. In this preplanned analysis of the AXEPT trial, we evaluated the relationship between UGT1A1 genotype and the efficacy and safety of irinotecan-based chemotherapy.

Methods

Patients were randomized (1:1) to receive standard FOLFIRI ± bevacizumab or modified XELIRI ± bevacizumab. Baseline UGT1A1 genotype was prospectively examined and patients were categorized into wild-type (*1/*1), heterozygosity (*28/*1 or *6/*1), and homozygosity (*28/*28, *6/*6, or *28/*6) groups. Irinotecan at a reduced dose of 150 mg/m² was administered for patients with homozygosity in both treatment arms. Assessed endpoints included overall survival, progression-free survival, response rate, and safety.

Results

UGT1A1 genotype was available for all 650 randomized patients (wild type, 309 [47.5%]; heterozygosity, 291 [44.8%]; and homozygosity, 50 [7.7%]). Median overall survival was 15.9, 17.7, and 10.6 months for wild type, heterozygosity, and homozygosity, respectively (p = 0.040 for wild type vs. heterozygosity and p = 0.048 for wild type vs. homozygosity). Median progression-free survival was 7.1, 8.6, and 5.3 months, respectively. The overall response rate was 22.0%, 22.7%, and 8.5%, respectively. Grade 3-4 toxicities of special interest were neutropenia (26.7%, 32.6%, and 34.0% for wild type, heterozygosity, and homozygosity, respectively), febrile neutropenia (3.7%, 3.3%, and 6.4%), and diarrhea (3.0%, 8.4%, and 0%).

Conclusions

Modified XELIRI with irinotecan 200 mg/m² was well tolerated in patients with wild type and heterozygosity of UGT1A1 genotype, and both FOLFIRI and XELIRI with a reduced irinotecan at 150 mg/m² were safe for patients with homozygosity. An unfavorable trend toward survival was identified in patients with homozygosity compared to those with wild type, whereas a favorable trend was seen in patients with heterozygosity.

Clinical trial identification

NCT01996306; UMIN000012263.

Legal entity responsible for the study

Epidemiological and Clinical Research Information Network.

Funding

Chugai Pharmaceutical. and F Hoffmann-La Roche.

Disclosure

K. Muro: Grants: Ono, MSD, Daiichi Sankyo, Kyowa Hakko Kirin, Shionogi Pharmaceutical, Pfizer, Gilead Sciences, Merck Serono; Personal fees: Chugai, Taiho Pharmaceutical, Takeda Pharmaceutical, Bayer, Eli Lilly. T.W. Kim: Research fund: AstraZeneca Pfizer Merck Serono. M. Kotaka: Honoraria for lecturing: Chugai Pharmaceutical Co.,Ltd.; Yakult Honsha Co.,Ltd.; Takeda Pharmaceutical Co.,Ltd.; Eli Lilly Japan K.K. J.B. Ahn: Financially supported: Chugai Pharmaceutical Co., Ltd., F. Hoffmann-La Roche Ltd. T. Kato: Chugai Pharmaceutical Co., Ltd,Takeda Pharmaceutical Company Limited, Eli Lilly and Company, Bayer Yakuhin, Ltd.,Sanofi S.A.,Yakult Honsha Company, Limited. S. Morita: Honorarium: Chugai, Yakuruto. S. Junichi: Consultant fee: Takeda Pharmaceutical Co. Inc. Honoraria: Chugai Pharmaceutical Co. Inc., Tsumura Pharmaceutical Inc., Nihon Kayaku Co. Inc. All other authors have declared no conflicts of interest.

Background

BTCs are a group of cancers with poor prognosis and few treatment options, encompassing intrahepatic (IHCC) and extrahepatic (EHCC) cholangiocarcinomas, gallbladder carcinoma (GC), and ampullary carcinoma (AC). For 2L chemotherapy, no standard of care exists, and overall response rates (ORRs) are <10%. M7824 is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of TGF-β receptor II (a TGF-β “trap”) fused to a human IgG1 mAb against PD-L1. We report the safety and efficacy of M7824 in Asian patients (pts) with pretreated BTC.

Methods

Pts who progressed after ≥1 line of chemotherapy receive M7824 1200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal in this expansion cohort of the ongoing phase 1, open-label trial NCT02699515. The primary objective is safety/tolerability; secondary objectives include best overall response per RECIST v1.1.

