Palmar-plantar Erythrodysaesthesia Syndrome Research Articles

A randomized, multi-center, phase 2 study of ivaltinostat (Ival) plus capecitabine (Cape) versus capecitabine alone in the maintenance setting in patients with metastatic pancreatic adenocarcinoma (mPDAC).

TPS4206 Background: Front-line chemotherapy for patients (pts) with advanced or mPDAC typically consists of mFOLFIRINOX or gemcitabine/nab-paclitaxel given until disease progression or intolerable toxicity. For pts with durable disease control on front-line treatment, maintenance therapy that can effectively delay disease progression while preserving quality of life with minimal cumulative toxicity is highly desirable. Ivaltinostat (ival) is a pan-histone deacetylase inhibitor that increases histone acetylation, suppresses PDAC cell proliferation, and promotes apoptosis in PDAC cell lines. Preclinical data demonstrated synergy with 5-FU/cape in mouse models. RP2D of the Phase 1b combination study of ival and cape in advanced pancreatic cancer was ival 250mg/m2 IV on days 1 and 8 with cape 1000mg/m2 po days 1-14 of a 21-day cycle. Both ival and cape treatment-related AEs >15% were fatigue, nausea, diarrhea, and decreased appetite. Palmar-plantar erythrodysaesthesia syndrome was also commonly observed; all events were attributed to cape. PK and PD demonstrated dose proportionality. Overall and progression-free survival (PFS) were immature, but 70% of pts who enrolled with measurable disease had stable disease as best response. Several pts remained on study with the longest duration of response about 10 months, as of the data cut off for ASCO GI 2024. Based on this data, a randomized phase 2 study is being conducted comparing the combination of ival and cape versus cape alone in the maintenance setting for pts with mPDAC after first line FOLFIRINOX, mFOLFIRINOX or NALFIRINOX therapy. Methods: Key eligibility criteria for the randomized Phase 2 study include: mPDAC; no evidence of disease progression following at least 16 weeks of front-line FOLFIRINOX or NALIRIFOX at full or modified doses; ECOG PS 0-1; and no known germline BRCA1/2 mutation. A total of 52 pts will be randomized 1:1 to receive cape with or without ival until disease progression, with tumor assessments occurring at 6-week intervals. The primary endpoint is investigator-adjudicated PFS, and the primary analysis will compare PFS distributions in the ival/cape and cape alone arms using a one-sided log rank test with an alpha=0.10. The assumed 6-mo PFS rates are 35% (cape), based on historic data, and 60% (ival/cape), corresponding to an HR of 0.487. Enrollment in the phase 2 study began in January 2024 across multiple sites in the US. Accrual is anticipated to complete 4Q2024. Clinical trial information: NCT05249101 .

Abstract LB_A13: Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer

Abstract Background: The MCT inhibitor CYT-0851 potently inhibits MCT1, has activity against MCT4, and blocks lactate transport resulting in cell death in glycolytic cancer cells. In an in vitro CRISPR screen, thymidylate synthetase was a significant hit in 2 resistant cell models, sensitizing them to CYT-0851. Follow-up in vitro combination studies showed that CYT-0851 synergized with 5-FU to inhibit cancer cell growth. Monotherapy clinical activity of CYT-0851 has been reported previously in lymphoma and solid tumors. In the phase 1 dose escalation trial of CYT-0851 plus cape, 400 mg was identified as the recommended phase 2 dose. In three phase 2 trials, cape had a RECIST response rate of 5-8% in ovarian cancer. Methods: An expansion cohort of 10 patients (pts) with platinum resistant advanced ovarian cancer were treated with CYT-0851, 400 mg QD in combination with cape, 1000 mg/m2 PO BID x 14 days every 21 days and were evaluable. One additional pt treated at the 300 mg dose level was evaluable and added to the analysis. The primary objective was safety, and secondary objectives were pharmacokinetics and preliminary anti-tumor activity by RECIST. Results: As of Aug 21, 2023, 11 pts were treated and evaluable, 9 white, 1 African American black, and 1 American Indian or Alaskan native, with a median age of 64 (range 52-76). Median prior therapies were 6 (range 2-14). All but one had 3 or more prior therapies. Median CYT-0851 dose compliance with continuous daily dosing was 99% (range 91– 100%). There were no treatment discontinuations or CYT-0851 dose reductions for treatment related adverse events. 7 pts (64%) experienced a treatment-related adverse event, all were Grade 1-2. There were no grade 3+ treatment related adverse events. The most common related AEs were fatigue reported in 5 pts (46%), and decreased appetite, diarrhea, nausea, palmar-plantar erythrodysaesthesia syndrome and vomiting, each reported in 2 patients (18%). Exposure of CYT-0851 in combination with capecitabine exhibits dose proportional behavior and was similar between combination therapy and monotherapy. One pt had a confirmed PR with progression on day 294, and 2 additional pts achieved a PR that has not been confirmed yet, with treatment ongoing on day 113 and 41. 7 pts had SD, and one patient PD as best response. The disease control rate was 91%. 5 Pts discontinued for progressive disease with a median of 133 days of treatment (range 43-300), and 2 withdrew consent on days 131-134. 4 patients continue therapy on days 42,47,106, and 113. Median PFS was 170 days (95% CI 79-NA). Conclusions: The oral outpatient combination of CYT-0851 and cape has demonstrated an acceptable safety and tolerability profile without any unanticipated toxicities at clinically active doses. The disease control rate of 91% and unconfirmed response rate of 27% in refractory platinum resistant ovarian cancer is promising and warrants further exploration. Furthermore, this regimen should be evaluated in other tumor types commonly treated with 5-FU, including breast and colorectal cancer. Citation Format: Elizabeth Swisher, Gerald Steven Falchook, Pamela N. Munster, Nina Beri, Kathleen N. Moore, Timothy A. Yap, David R. Spigel, Susan Doleman, William D. Bradley, Thomas J. O'Shea, Markus F. Renschler, Ryan C. Lynch. Phase 1 dose expansion results of CYT-0851, a monocarboxylate transporter (MCT) inhibitor, in combination with capecitabine (cape) in platinum-resistant ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A13.

