Background

Artificial intelligence (AI) models have been widely shown to be useful in making pathological diagnoses, and we previously established a reliable AI model for distinguishing major lung cancer subtypes (adenocarcinoma [ADC], squamous cell carcinoma [SCC] and small cell lung cancer [SCLC]) with extremely high accuracy using samples obtained from transbronchial lung biopsy (TBLB). In the current study, we validated the accuracy of this AI model using a large cohort of samples obtained from TBLB.

Methods

In the previous study, we trained a convolution neural network based on the EfficientNet-B1 architecture to classify ADC, SCC, SCLC, and non-neoplastic lesions from TBLB specimen whole slide images (WSIs; 70, 23, 12 and 171 specimens of ADC, SCC, SCLC and non-neoplastic lesions, respectively) using a training dataset of 276 images. The WSIs were manually annotated by pathologists by drawing around the regions that contained each subtype. We used a transfer learning approach, in which the starting weights were obtained from a pre-trained model on ImageNet. The model was then trained on our dataset using a supervised learning approach. To classify a WSI, the model was applied in a sliding window fashion with an input tile size of 224x224 and a stride of 128 on a magnification of x10. The maximum probability was then used as a WSI diagnosis. In this study, this established model was validated in 2171 TBLB specimen WSIs (439, 143, 73 and 1516 specimens of ADC, SCC, SCLC and non-neoplastic lesions, respectively).

Results

The model achieved a Receiver Operator Curve Area Under the Curve (ROC-AUC) of 0.9458 (95% confidence interval [CI] 0.9316-0.9575) for non-neoplastic lesions with an accuracy, sensitivity and specificity of 0.8738, 0.8971 and 0.8661, respectively. The ROC-AUCs for ADC, SCC and SCLC were 0.8469 (95% CI 0.8170-0.8725), 0.9141 (95% CI 0.8825-0.9443) and 0.9412 (95% CI 0.905-0.9703), respectively.

Conclusions

Our model achieved high ROC-AUCs for the differentiation of ADC, SCC, SCLC and non-neoplastic lesions. Further studies are warranted to refine the established model.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

PARP inhibition with olaparib is a treatment with high efficacy in HR deficient cancers that arise in carriers of a germline mutation in the BRCA1/2 genes, particularly in ovarian cancer, a registered indication. Olaparib is also active in other BRCA1/2 mutation related cancers, including breast, prostate and pancreatic cancer. Olaparib acts through synthetic lethality in HR deficient cancers. Olaparib responses have however also been documented in cancers in which no BRCA1/2 mutations were found. It is possible that other HR deficiencies may play a role in such sensitivities. An array of other genes involved in HR deficiency, when mutated in the germline lead to an increased risk at least for breast and/or ovarian cancer and other cancers and may sensitize to olaparib. These genes include ATM, CHEK2, NBN, BRIP1, MRE11A, RAD50, NBS1, RAD51C, RAD51D, PALB2, and TP53 as well as BARD1.

Methods

The study recruits advanced cancer patients (pts) that harbor a somatic or a germline mutation in a HR gene. For each cohort a Simon minimax two-stage design is used. In the first stage, 13 patients will be accrued in each cohort. If there are no responses in these 13 patients, that cohort will be stopped.

Results

Currently, the BRCA and ATM cohort are the most advanced with regard to recruitment. Due to the low prevalence of other HR mutations, recruitment is slow in these cohorts. Currently, a total of 72 pts are included and 56 pts underwent a response assessment. Twenty-nine out of 56 pts experienced clinical benefit with olaparib. One complete response was observed in a stage IV breast cancer that harbours a PALB2 germline mutation. Six partial responses occurred: a RAD51D breast cancer, a BRCA1 gallbladder cancer, two BRCA1 and two BRCA2 pancreatic cancer pts. Recently we closed the ATM cohort due to the absence of a response in the first 13 pts.

In general, adverse events were mild to moderate (grade 1 and 2). Only 8 pts (11%) presented with a grade 3 adverse event (an allergic reaction, 5 pts anemia, anorexia and neutropenia).

Conclusions

Treatment with olaparib shows activity in cancer pts with a HR gene mutation and is well tolerated.

Clinical trial identification

NCT03967938, May 30 2019.

Legal entity responsible for the study

UZ Brussel.

Funding

De Stichting Tegen Kanker, Kom op Tegen Kanker, AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.