Results

At 39 wk median follow-up, 30 pts received M7824 for a median of 8.9 (range, 2.0–57.6) wk; 5 pts were on active treatment. Treatment-related adverse events (TRAEs) occurred in 60% of pts; most common were maculopapular rash and pyrexia (13.3% each), as well as lipase increase and rash (10.0% each). 10 pts (33.3%) experienced grade ≥3 TRAEs, including 3 grade 5 (1 septic shock [bacteremia, unknown etiology; 249 and 14 days after first and last dose, resp.], 2 due to interstitial lung disease [ILD; 1 on treatment post 3 doses, 1 after 6 mo of initial ILD diagnosis and last dose). Objective responses were observed in 7 pts (ORR, 23.3%; IHCC, 4/10 pts; EHCC, 1/7 pts; GC, 2/12 pts; AC, 0/1 pts), with 1 durable complete response (5.6+ mo) and 4/6 partial responses (PRs) ongoing at data cutoff (0.7+, 2.8, 3.9+, 5.5+, 5.6, and 6.9+ mo). 1 additional pt with GC had an ongoing PR for 7.6+ mo after initial pseudoprogression.

Conclusions

M7824 monotherapy has an acceptable safety profile and promising efficacy in Asian pts with pretreated BTC, with durable responses in 8/30 pts (27%; includes 1 pt with pseudoprogression) across BTC subtypes, including responses in pts with IHCC, EHCC, and GC (ORRs, 40%, 14%, and 17%, resp.).

Editorial acknowledgement

Medical writing support was provided by ClinicalThinking and was funded by Merck KGaA, Darmstadt, Germany.

Clinical trial identification

NCT02699515.

Legal entity responsible for the study

Merck KGaA.

Funding

Merck KGaA.

Disclosure

C. Yoo: Research Funding CKD Pharm, Shire, Honoraria: Bayer, Ipsen. D-Y. Oh: Research Funding AstraZeneca. M. Kudo: Research Funding Otsuka, Taiho, Abbvie, Daiichi Sankyo, Medico’s Hirata, Astellas Pharma, Chugai, BMS, Takeda, Sumitomo Dainippon, MSD, Eisai, Bayer; Lecture: MSD, Bayer, Eisai, Ajinomoto; Advisory consulting: Eisai, Bayer, Kowa, MSD, BMS, Chugai, Taiho, ONO. M. Ueno: Research funding, Honoraria: Taiho Pharmaceutical, Shire, AstraZeneca, Ono Pharmaceutical; Research Funding Daiichi Sankyo, Eisai, MSD, Merck Serono, NanoCarrier, Dainippon Sumitomo Pharma, Incyte; Honoraria: Yakult Honsha, Novartis, Lilly, Teijin Pharma. S. Kondo: Research Funding MSD, Bayer, ASLAN, Pfizer, AZ, Lilly. L-T. Chen: Research funding, honoraria: Novartis, TTY, SyncorePharm; Research Funding Merck Serono, Polaris, Pfizer, BMS. Honoraria: Ono, Eli Lilly, MSD, PharmaEngine, AstraZeneca, Ipsen, Astellas; Patents & Royalties: ENO-1 mAb/HuniLife; Board of directors/Advisory committee member: PharmaEngine. M. Osada: Merck Serono, Tokyo, Japan. C. Helwig: Merck KGaA, Darmstadt, Germany. I. Dussault: EMD Serono. M. Ikeda: Research funding, Honoraria: Bayer Yakuhin, Yakult, Taiho, Eli Lilly Japan, Eisai, Chugai, BMS; Research Funding Kyowa Hakko Kirin, Ono, AZ, Zeria, Baxter, Merck Serono, Kowa, Nano Carrier, ASLAN; Honoraria: Novartis, Abbott Japan, Daiichi-Sankyo, Otsuka, Nobelpharma; Board of directors/Advisory committee member: Nano Carrier, Bayer Yakuhin, Eisai, Kyowa Hakko Kirin, Novartis Pharma, Shire, MSD. All other authors have declared no conflicts of interest.

Background

Atezolizumab (atezo; anti–PD-L1) has proven efficacy in large global studies. To better understand the benefit of atezo in tumours that are highly prevalent in China, a basket trial was conducted in Chinese patients (pts) with locally advanced or metastatic solid tumours.

Methods

This phase I study (NCT02825940) consisted of a PK phase (solid tumour) and an extension phase (HCC, EC, NPC or GC) in pts who had exhausted all available standard treatment (tx) options. Pts received 1200 mg atezo IV every 3 weeks until loss of clinical benefit. Study objectives were to evaluate PK, safety, and efficacy by investigator-assessed objective response rate (ORR), duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1, as well as overall survival (OS).