Erdafitinib in patients with advanced solid tumours with FGFR alterations (RAGNAR): an international, single-arm, phase 2 study

FGFR alterations are reported across various malignancies and might act as oncogenic drivers in multiple histologies. Erdafitinib is an oral, selective pan-FGFR tyrosine kinase inhibitor with activity in FGFR-altered advanced urothelial carcinoma. We aimed to evaluate the safety and activity of erdafitinib in previously treated patients with FGFR-altered advanced solid tumours. The single-arm, phase 2 RAGNAR study was conducted at 156 investigative centres (hospitals or oncology practices that are qualified oncology study centres) across 15 countries. The study consisted of four cohorts based on tumour histology and patient age; the results reported in this Article are for the primary cohort of the study, defined as the Broad Panel Cohort, which was histology-agnostic. We recruited patients aged 12 years or older with advanced or metastatic tumours of any histology (except urothelial cancer) with predefined FGFR1-4 alterations (mutations or fusions according to local or central testing). Eligible patients had disease progression on at least one previous line of systemic therapy and no alternative standard therapy available to them, and an Eastern Cooperative Oncology Group performance status of 0-1 (or equivalent for adolescents aged 12-17 years). Patients received once-daily oral erdafitinib (8 mg/day with provision for pharmacodynamically guided up-titration to 9 mg/day) on a continuous 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was objective response rate by independent review committee according to Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, or Response Assessment In Neuro-Oncology (RANO). The primary analysis was conducted on the treated population of the Broad Panel Cohort. This ongoing study is registered with ClinicalTrials.gov, number NCT04083976. Patients were recruited between Dec 5, 2019, and Feb 15, 2022. Of 217 patients treated with erdafitinib, 97 (45%) patients were female and 120 (55%) were male. The data cutoff was Aug 15, 2022. At a median follow-up of 17·9 months (IQR 13·6-23·9), an objective response was observed in 64 (30% [95% CI 24-36]) of 217 patients across 16 distinct tumour types. The most common grade 3 or higher treatment-emergent adverse events related to erdafitinib were stomatitis (25 [12%]), palmar-plantar erythrodysaesthesia syndrome (12 [6%]), and hyperphosphataemia (11 [5%]). The most commonly occurring serious treatment-related adverse events (grade 3 or higher) were stomatitis in four (2%) patients and diarrhoea in two (1%). There were no treatment-related deaths. RAGNAR results show clinical benefit for erdafitinib in the tumour-agnostic setting in patients with advanced solid tumours with susceptible FGFR alterations who have exhausted other treatment options. These results support the continued development of FGFR inhibitors in patients with advanced solid tumours. Janssen Research & Development.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study

Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Abstract P4-01-43: PyrotInib in combination with Capecitabine for trasTUzumab-REsistant, HER2-positive advanced breast cancer (PICTURE): a multicenter phase 2 trial

Abstract Background: Approximately 10% of patients with HER2-positive breast cancer have primary resistance to trastuzumab, leading to poor prognosis. Although several trials enrolled those hard-to-treat patients, there has been no strong evidence available for the clinical decision making. This multicenter phase 2 trial aimed to investigate the activity and safety of pyrotinib plus capecitabine only in those patients with trastuzumab-resistant, HER2-positive advanced breast cancer. Methods: Patients from 17 sites in China received pyrotinib 400 mg once a day and capecitabine 1000 mg/m2 twice a day on days 1-14 every 21 days until disease progression or intolerable toxicity. Based on the definitions used in prior clinical trials, primary trastuzumab resistance was defined as progression during trastuzumab treatment (Group 1) or within 12 months after completing trastuzumab treatment in the (neo)adjuvant setting (trastzuzumab should have been for ≥9 weeks, Group 2), or progression within 6 months after the initiation of trastuzumab treatment in the advanced setting (treatment should have been for ≥6 weeks, Group 3). The primary endpoint was progression-free survival (PFS). The study is registered with ClinicalTrials.gov, NCT04001621. Results: Between June 2019 and September 2021, a total of 100 patients enrolled; 35 (35.0%) patients had hormone receptor (HR)-positive disease, and 65 (65.0%) had HR-negative disease. Prior use of trastuzumab, pertuzumab and antibody-drug conjugate was reported in 100%, 21.0% and 2.0% of patients, respectively. By the data cutoff on July 10, 2022, the median follow-up duration was 23.4 months (95%CI, 20.5-25.6) with 66 PFS events documented. Median PFS was 11.8 months (95%CI, 8.4-15.1) in the overall population. Patients in Group 2 (n=49) had the longest median PFS of 17.8 months (95%CI, 13.8-not reached), which was significantly different from either 8.2 months (95%CI, 3.0-20.7; p = 0.001) in Group 1 (n=21) or 5.6 months (95%CI, 4.1-6.9; p &amp;lt; 0.001) in Group 3 (n=30). No significant difference in median PFS was observed in subgroup by HR status (HR-positive: 9.7 months [95%CI, 6.4-18.4]; HR-negative: 12.3 months [95%CI, 8.2-17.8]; p = 0.764). Objective response rate was 70.0% (95%CI, 60.0%-78.8%). Overall survival data was immature. The most common grade ≥3 treatment-emergent adverse events included diarrhea (24.0%), palmar-plantar erythrodysaesthesia syndrome (9.0%), neutrophil count decreased (7.0%), hypokalemia (5.0%), and decreased appetite (5.0%). No treatment-related deaths occurred. Conclusions: Pyrotinib plus capecitabine resulted in a promising PFS that crossed the pre-specified efficacy boundary in patients with HER2-positive advanced breast cancer who met the traditional definition of primary trastuzumab resistance. Patients in Group 2 had a significant longer PFS than those in either Group 1 or Group 3, highlighting the need to re-define primary trastuzumab resistance and to clarify efficacy of new anti-HER2 biologicals for each subpopulation. Citation Format: Xichun Hu, Jun Cao, Yue’e Teng, Hui-Ping Li, Lili Zhang, Quchang Ouyang, Weimin Xie, Yueyin Pan, Zhenchuan Song, Xiaoling Ling, Xiaohong Wu, Jingwei Xu, Li Li, Liping Ren, Hong Wang, Dongxian Zhou, Jing Luo. PyrotInib in combination with Capecitabine for trasTUzumab-REsistant, HER2-positive advanced breast cancer (PICTURE): a multicenter phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-43.

First-in-human, phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors.