Background

Considering the efficacy and safety of capecitabine and cetuximab as potent agent for maintenance therapy from previous studies, evaluation on the efficacy of cetuximab in combination with capecitabine as a potential maintenance regimen for RAS and BRAF wild-type mCRC patients is warranted. This abstract describes the design of this study.

Trial design

The phase III, open-label, multicentre, randomized study will evaluate the efficacy and safety of cetuximab plus capecitabine among Chinese patients with RAS and BRAF WT mCRC. Patients ≥18 years, with histologically or cytologically confirmed adenocarcinoma of colon or rectum with RAS and BRAF wild-type, will be included. A total of 348 patients who have already completed 9 cycles of FOLFOX+cetuximab will be randomized in a 1:1 ratio to two maintenance treatment, Arm A (cetuximab: IV 500mg/m2, D1 every 2 weeks+capecitabine: orally 850 mg/m2 BID, D1–10 in 2-week cycles) and Arm B (cetuximab: IV 500mg/m2, D1 every 2 weeks). The randomization will be stratified by induction treatment response (CR+PR vs. SD) and tumour location (only left side vs. right side). All patients will be followed-up until progression (at least 247 events) or completion of study treatment (∼24 months after randomization of last patient) or death from any cause or unacceptable toxicity or informed consent withdrawal, whichever occurs earlier. Primary objective is to evaluate whether cetuximab plus capecitabine can prolong maintenance progression-free survival compared with cetuximab alone. Primary endpoint is maintenance PFS. Other efficacy endpoint is OS. Safety endpoint is incidence of adverse events, drug exposure, safety laboratory assessments, etc. Efficacy endpoints will be compared between the two maintenance regimens. Log-rank test, stratified cox-proportional hazards regression model and Kaplan-Meier method will be performed for PFS. Efficacy endpoints were compared using two-sided stratified log-rank test. Superiority of Arm A to Arm B in terms of mPFS can be concluded if two-sided p value <0.05.

Clinical trial identification

NCT04262635.

Legal entity responsible for the study

Dr Ruihua Xu, Department of Medical Oncology, Sun Yat-sen University Cancer Hospital.

Funding

Funded by Merck Serono, Co. Ltd., China; an affiliate of Merck KGaA, Darmstadt, Germany.

Disclosure

All authors have declared no conflicts of interest.

Background

Chemotherapy induced alopecia (CIA) is one of the most common adverse events caused by conventional chemotherapy, yet it is often overlooked as a cancer research priority. Therefore, evidence regarding the physical and psychosocial experiences of alopecia for women receiving chemotherapy received critical review.

Methods

An integrative review was conducted assimilating evidence from peer-reviewed, primary quantitative, qualitative, and mixed methods studies, published in the English language. A systematic search of MEDLINE, CINAHL and PsycInfo identified 23 studies which met the inclusion criteria. Data relating to women’s experiences of alopecia was extracted and synthesised thematically using the Braun and Clark framework (2006).

Results

Analytical themes were formed including “more than the loss of hair”. Studies mainly employed qualitative designs (n = 13) and mostly recruited women from single sites with a homogenous diagnosis of breast cancer (n = 13). Furthermore, studies predominantly included younger age groups with disparity in current evidence relating to older age groups (>75 years), haematological malignancies and rarer tumour groups. CIA was often found to be the most problematic or feared part of the cancer journey and chemotherapy process. For many women, initial conversations about chemotherapy created psychological distress and anxiety. The physical loss of hair was found to interrupt quality of life and functioning for women, involving a loss of privacy and self-confidence. CIA is more than the loss of hair; it is a highly individualised experience for women which requires enhanced understanding to ameliorate the physical and psychosocial impact of this adverse event of cancer treatment.

Conclusions

This review acknowledges the continued pervasive physical and psychosocial implications arising from the burdensome experience of CIA. Existing knowledge regarding the experience of CIA for women among older age groups, with haematological malignancies or rarer tumour groups is limited; further research should endeavour to address these shortcomings. Healthcare professionals must discuss the potential risks of alopecia, providing patients with an opportunity to voice their experiences of CIA.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Drury: Non-Financial Interests, Institutional, Member, Board Member: EONS. All other authors have declared no conflicts of interest.