Results

As of 1 Apr 2018, 94 pts with median follow-up of 10.6 mo (range, 0+ to 19+) were evaluable. 85 pts (90%) received prior systemic tx for recurrent/metastatic disease. PK parameters from the PK cohort will be presented. ORR results are presented in the table. Median DOR for all responders was not reached. Among 43 pts (46%) treated beyond progression, 3 pts (2 GC, 1 PK) achieved new partial responses. The median PFS was 2.8 mo (95% CI: 1.4, 3.8) in the 94 overall pts and 2.8 mo (95% CI: 1.4, 4.4) in the 42 PD-L1+ pts. Median OS was 8.4 mo (95% CI: 6.4, 12.4) overall and 11.3 mo (95% CI: 5.6, NE) in PD-L1+ pts. All grade (Gr) tx-related adverse events (TRAE) occurred in 78 of 94 pts (83%). The most common Gr 3-4 TRAEs were hyponatremia (5%), aspartate aminotransferase (3%) and lipase increased (3%). 2 pts with EC (2%) had a Gr 5 TRAE (fistula and unexplained death).Table: 154O

Efficacy

Conclusions

Efficacy was seen in multiple solid tumour types, with a tolerable safety profile and a consistent PK profile in line with previous global studies. Atezo will be further studied as monotherapy and in combination with other agents in tumour types highly prevalent in China, particularly in HCC.

Editorial acknowledgement

Medical writing assistance for this abstract was provided by Steffen Biechele, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.

Clinical trial identification

NCT02825940.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

Y-C. Chen: Employment: Genentech/Roche. J. Huang, T. Xu, W. Hsu, J. Shi: Employment: Roche. All other authors have declared no conflicts of interest.

Background

TAS-120, an irreversible FGFR1–4i, has demonstrated preclinical efficacy in tumour models bearing FGFR aberrations. A phase 1 study of TAS-120 (8–24 mg QD) in adult patients (pts) with advanced solid tumours (NCT02052778) found the maximum tolerated dose to be 20 mg QD. Here, we report results from pts with cholangiocarcinoma (CCA) enrolled in this study.

Methods

Pts with CCA were enrolled at 16-, 20-, and 24-mg dosing levels and were included in this analysis. FGF/FGFR status was evaluated by local institutions or commercial laboratories. Pts were treated until disease progression or unacceptable toxicity.

Results

45 pts with CCA (intrahepatic n = 41) harbouring FGF/FGFR aberrations were treated at 16 (n = 24), 20 (n = 14), and 24 mg (n = 7) QD (median age 53 y [range 29–73], 76% female, 58% ECOG PS 1, 42% ECOG PS 0). 28 pts (62%) had tumour FGFR2 gene fusions; 17 (38%) had other FGF/FGFR aberrations. All pts received prior systemic therapy; 13 received ≥1 prior reversible FGFRi. Of the 28 pts with FGFR2 gene fusions, 20 (71%) experienced tumour shrinkage and 7 achieved confirmed partial responses (cPRs; 6 remain on treatment, 1 with an ongoing cPR >1 y). The objective response rate was 25%. 15/28 (54%) pts had stable disease as best response; 7 remain on treatment. The disease control rate was 79%. Of the 17 patients with other FGF/FGFR aberrations, 3 had cPRs (all had FGFR2 rearrangements; 1 also had FGFR2 amplification). Median treatment time was 7.4 mo. Of the 13 patients with prior FGFRi treatment, 4 (3 with FGFR2 gene fusions, 1 with FGFR2 amplification) had cPRs. Treatment-related adverse events (TRAEs) of any grade included hyperphosphatemia (78%), increased aspartate aminotransferase (29%), dry skin (29%), diarrhoea (27%), and dry mouth (27%). Grade ≥3 TRAEs were reported in 23/45 (51%) pts; the most common was hyperphosphatemia (22%).

Conclusions

TAS-120 demonstrated compelling clinical activity and a manageable AE profile in pts with CCA and FGFR2 gene fusions and showed efficacy in pts with progression on prior FGFRi’s. A phase 2 study has been initiated.

Editorial acknowledgement

Editorial assistance was provided by Wendy Sacks of Scientific Connexions (Lyndhurst, NJ, USA).

Clinical trial identification

NCT02052778.

Legal entity responsible for the study

Taiho Oncology, Inc. and Taiho Pharmaceutical Co., Ltd.

Funding

Taiho Oncology, Inc. and Taiho Pharmaceutical Co., Ltd.

Disclosure

F. Meric-Bernstam: Grant/research support: Novartis, AstraZeneca, Taiho, Debiopharm. R.K. Kelley: Consulting/advisory: Bayer AG, Debiopharm, Agios, AZ, BMS; Research Funding Eli Lilly, Exelixis, Regeneron, Celgene, Tekmira, Sanofi, Novartis, BMS, MedImmune, Merck Sharp & Dohme, Agios, AZ, Adaptimmune Therapeutics. C. Hierro: Research: Bayer; Travel, accomodation: Roche, Lilly. R. Winkler: Employment: Taiho Oncology, Inc.; Travel, accommodations, expenses: Taiho Oncology, Inc, H. He: Full-time employment: Taiho Oncology. J. Huang: Employment: Taiho Oncology, Inc. L. Goyal: Consulting: Debiopharm. All other authors have declared no conflicts of interest.