3013 Background: TT-00420 is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B and Janus kinases (JAK) involved in cytokine signaling and receptor tyrosine kinases (FGFRs and VEGFRs) involved in the tumor microenvironment. TT-00420 has demonstrated anti-tumor activity in both in vitro and in vivo preclinical models of solid tumors, including triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA). Methods: This phase I, first-in-human, dose escalation and expansion study of TT-00420 ( NCT03654547 ) enrolled adult patients with advanced or metastatic solid tumors. Capsules in 1 mg or 5 mg formulation were administered orally once daily in 28-day cycles. Dose escalation was guided by Bayesian modeling with overdose control. The primary safety endpoints were to determine dose limiting toxicities (DLTs) and a dose recommended for dose expansion (DRDE). Secondary endpoints included pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criterion. Results: As of February 7, 2022, 48 advanced solid tumor patients were enrolled in the study, and received at least one dose of TT-00420 in 7 dose levels: 1 mg q.d. (N = 1), 3 mg q.d. (N = 1), 5 mg q.d. (N = 4), 8 mg q.d. (N = 10), 10 mg q.d. (N = 6), 12 mg q.d. (N = 20), and 15 mg q.d. (N = 6). DLTs were observed in 3 out of 40 DLT-evaluable patients, including 1 patient at 8 mg q.d. who had Grade (Gr) 3 palmar-plantar erythrodysaesthesia syndrome and 2 patients at 15 mg q.d. who both had Gr 3 hypertension. Among the twenty (20) safety evaluable patients treated at 12 mg, the DRDE, drug-related TEAEs included hypertension (n = 11, 55.0%; Gr 3: n = 6, 30%); diarrhea (n = 7, 35%, Gr 3: n = 1, 5%); mucosal inflammation (n = 7, 35%; Gr 3: n = 1, 5%); palmar-plantar erythrodysaesthesia syndrome (n = 6, 30%; Gr 3: n = 0, 0%); and vomiting (n = 4, 20%; Gr 3: n = 0, 0%). No grade 4 suspected adverse events were reported. Out of 42 patients who had at least one post-baseline scan, 7 (16.7%) had a best response of partial response (PR) and 22 (52.4%) had stable disease (SD). Among 7 PRs, 3 were CCA patients (one for each treated at 8 mg, 10 mg, or 12 mg), 2 were TNBC patients (one for each at 10 mg, or 12 mg), 1 was HER2-negative BC patient at 12 mg, and 1 was CRPC patient at 12 mg. Sustainable stable disease for six months or longer was observed in patients with colon cancer (n = 1), head and neck cancer (n = 1), and peritoneal mesothelioma (n = 1). Conclusions: TT-00420 monotherapy was well tolerated and had favorable PK characteristics. The TEAEs observed in dose escalation and dose expansion cohorts were manageable with concomitant treatment and/or dose interruptions of TT-00420 and reversible upon the discontinuation of TT-00420 treatment. Taking safety, efficacy and clinical PK into consideration, 10 mg p.o. q.d. was recommended for phase II study of TT-00420 in patients with advanced CCA. Clinical trial information: NCT03654547.

Camrelizumab plus famitinib in patients with recurrent or metastatic nasopharyngeal carcinoma: Data from an open-label, multicenter phase II basket study.

e18031 Background: Immune-checkpoint inhibitor (ICI) in combination with antiangiogenic therapy have the potential for synergistic activity. We report the results of camrelizumab plus famitinib for the treatment of recurrent or metastatic, ICI-resistant nasopharyngeal carcinoma (NPC) from an open-label, multicenter, phase II basket trial. Methods: Patients (pts) with histologically confirmed recurrent or metastatic NPC (nonkeratinizing carcinoma, WHO type II-III), who had been treated with platinum-based chemotherapy and ICIs (≤2 lines of systemic treatment), were enrolled to receive camrelizumab (200 mg intravenously every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1, and secondary endpoints included duration of response (DoR), disease control rate (DCR), time to response (TTR), progression-free survival (PFS), overall survival (OS) and safety. Results: Between Oct 23, 2020, and Sep 24, 2021, 15 recurrent or metastatic NPC pts were enrolled. Among them, 12 (80.0%) and 3 (20.0%) pts had received their prior 1st-line and 2nd-line treatment, respectively. All pts were pretreated with anti-PD-1/PD-L1 immunotherapy (toripalimab, n = 9; tislelizumab, n = 4; sintilimab, n = 1; pembrolizumab, n = 1). As of Nov 30, 2021, median time from enrollment to data cutoff was 6.3 months (range, 2.2-13.3). No pt had a complete response, 5 (33.3%) pts had a confirmed partial response, 7 (46.7%) pts had stable disease, 2 (13.3%) pts had progressive disease and 1 (6.7%) pt was not evaluable. The ORR was 33.3% (95% confidence interval [CI], 11.8-61.6), the DCR was 80.0% (95% CI, 51.9-95.7). Most pts (73.3%) experienced reduction in target lesion size from baseline, with a median change of -36.0%. The median DoR was 4.2 months (95% CI, 2.1-not reached [NR]), median PFS was 6.3 months (95% CI, 4.1-NR), and median OS has not been reached. Treatment-related adverse events (TRAEs) of grade 3 or higher were reported in 7 (46.7%) pts, mainly decreased platelet count (13.3%), decreased neutrophil count (13.3%) and palmar-plantar erythrodysaesthesia syndrome (13.3%). Treatment interruption and discontinuation due to TRAEs occurred in 11 (73.3%) and 1 (6.7%) pts, respectively. Five (33.3%) pts had serious TRAEs (grade 2 platelet count decreased, grade 2 pharyngeal necrosis, grade 2 pulmonary tuberculosis, grade 3 left ventricular dysfunction, grade 3 pharyngeal hemorrhage; n = 1 for each), and no treatment-related death was reported. Conclusions: Camrelizumab plus famitinib showed encouraging antitumor activity in recurrent or metastatic NPC patients who were resistant to ICI treatment, with an acceptable and manageable safety profile. This combination might provide a novel alternative treatment strategy in this challenging disease setting and support further investigation. Clinical trial information: NCT04346381.

Camrelizumab plus famitinib in patients with metastatic colorectal cancer: Results from an open-label, multicenter phase II basket study.

3577 Background: Dual blockade of immune checkpoint and angiogenesis is an effective strategy for multiple cancers. We initiated an open-label, multicenter phase II basket study to evaluate the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients (pts) with advanced solid tumors. Herein, we report the results from the metastatic colorectal cancer (mCRC) cohort. Methods: Pts with histologically confirmed mCRC, who had received previous irinotecan, oxaliplatin, and fluoropyrimidine combination chemotherapy, and progressed after ≥ 2 lines of systemic treatment were enrolled to receive camrelizumab (200 mg i.v. every 3 weeks) and famitinib (20 mg orally once daily). Primary endpoint was objective response rate (ORR) per RECIST version 1.1. Results: Between Jul 10, 2020, and Jul 12, 2021, of all the 44 mCRC pts enrolled, 14 (31.8%) pts had colon cancer (CC) and 30 (68.2%) pts had rectal cancer (RC). As of Nov 30, 2021, the median time from enrollment to data cutoff was 10.6 months (range, 4.7-16.7). The ORR was 13.6% (95% CI, 5.2-27.4) and the DCR was 45.5% (95% CI, 30.4-61.2) in all mCRC pts. Of them, no pts with CC achieved response; six pts with RC achieved PR, with the ORR of 20.0% (95% CI, 7.7-38.6) and the DCR of 46.7% (95% CI, 28.3-65.7). Pts with RC showed a median duration of response (DoR) of 7.1 months (95% CI, 2.3-not reached [NR]). The median overall survival (OS) was 15.2 months (95% CI, 7.2-NR) in pts with RC. Of all 44 mCRC pts, 28 (63.6%) had grade 3 or higher treatment related adverse events (TRAEs), mainly hypertension (25.0%), proteinuria (18.2%), decreased platelet count (11.4%), decreased neutrophil count (11.4%) and palmar-plantar erythrodysaesthesia syndrome (11.4%). Three (6.8%) pts discontinued any study treatment due to TRAEs. No grade 5 TRAE was reported. Conclusions: Camrelizumab plus famitinib appeared to show encouraging antitumor activity in pts with mCRC, especially in those with RC, and the safety profile of this combination regimen seemed to be manageable and consistent with single agent alone. Clinical trial information: NCT04346381. [Table: see text]