Background

The new therapy for the patient (pt) with drug-resistant mCRPC (dr-mCRPC) is a definite unmet medical need. The ORR of dr-mCRPC pts were only 7% to 17% in second to fourth line settings. Other studies reported that AKT inhibitor plus anti-androgen is a potential treatment for dr-mCRPC. This study assessed the safety and efficacy of combination therapy of afuresertib (a AKT inhibitor) and LAE001 (a dual inhibitor of CYP17A1 (testosterone synthesis) and CYP11B2 (aldosterone synthase) in dr-mCRPC.

Methods

This is a multicenter, open-label, dose-escalation phase I study to assess the safety and to determine the the Recommended phase II dose (RP2D) of the combined therapy of LAE001/prednisone and afuresertib in mCRPC patients who failed at least 1 prior SOC. The pts in cohort 1 and cohort 2 received (LAE001 75 mg BID/prednisone 5 mg BID and afuresertib 100 mg QD) and (LAE001 75 mg BID/prednisone 5 mg BID and afuresertib 125 mg QD), respectively.

Results

As of 02/28/2021, 14 pts (8 in cohort 1 and 6 in cohort 2) received study treatment with median 8.5 months follow up. The dose of LAE001 75 mg BID/prednisone 5 mg BID and afuresertib 125 mg QD was determined as the RP2D. There were 2 DLTs reported in cohort 1 (thrombocytopenia) and cohort 2 (skin rash). The only one non-DLT grade >= 3 treatment-emergent adverse events (TEAE) in RP2D was a skin rash. The 10 evaluable pts (received at least 1 cycle of study treatment) in both cohorts were included in efficacy analysis. Two pts had a PSA response (2/10, 20%). Among 5 pts who have measurable lesions, 1 non-confirmed PR (37% tumor reduction) and 2 SDs were reported. These 10 pts on average had 3 lines of SOC. Table: 599P

Conclusions

The combination therapy of LAE001 75mg BID/prednisone 5mg BID and afuresertib 125mg QD was determined as the RP2D. The preliminary antitumor activity under the RP2D supports the potential clinical benefit for treating dr-mCRPC and moves forward this study to phase II stage.

Clinical trial identification

NCT04060394.

Legal entity responsible for the study

Laekna Limited.

Funding

Laekna Limited.

Disclosure

A. Bessudo, J.F. Strauss, D.E. Slater, C. Pieczonka: Non-Financial Interests, Institutional, Principal Investigator: Laekna Therapeutics. X. Wang, P. Guo, J. Liu, Y. Yue, C. Lu: Financial Interests, Personal, Full or part-time Employment: Laekna Therapeutics.

Background

Gliomas are the most frequently occurring primary tumor of the central nervous system, of which HGG is an aggressive form with no effective therapy. So far, standard therapy in the adult setting includes maximal safe surgical resection followed by adjuvant temozolomide and radiation therapy (RT). Stromal Antigen-2 (STAG2) is a component of the cohesion complex that is required for DNA replication, the cohesion of the sister chromatids, and transcriptional regulation. Inactivating mutations in STAG2 can lead to aneuploidy and chromosomal instability in cancer. Within glioblastoma, approximately 4-6% of tumors harbor STAG2 mutations, according to large-scale genomic databases. At present, cell line trials have reported that glioblastomas carrying STAG2 mutations are sensitive to PARP inhibitors. To explore the possibility of more targeted drugs in glioma, herein, we explore STAG2 mutation profiles in Chinese adult gliomas.

Methods

Tumor specimens from 915 Chinese clinical glioma patients were analyzed using the 131-gene profiling, including all the exons of the STAG2 gene, flanking intronic regions. STAG2 mutations were detected by following the standard operating procedure (SOP).

Results

A total of 67 STAG2 aberrations, including mutations, amplification, and deletion were detected in 50/915 adult glioma patients. Loss of function (LOF) mutations, including frameshift, nonsense, splicing was more (43/67, 71.6%) observed, and 26.9% are missense mutations. STAG2 mutations were more frequently observed in IDH wild-type glioma (7.3%, 43/590) than IDH mutation glioma (2.15%, 7/325). There was a significant difference in the frequency of IDH wild-type and IDH-mutant gliomas with STAG2 mutations (7.3% vs. 2.15%, P=0.001217). 36/43 cases of clinical staging are grade IV and others are unknown. Pathway enrichment analysis was performed, and both GO and KEGG enrichment revealed no significant differences in the functions or biological processes between STAG2 mutation and wild type.

Conclusions

In our Chinese patients, STAG2 gene mutations mostly occur in IDH wild-type gliomas and may be a molecular marker of IDH wild-type glioma. PARP inhibitors may be a potential treatment option for IDH wild-type gliomas accompanying STAG2 mutation.