The safety, tolerability, and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with locally recurrent or metastatic triple-negative breast cancer.

1070 Background: Anti-PD-1 antibody plus chemotherapy has been demonstrated promising anti-tumor activity in patients with locally recurrent or metastatic triple negative breast cancer (TNBC). However, this regime only limited to TNBC patients with PD-L1 positive. As antiangiogenic agents could enhance the response to immune checkpoint inhibitors, we conducted this phase 2 study to assess the efficacy and safety of novel chemotherapy-free regimen of sitravatinib (targets receptor TKI against TYRO3, AXL, MERTK and VEGF family of receptors) in combination with tislelizumab (anti-PD-1 antibody) in patients with locally recurrent or metastatic TNBC regardless of PD-L1 status. Methods: Patients with locally recurrent or metastatic TNBC were included and divided into two cohorts. Patients received 70 mg (cohort A) or 100 mg (cohort B) sitravatinib QD PO and 200 mg tislelizumab IV Q3W until disease progression or intolerable toxicity. The primary endpoints included overall response rate (ORR) (cohort A and B) and rate of grade ≥3 treatment-related adverse events (AEs) (cohort B). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), duration of response (DOR), 1-year overall survival rate and safety/tolerability. In cohort A, the first statistical analysis would be performed when 12 patients were enrolled; if ≥1 of 12 patients were with confirmed response during the first stage, additional 9 patients would be enrolled to the second stage based on Simon's two-stage design. We would deem cohort A to be statistically superior to a historical control of 8% under the settings if &gt; 3 of 21 patients responded (one-sided a = 0.1 and power of 80%). Patients’ recruitment in cohort B would begin after completing the recruitment in cohort A. Results: Herein we reported the preliminary results in cohort A. Four patients were with confirmed response during the first stage, and additional nine patients were enrolled to the second stage. A total of 21 patients with 0-3 lines of prior chemotherapy were included from April 2021 to September 2021. The median age was 51 (32-66) years and 20 (95%) patients had ECOG PS 0. At data cut off 13 Jan 2022, 19 patients were alive, 11 are still on treatment. The confirmed ORR was 38.1% (95% CI, 18.1%-61.6%) based on current 21 efficacy evaluable patients. DCR was 95.2% (95% CI, 76.2%-99.9%), and median PFS was 7.0 (95% CI, 3.7 - not reached) months. 4/21 (19%) of patients experienced grade 3 treatment-related AEs. Grade 3 AEs reported in ≥5% of patients were aspartate aminotransferase increased (9.5%) and palmar-plantar erythrodysaesthesia syndrome (9.5%). No patients experienced grade 4 AEs. Conclusions: Sitravatinib combined with tislelizumab demonstrated clinically meaningful anti-tumor activity and had a manageable safety profile. Clinical trial information: NCT04734262.

Efficacy and safety of camrelizumab plus apatinib in previously treated patients with advanced non-small cell lung cancer harboring EGFR or ALK genetic aberration.

BackgroundCamrelizumab plus apatinib shows encouraging antitumor activity and acceptable toxicity in chemotherapy-pretreated patients with advanced non-small cell lung cancer (NSCLC); however, clinical benefits from this combination regimen in NSCLC patients with EGFR mutations or ALK rearrangements (EGFR+/ALK+) have not been reported. We assessed the efficacy and safety of this combined regimen in pretreated patients with advanced NSCLC and defined EGFR/ALK status (EGFR+/ALK+) in a phase 1b/2 trial.MethodsPreviously treated patients with advanced EGFR+/ALK+ NSCLC were enrolled and given camrelizumab 200 mg intravenously every 2 weeks plus apatinib at the recommended dose of 250 mg orally once daily. Patients harboring sensitive EGFR mutations or ALK fusion genes had received at least one EGFR/ALK TKI and a platinum-based chemotherapy regimen before the enrollment. The primary endpoint was objective response rate (ORR).ResultsAll 43 enrolled patients comprised the efficacy and safety analysis population. The confirmed ORR was 18.6% (95% CI: 8.4–33.4%) and the clinical benefit response rate was 27.9% (95% CI: 15.3–43.7%). Median progression-free survival (PFS) was 2.8 months (95% CI: 1.9–5.5 months) and median overall survival was not reached (95% CI: 7.3 months–not reached), with a median follow-up period of 15.7 months (range, 0.5–24.4 months). The most common grade ≥3 treatment-related adverse events (TRAEs) were hypertension (16.3%), proteinuria (11.6%) and palmar-plantar erythrodysaesthesia syndrome (9.3%). No unexpected adverse events were recorded.ConclusionsCamrelizumab plus apatinib showed moderate antitumor activity and acceptable safety profile in previously treated patients with advanced NSCLC and EGFR or ALK genetic aberrations, which warranted further validation.Trial RegistrationClinicalTrials.gov identifier: NCT03083041. Registered March 17, 2017.

Phase I study of TT-00420, a multiple kinase inhibitor, as a single agent in advanced solid tumors.

3090 Background: TT-00420 is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B and Janus kinases (JAK) involved in cytokine signaling and receptor tyrosine kinases (FGFRs and VEGFRs) involved in the tumor microenvironment. TT-00420 has demonstrated anti-tumor activity in both in vitro and in vivo preclinical models of solid tumors, including triple-negative breast cancer (TNBC) and cholangiocarcinoma (CCA). Methods: The phase I, first-in-human dose escalation and expansion study of TT-00420 is enrolling adult patients with advanced or metastatic solid tumors. TT-00420 capsules in 1 mg or 5 mg formulation are administered orally once daily in 28-day cycles. Dose escalation is guided by Bayesian modeling with overdose control. The primary safety endpoints are to determine dose limiting toxicities (DLTs) and a dose recommended for dose expansion (DRDE). Secondary endpoints include pharmacokinetics (PK) and preliminary efficacy evaluated per RECIST v1.1 criteria. Results: As of February 17, 2021, 40 advanced solid tumor patients were enrolled in dose escalation cohorts and received at least one dose of TT-00420 in 7 dose levels: 1 mg q.d. (N=1), 3 mg q.d. (N=1), 5 mg q.d. (N=4), 8 mg q.d. (N=10), 10 mg q.d. (N=6), 12 mg q.d. (N=12), and 15 mg q.d. (N=6). DLTs were observed in 3 out of 32 DLT-evaluable patients, including 1 patient at 8 mg q.d. who had grade (Gr) 3 palmar-plantar erythrodysaesthesia syndrome and 2 patients at 15 mg q.d. who both had Gr 3 hypertension. Suspected adverse events (AEs) reported in ≥ 20% of patients across all tested dose levels include hypertension (any grade: n=17, 42.5%; Gr 3: n=8, 20.0%), diarrhea (n=10, 25.0%; Gr 3: n=1, 2.5%), vomiting (n=9, 22.5%; Gr 3: n=0), palmar-plantar erythrodysaesthesia syndrome (n=9, 22.5%; Gr 3: n=1, 2.5%), and nausea (n=8, 20.0%; Gr 3: n=1, 2.5%). No Gr 4 AEs, regardless of causality, were reported. Out of 26 patients who had at least one post-baseline scan, 4 (15.4%) had a best overall objective response of partial response (PR) and 13 (50.0%) had stable disease (SD). Of the patients who achieved PRs are 2 CCA patients (8 mg q.d., n=1; 10 mg q.d., n=1), 1 HER2-negative breast cancer patient (12 mg q.d.), and 1 TNBC (10 mg q.d.). Both CCA patients with PRs had disease control for ≥ 8 months. Of the patients who achieved SD, 1 salivary gland patient (5 mg q.d.) and 1 CCA patient (10 mg q.d.) had disease control for 8 months, and 2 TNBC patients (5 mg q.d., n=1; 8 mg q.d., n=1) had disease control for 6 months prior to disease progression. Conclusions: Toxicities observed in dose escalation cohorts were manageable with concomitant treatment and/or dose interruptions of TT-00420. 12 mg p.o. q.d. was recommended as the dose for dose expansion cohort for further safety and efficacy evaluation of TT-00420 capsules with focus on enrollment of TNBC and CCA patients. Clinical trial information: NCT03654547.

Penpulimab plus anlotinib as second-line treatment for the small cell lung cancer after failure of platinum-based systemic chemotherapy.

8568 Background: Combined therapy of an immune checkpoint inhibitor with a targeted anti-angiogenic agent had been proved to be effective for lung cancer. Penpulimab (AK105) was engineered to eliminate FcγR binding and antibody-dependent cell-mediated cytotoxicity (ADCC)/ antibody-dependent celluar phagocytosis (ADCP) completely, where ADCC/ADCP effects could induce T-cell apoptosis and clearance and therefore compromise anti-tumor activity. Penpulimab demonstrated a slower programmed death-1(PD-1) antigen binding off-rate, which resulted in better cellular activity and higher receptor occupancy. Penpulimab also showed numerous contacts with N58 glycosylation on the BC loop of PD-1. These structural differentiations enhance the anti-tumor activity of penpulimab and improve its safety. Anlotinib is a multi-targeted tyrosine kinase inhibitor selective for VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit. Anlotinib has been approved by National Medical Products Administration as the treatment for small cell lung cancer (SCLC) patients, who had progressed/relapsed on or after at least two regimens of chemotherapy. Here we report the results of one cohort which received penpulimab plus anlotinib in a Phase II study. Methods: In Cohort 4 of an open-label, multi-center, multi-cohort Phase II study evaluating the efficacy and safety of penpulimab plus anlotinib in pts with advanced head, neck or chest tumors(NCT04203719), the SCLC patients, who failed to platinum-based systemic chemotherapy treatment, received penpulimab (200 mg IV Q3W) and anlotinib (12/10 mg PO 2 weeks on/1 week off). Primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints were disease control rate (DCR), duration of response, progression-free survival (PFS) and overall survival. Results: 20 patients (median age was 61 [range:37–75] years old, Eastern Cooperative Oncology Group performance status 0/1 [5%/95%], male/female [65%/35%]) were enrolled and received combination therapy (17 received 12 mg anlotinib, 3 received 10 mg anlotinib; and all received 200 mg penpulimab). At data cut-off (Jan 25, 2021), the confirmed ORR was 50.0% (10/20, 1 complete response and 9 partial response) and DCR was 75.0% (15/20). 9 PFS events (45%) had occurred, and the median PFS was 4.7 months (95% CI: 3.6-not reached). Grade 3 treatment-related adverse events (TRAEs) occurred in 30% (6/20, 2 hypertension, 1 hypertriglyceridaemia, 1 gamma-glutamyltransferase increased, 1 palmar-plantar erythrodysaesthesia syndrome and 1 hyponatraemia) of patients, No Grade 4 or 5 TRAEs had occurred. Conclusions: Penpulimab plus anlotinib showed favorable antitumor activity and an acceptable safety profile in SCLC patients who failed to platinum-based systemic chemotherapy. This new combination therapy warrants further evaluation for the treatment of SCLC. Clinical trial information: NCT04203719.

Preliminary results of a phase 1b study of fruquintinib plus sintilimab in advanced colorectal cancer.