Legal entity responsible for the study

Y. Bo.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Fulvestrant and exemestane are both standard of care for estrogen receptor (ER) positive locally advanced or metastatic breast cancer. It is still controversial which drug is the optimal first-line endocrine monotherapy for postmenopausal ER+/HER2- breast cancer who exposed to adjuvant nonsteroidal aromatase inhibitors (NSAIs).

Methods

In this randomized, open-label, multi-center, parallel-group study, postmenopausal women with recurrent ER+/HER2- advanced breast cancer receiving at least 2 years NSAIs as adjuvant treatment were randomly assigned to receive fulvestrant (500 mg on days 0, 14, and 28 and every 28 (± 3) days thereafter) or exemestane (25 mg daily).

Results

A total of 144 patients were randomly assigned to receive fulvestrant(n=77) or exemestane(n=67). The median progression-free survival (PFS) was 8.51 months in fulvestrant group versus 5.55 months in exemestane group (P = 0.014, HR=0.615, 95%Cl: 0.417∼0.907). The ORR of the fulvestrant group was 19.48% compared to 5.97% of the exemestane group (P =0.017). Time to failure (TTF) was significantly longer for fulvestrant versus exemestane (median TTF was 8.38 months in the fulvestrant group and 5.45 months in the exemestane group, P=0.008). No significant differences in the incidence of adverse events and severe adverse events between the two groups. As an exploratory outcome, there were 22 patients with ESR1 mutation in 139 patients (15.8%). PFS had no significant differences for fulvestrant vs exemestane therapies in ESR1 mutation (P = 0.058) or wild-type patients (P = 0.087).

Conclusions

Fulvestrant 500 mg was associated with a statistically significant increase in PFS compared with exemestane and was generally well tolerated. There were no significant differences in PFS between the two groups irrespective of ESR1 status.

Clinical trial identification

NCT02646735.

Legal entity responsible for the study

Beijing Association of Breast Diseases Prevention and Treatment.

Funding

AstraZeneca China.

Disclosure

All authors have declared no conflicts of interest.

Background

Brain metastases (BM) are frequently diagnosed in HER2-positive breast cancer (BC) and add to morbidity and mortality. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate approved for the treatment of HER2-positive metastatic BC but has not been specifically investigated in the context of BM. Here, we present preliminary results of the prospective, single-centre, single-arm, phase II TUXEDO-1 trial investigating T-DXd in HER2-positive BC patients (pts) with active BM.

Methods

TUXEDO-1 enrols pts with HER2-positive BC and newly diagnosed BM or BM with radiological progression after prior local therapy, prior exposure to trastuzumab and pertuzumab, and no indication for immediate local therapy. The primary endpoint is intracranial response rate (RR) centrally assessed by Response Assessment in Neuro-Oncology (RANO)-BM criteria. Secondary endpoints consist of extracranial RR, progression-free survival, overall survival, safety, and quality-of-life. Based on a Simon’s two-stage phase II design with RR under alternative hypothesis of >60% and under null hypothesis of <26%, six evaluable pts with 3 responses are required for the first stage and additional 9 pts for the second stage. The null hypothesis will be rejected with a type I error rate of 5% and a power of 80% if ≥7 responses are observed in the overall sample.

Results

By April 1^st 2021, a total of 10 pts received at least one dose of T-DXd. Median age is 48.5 years, 60% received prior radiotherapy for BM, and 70% prior T-DM1. At a median follow-up of 3.5 months (range 1-8), 9 pts are still on treatment. T-DXd yielded an intracranial response in 5/6 pts (83.3%) enrolled in the first stage (3/4 progressing after prior local therapy); thus, the trial progressed to the second stage. Main toxicities in the overall sample consisted of grade 1/2 nausea, neutropenia, and fatigue. No case of interstitial lung disease was detected; one patient with pre-existing diabetes experienced a reversible symptomatic drop of left-ventricular ejection fraction.

Conclusions

Based on clinically relevant preliminary activity in HER2-positive BC pts with active BM, TUXEDO-1 met the criteria to move to the second stage.

Clinical trial identification

EudraCT 2020-000981-41; NCT04752059.

Legal entity responsible for the study

Medical University of Vienna, Department of Medicine 1.

Funding

Daiichi Sankyo.