2514 Background: To explore the safety and synergistic anti-tumor effect of fruquintinib (a VEGFR inhibitor) in combination with sintilimab (an anti-PD-1 Ab) in patients (pts) with advanced colorectal cancer (CRC) and other solid tumors. Methods: This is an ongoing phase Ib/II, multicenter, two-stage study. Pts with variety cancer types, including CRC, were enrolled and is continuously enrolling in the study. For this interim analysis, all pts were analyzed for safety whereas only CRC pts were analyzed for efficacy. MMR status were analyzed for all enrolled CRC pts. Stage 1 was classical “3+3” dose escalation with pts assigned to one of the following 4 cohorts, fruquintinib taken orally at 3mg (Cohort A, 3 weeks on/ 1 week off), 4mg (Cohort B, 3 weeks on/ 1 week off), 5mg-intermittent (Cohort C, 2 weeks on/ 1 week off) or 3mg-continuous (Cohort E, once daily), while sintilimab was given at 200mg intravenously with Q4W in Cohort A and Cohort B whereas Q3W in Cohort C and Cohort E. DLT was observed for 28 days. Stage 2 was dose expansion with pts receiving 5mg-intermittent or 3mg-continuous fruquintinib plus sintilimab (200mg, Q3W). The primary endpoints were safety and tolerability and secondary endpoint was objective response rate (ORR). Results: As of Jan 5, 2021, 44 CRC pts which failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan were enrolled. They received either 5mg-intermittent or 3mg-continous dosage (n = 22, each), the ORR was 22.7% (10/44, 95% CI: 11.5-37.8%) with 27.3% (6/22, 95% CI: 10.7-50.2%) in 5mg-intermittent group and 18.2% (4/22, 95% CI: 5.2-40.3%) in 3mg-continuous group. With a median follow-up time of 8.3 (range: 0-9.6) months, the K-M estimated median PFS was 6.8 (95% CI:5.6-NA) months and 4.3 (95% CI:3.5-NA) months for 5mg-intermittent group and 3mg-continuous group, respectively. Overall, 60 pts were enrolled for safety analysis, including 23 in stage1 and 37 (only CRC) in stage 2. In stage 1, all pts experienced TEAEs, 52.2% of which were ≥ grade 3. The most frequently reported TEAEs were TSH increasing (73.9%), fecal occult blood positive (56.5%), and Palmar-plantar erythrodysaesthesia syndrome (PPES) (56.5%). SAEs occurred in 8 (34.8%) pts and no treatment-related death was reported. One patient in Cohort B reported manageable DLT. In stage 2, all pts experienced TEAEs, 18 (48.6%) pts experienced ≥ grade 3 TEAEs with 6 (31.6%) in 5mg-intermittent group and 12 (66.7%) in 3mg-continuous group. The most common TEAEs were proteinuria (45.9%) and TSH increasing (37.8%). TEAEs leading to either fruquintinib or sintilimab discontinuation occurred in 3 (5%) pts each. Conclusions: Fruquintinib plus sintilimab showed promising efficacy and favorable safety profile in advanced CRC. Clinical trial information: NCT03903705.

Lenvatinib in patients with advanced or metastatic thymic carcinoma (REMORA): a multicentre, phase 2 trial

Thymic carcinoma is a rare malignant disease and standard treatment for advanced or metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Lenvatinib is a novel multi-targeted inhibitor of VEGFR, FGFR, RET, c-Kit, and other kinases. The aim of this trial was to assess the activity and safety of lenvatinib as a second-line treatment in thymic carcinoma. This single-arm, phase 2 trial done in eight institutions in Japan (five cancer centres, two medical university hospitals, and one public hospital) enrolled patients with pathologically confirmed unresectable advanced or metastatic thymic carcinoma that progressed following at least one platinum-based chemotherapy. Key inclusion criteria were age 20 years or older, at least one measurable lesion as defined by the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 24 mg of lenvatinib orally once daily in 4-week cycles until disease progression or occurrence of unacceptable adverse events. The primary endpoint was objective response rate evaluated at the data cutoff date (Feb 22, 2019), by independent central review in the intention-to-treat population. This trial is registered on JMACCT, JMA-IIA00285, and on UMIN-CTR, UMIN000026777. Between April 21, 2017, and Feb 22, 2018, 42 patients were enrolled and all patients were included in the activity and safety analysis. The median follow-up period was 15·5 months (IQR 13·1-17·5). The objective response rate was 38% (90% CI 25·6-52·0, p<0·0001). 16 (38%) of 42 patients had a partial response and 24 (57%) had stable disease. The most frequent grade 3 treatment-related adverse events were hypertension (27 [64%]) and palmar-plantar erythrodysaesthesia syndrome (three [7%]). No patient died from adverse events. The activity and safety of lenvatinib in patients with advanced or metastatic thymic carcinoma was confirmed. These results suggest that lenvatinib could become a standard treatment option for patients with previously treated advanced or metastatic thymic carcinoma. Center for Clinical Trials, Japan Medical Association.

Durable Anti-Tumour Activity of the Multi-Targeted Inhibitor Lenvatinib in Patients with Advanced or Metastatic Thymic Carcinoma: A Multicentre Phase II (REMORA) Trial

Background: Thymic carcinoma is a rare malignant disease, and standard treatment for advanced/metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Several multi-targeted inhibitors have demonstrated efficacy as second-line treatment. Lenvatinib is a novel multi-targeted inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor, RET, c-Kit, and other kinases. It has shown anti-tumour activity and manageable toxicity profiles and has been approved for thyroid cancer and hepatocellular cancer in several countries. Methods: The open-label, single-arm, multi-centre phase II trial investigated the efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma. Patients with pathologically confirmed thymic carcinoma that progressed following at least one platinum-based chemotherapy were enrolled. Lenvatinib was administered orally once daily until disease progression or unacceptable adverse events. The primary endpoint was objective response rate (ORR) by independent central review. Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety profiles. Findings: Between April 2017 and February 2018, 42 patients were enrolled from eight institutions in Japan. The median follow-up period was 15·5 months (interquartile range: 13·1–17·5 months). The ORR was 38·1% (90% confidence interval [CI]: 25·6–52·0%); 16 of 42 patients had partial response, while 24 of 42 patients had stable disease. The DCR was 95·2% (95% CI: 83·8–99·4%). The median duration of PFS was 9·3 months (95% CI: 7·7–13·9 months), and the median OS was not reached. The most frequent treatment-related adverse events were hypertension, diarrhoea, palmar-plantar erythrodysaesthesia syndrome, proteinuria, hypothyroidism, and reduced platelet count. Interpretation: The efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma was confirmed. These encouraging results suggested that lenvatinib can become a standard treatment option for patients with previously treated advanced/metastatic thymic carcinoma. Trial Registration: This trial is registered as JMA-IIA00285 and UMI26777. Funding Statement: Lenvatinib was provided by Eisai Co., Ltd. (Bunkyō, Tokyo, Japan) and distributed by SAROUTE Co., Ltd (Shinjuku-ku, Tokyo, Japan). The funder of the study was the Center for Clinical Trials, Japan Medical Association, which approved the study protocol and the final version but did not contribute to the clinical data collection. Declaration of Interests: JS reports honoraria from Chugai Pharmaceutical Co.. NY reports research grant from Chugai Pharmaceutical Co., Taiho Pharmaceutical, Eisai, Eli Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical, Takeda, Janssen Pharma, MSD, Merck and GSK; and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical Co., AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb and Sysmex; and personal fees for consulting from Eisai, Otsuka, Takeda, Boehringer Ingelheim and Cimic. YO* reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Kissei, Ignyta, Janssen and LOXO; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Boehringer Ingelheim, Pfizer, Kyowa Hakko Kirin, Celtrion, Amgen and Nippon Kayaku. YO** reports research grant from Chugai Pharmaceutical Co. and Takeda, and received personal fees from MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical Co., Takeda, Eli Lilly, AstraZeneca, Boehringer Ingelheim and Pfizer. SN reports research grant from AstraZeneca, Pfizer, Eli Lilly, MSD and Merck, and personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Novartis, Shionogi and Yakult. HM reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Takeda, Abbvie, Daiichi-Sankyo and IQvia; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, MSD and Takeda. MS reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, EPS international, Novartis, MSD, Takeda and Ignyta; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis and MSD. TK reports reserch grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Bristol-Myers Squibb and Merck; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim and Nippon Kayaku. KN reports personal fees from Chugai Pharmaceutical Co., Taiho Pharmaceutical and Bayer. RM reports research grant from Ministry of Health, Labour and Welfare, Japan. YK reports personal fees from Chugai Pharmaceutical Co.. All other authors declare no competing interests. YO*; Yuichiro Ohe, YO**; Yusuke Okuma Ethics Approval Statement: The study was approved by the institutional review board at each participating institution and was conducted in accordance with the principles of Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all the patients before enrolment in the study.

REFLECT\u2014a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset

BackgroundA phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79–1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported.MethodsThe intent-to-treat population enrolled in Japan was analyzed.ResultsOf 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62–1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm.ConclusionsThe efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC.Trial registration IDClinicalTrials.gov. No. NCT01761266.

LBA9 - Real-world assessment of clinical effectiveness and safety of pazopanib in patients with advanced or metastatic renal cell carcinoma (RCC) in Asia, North Africa and Middle East countries: A prospective, observational study (PARACHUTE)

BackgroundPARACHUTE, a phase IV, prospective, observational study of treatment patterns and outcomes planned to describe the clinical effectiveness and safety of pazopanib in patients (pts) with advanced or mRCC who are naïve to VEGF-TKI therapy in the real-life setting from Asia Pacific, North Africa, and the Middle East countries where data from the registration trials are lacking. MethodsEligible pts were ≥18 years with advanced or mRCC and clinical decision to initiate pazopanib treatment or had already started new treatment with pazopanib within 15 days prior to study entry and naïve to any prior anti-VEGF therapy. Primary endpoint was the proportion of patients remaining progression free at 12 months (mo). The secondary endpoints were ORR, PFS, safety and tolerability, and relative dose intensity (RDI). ResultsBetween Jun 2017 and Dec 2018, 200 pts were enrolled from 15 countries in Asia, North Africa and Middle East. A total of 101 pts with a median age of 62 y (range, 32.0-95.0) were included in this interim analysis. Majority of the pts were Asian (63%) followed by Caucasian (36%). Clear cell was the main (82%) histologic type. At data cut-off (May 2, 2019) of 12 mo observation period, 29 pts completed the observational period and 72 discontinued the study. Only 57% of pts had the starting dose at 800mg. Median RDI was 79% with 52% pts received under <85%. 25 of 92 evaluable pts (27%) remained progression-free and median PFS was 4 mo (95% CI, 3.02-6.54). The best overall response per RECIST 1.1 is CR (2%), PR (18%) and SD (41%). 74% pts experienced ≥1 treatment related adverse event (TRAE) and 11% of pts discontinued due to TRAE. Most frequent (>10%) TRAEs include diarrhoea (27%), palmar-plantar erythrodysaesthesia syndrome (12%) and hypertension (15%). ConclusionsThe interim results of the PARACHUTE study support the use of pazopanib in pts with advanced or mRCC who are naïve to VEGF-TKI therapy. Safety profile is consistent with the previously reported pivotal and realworld evidence studies. The efficacy data are still immature due to limited number of pts and the short follow-up duration. Editorial acknowledgementAnuradha Bandaru, Novartis Healthcare Pvt Ltd (Hyderabad, India). Legal entity responsible for the studyNovartis. FundingHas not received any funding. DisclosureR. Kanesvaran: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Novartis, MSD, BMS, Ipsen, Eisai, J&J, Astellas, Amgen, Mundipharma, Sanofi, Roche, AZ. P. Danchaivijitr: Advisory / Consultancy: MSD and Pfizer. B. Karabulut: Honoraria (institution), Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono, Bayer, Pfizer, Novartis, MSD, BMS, J&J, Astellas, Amgen, Sanofi, Roche. Y.F. Wong: Advisory / Consultancy: Merck and Roche. K. Slimane: Full / Part-time employment: Novartis. M. Erman: Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer, Novartis, BMS, Astellas, Roche, AstraZeneca, Boehringer Ingelheim, Nobel, Gen Pharma, MSD, Pierre Fabre, Amgen, Takeda, Mustafa Nevzat Pharma, Teva.

787P - Multicenter phase I/II feasibility study of adjuvant treatment with S-1 in patients after R0-resection of adenocarcinoma of the stomach and esophagogastric junction (GMBH-STO-0114)

BackgroundS-1 has been shown to be an effective adjuvant treatment for East Asian patients who underwent gastrectomy with a D2 lymph-node dissection for stage II/III gastric cancer. We designed a phase I/II study to evaluate the efficacy, toxicity and feasibility of administering S-1 in the adjuvant setting after R0-Resection of adenocarcinoma of the stomach and esophagogastric junction in caucasian patients. MethodsEligible patients with histologically confirmed adenocarcinoma T2/T3/T4, any N category, M0 or any uT, N+, M0 of the stomach or esophago gastric junction had undergone R0-resection with or without neoadjuvant treatment and D2 lymph node dissection. They had performance status of ECOG 0-1 and adequate organ function. Treatment was orally administered S-1 (30mg/m² twice daily) for 14 days every three weeks for 18 cycles (54 weeks). A primary endpoint of the study is the determination of the recommended dose for S-1. Follow up will be continued until one year after last patient’s end of treatment. ResultsBetween Oct 2015 and Feb 2018, 30 patients were enrolled in 12 German centres. Male/female ratio was 56.7%/43.3%, median age was 61.5 years. Of 30 patients included, 10 were diagnosed with gastric cancer, 20 with EGJ cancer (3 AEG I, 6 AEG II and 11 AEG III). Of 30 patients starting adjuvant therapy, 17 completed all 18 cycles, 2 patients had to terminate study treatment due to adverse events. Five patients terminated study treatment due to patients wish, 4 patients suffered a relapse or distant metastasis. Nine patients had to be reduced to dose level 25mg/m², 1 patient had to be reduced to 20mg/m². One patient was underdosed for the first 6 cycles and received full dosage from cycle 7. Of patients completing all 18 cycles, 5 had did so with reduced dosage of S-1. Documented grade ≥ 3 adverse events were neutropenia (n=2), diarrhoea (n=2), vomiting (n=1), polyneuropathy (n=1), palmar-plantar erythrodysaesthesia syndrome (n=1) and rash (n=1). ConclusionsFrom this first analysis we can conclude that adjuvant treatment with S-1 for one year of patients suffering from gastric adenocarcinoma or EGJ cancer after R0-resection is a feasible and safe option for Caucasian patients. Clinical trial identification2014-004116-11. Legal entity responsible for the studyAIO-Studien-gGmbH, Berlin. FundingFunded by AIO-Studien-gGmbH, supported by Taiho Pharmaceutical Co., Ltd and Nordic Pharma Group. DisclosureAll authors have declared no conflicts of interest.

Phase I study of DFP-11207, a novel oral 5-FU with enhanced PK and improved tolerability, in patients with solid tumors.

3034 Background: DFP-11207 combines a 5-fluorouracil (5-FU) pro-drug with a reversible dihydropyrimidine dehydrogenase inhibitor and a potent inhibitor of orotate phosphoribosyl transferase resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicity. Methods: Patients with advanced solid tumors were treated in this single arm, dose escalation study. Accelerated dose escalation using single pt cohorts was followed until drug-related Gr2 adverse events occurred; then a 3+3 design was followed to determine maximum tolerated dose (MTD). Pts were dosed daily in 28-day cycles until intolerable toxicity or disease progression. PK sampling was performed for DFP-11207 metabolites on all pts and a 6 pt cohort received DFP-11207 in fed and fasted states to determine drug bioavailability. Results: Primary tumors among the 23 enrolled pts included esophageal, colorectal, gastric, pancreatic and gallbladder. Seventeen pts were treated at 8 dose levels of oral DFP-11207 administered daily, ranging from 40 to 440 mg/m2/d. At 440 mg/m2/d one pt experienced drug-related Gr3 dehydration and mucosal inflammation, and Gr4 febrile neutropenia; a second pt experienced Gr4 febrile neutropenia. One DLT of Gr3 vomiting occurred among 6 pts treated at 330 mg/m2/d dosed q12hrs confirming the MTD. Six pts were administered 300 mg DFP-11207 q12 hrs in a fed or fasted state to determine drug bioavailability. Among all pts, the most frequently reported drug-related TEAEs were fatigue (47.8%), nausea (47.8%), decreased appetite (39.1%), diarrhea (26.1%), vomiting (21.7%), anemia (13.0%), dysgeusia (13.0%), mucosal inflammation (13.0%) and palmar-plantar erythrodysaesthesia syndrome (13.0%). PK analyses of pts treated at 330 and 440 mg/m2/d indicate 5-FU concentrations of ~20 ng/mL throughout the dose cycle. There was no substantial difference in DFP-11207 bioavailability among pts in a fed or fasted state. Out of 21 efficacy evaluable pts, 7 pts had stable disease (33.3%), of which 2 had prolonged stable disease of &gt; 6 months. No pts achieved CR or PR. Conclusions: DFP-11207 at the dose of 330 mg/m2/d q12hrs is well-tolerated in pts with solid tumors with mild myelosuppressive and gastrointestinal side effects, and results in circulating 5-FU levels conducive to an anti-tumor effect. DFP-11207 can be explored as monotherapy or substitute for 5-FU, capecitabine or S-1 in combination treatment regimens. Clinical trial information: NCT02171221.

Tucatinib with capecitabine and trastuzumab in advanced HER2-positive metastatic breast cancer with and without brain metastases: a non-randomised, open-label, phase 1b study

Tucatinib is a potent and selective oral HER2 tyrosine kinase inhibitor, with the potential to provide a well tolerated new treatment option for patients whose disease has progressed on currently available therapies. We aimed to determine the recommended phase 2 dose, safety, pharmacokinetics, and preliminary activity of tucatinib in combination with capecitabine or trastuzumab in patients with HER2-positive breast cancer with or without brain metastases. In this non-randomised, open-label, phase 1b trial done in five sites in the USA, we recruited patients aged 18 years or older with HER2-positive progressive breast cancer who had been previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. Eligible patients required HER2-positivity assessed locally, evaluable lesions as defined per Response Evaluation Criteria in Solid Tumors, version 1.1, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Tucatinib was administered twice a day in conjunction with capecitabine 1000 mg/m2 orally twice a day for 14 days of a 21-day cycle, trastuzumab 6 mg/kg intravenously once every 21 days, or both. A modified 3 + 3 dose-escalation design was used to determine the recommended phase 2 dose, starting with tucatinib in combination with capecitabine or trastuzumab, and subsequently evaluating the triplet combination. The primary endpoint was to establish the maximum tolerated dose and recommended phase 2 dose of tucatinib, evaluated by toxicity assessments. Efficacy was assessed in all patients by contrast CT of the body. Analyses included all patients who had received at least one dose of study treatment. The study is registered with ClinicalTrials.gov, number NCT02025192. Between Jan 15, 2014, and Dec 15, 2015, 60 patients were enrolled and treated. The current report is from mature data as of June 30, 2017. The tucatinib recommended phase 2 dose was determined to be 300 mg orally twice a day, equivalent to single-agent maximum tolerated dose. Pharmacokinetic analysis showed that there was no drug-drug interaction with capecitabine. Adverse events seen at the recommended phase 2 dose regardless of causality, grade, and treatment group included diarrhoea (35 [67%] of 52 patients), nausea (31 [60%] patients), palmar-plantar erythrodysaesthesia syndrome (23 [44%] patients), fatigue (20 [38%] patients), and vomiting (20 [38%] patients). In all patients, treatment-related toxicities of grade 3 and worse included fatigue (five [8%] patients), diarrhoea (four [7%] patients), and palmar-plantar erythrodysaesthesia (four [7%] patients). No treatment-related deaths were reported. The proportion of patients with measurable disease achieving objective response was 83% (five of six patients) in the combination of tucatinib with capecitabine, 40% (six of 15 patients) in the combination of tucatinib with trastuzumab, and 61% (14 of 23 patients) in the combination of tucatinib with both capecitabine and trastuzumab. Tucatinib in combination with capecitabine and trastuzumab had acceptable toxicity and showed preliminary anti-tumour activity. Validation of the current study results will be determined in the double-blinded randomised study, HER2CLIMB (ONT-380-206; NCT02614794). Cascadian Therapeutics, a wholly owned subsidiary of Seattle Genetics.