Disclosure

R. Bartsch: Financial Interests, Personal, Invited Speaker: Astra-Zeneca; Financial Interests, Personal, Advisory Board: Daiichi; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Seagen; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Pierre-Fabre; Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Institutional, Funding, Investigator Initiated Trial: Daiichi; Financial Interests, Institutional, Invited Speaker, Drug support for investigator initiated Trial: MSD. A.S. Berghoff: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal and Institutional, Other: Roche; Financial Interests, Personal and Institutional, Other: Amgen; Financial Interests, Personal and Institutional, Other: AbbVie; Financial Interests, Institutional, Research Grant: Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Roche. M. Marhold: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Daiichi; Financial Interests, Personal, Invited Speaker: Medmedia; Financial Interests, Personal and Institutional, Other: Amgen; Financial Interests, Personal and Institutional, Other: Roche; Financial Interests, Personal and Institutional, Other: Novartis; Financial Interests, Personal and Institutional, Other: Pierre Fabre; Financial Interests, Personal and Institutional, Other: Daiichi; Financial Interests, Personal and Institutional, Other: Eisai. A.M. Starzer: Financial Interests, Personal and Institutional, Other: PharmaMar. A. Ilhan-Mutlu: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Servier; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Institutional, Principal Investigator: BMS; Financial Interests, Institutional, Principal Investigator: Roche; Financial Interests, Personal and Institutional, Other: BMS; Financial Interests, Personal and Institutional, Other: Eli Lilly; Financial Interests, Personal and Institutional, Other: Daiichi; Financial Interests, Personal and Institutional, Other: Roche. C. Minichsdorfer: Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal and Institutional, Other: MSD; Financial Interests, Personal and Institutional, Other: Merck. T. Fuereder: Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Accord; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Merck; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Merck. C.F. Singer: Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Personal and Institutional, Other: Roche; Financial Interests, Personal and Institutional, Other: Tesaro; Financial Interests, Personal and Institutional, Other: AstraZenca; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Sanofi. M. Preusser: Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: GLG; Financial Interests, Personal, Advisory Board: CMC Contrast; Financial Interests, Personal, Invited Speaker: GSK; Financial Interests, Personal, Invited Speaker: Munidpharma; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Other: BMJ Jorunals; Financial Interests, Personal, Other: MedMedia; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: AbbVie; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: Medahead; Financial Interests, Personal, Invited Speaker: Daiichi; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Tocagen; Financial Interests, Personal, Invited Speaker: AdAstra; Financial Interests, Institutional, Funding: Boehringer Ingelheim; Financial Interests, Institutional, Funding: BMS; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Daiichi Sankyo; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Novocure; Financial Interests, Institutional, Funding: GSK; Financial Interests, Institutional, Funding: AbbVie. All other authors have declared no conflicts of interest.

Background

Cutaneous squamous cell carcinoma (CSCC) is the second most common cutaneous malignancy and patients with locally advanced or metastatic disease have a poor prognosis. Cemiplimab, a monoclonal anti-PD-1 antibody, has recently been approved by the FDA and EMA for this patient cohort based on single-arm phase II studies. Real-world data on clinical outcome and tolerability is still scarce.

Methods

In this retrospective cohort analysis, patients treated with cemiplimab for advanced CSCC from 3 sites in the Netherlands from November 2018 until August 2020 were evaluated for response and toxicity. Collected data comprised patient’s demographics, tumor characteristics and treatment course. Clinical response, adverse events (AE), progression-free survival (PFS) and overall survival (OS) were assessed.

Results

In total, 66 patients (50 male, 16 female, median age 75; range 30-93 years) with unresectable locoregional (41 (62%) patients) or metastatic (25 (38%) patients) CSCC treated with flatdose cemiplimab 350mg Q3W were included. All but 8 patients (88%) had severe comorbidities, the most common site of the primary tumor was the head or neck (79%) and 7 (11%) patients were pretreated with systemic therapy. A median of 6.5 doses of cemiplimab (range 1-31 doses) were administered and treatment was well-tolerated, with grade 1-2 AEs in 70% and grade 3-4 AEs in 17% of patients. An objective clinical response was seen in 33 (50%) patients, of whom 9 (14%) reached CR and 24 (36%) PR. With a median follow-up of 11.7 months (95% CI 8.4-15.0 months), median PFS was 17.3 months and median OS was not reached. In 39 (59%) patients treatment was discontinued, mostly due to disease progression (49%). In 8 (21%) patients with ongoing response treatment was stopped after a median of 11.5 months (range 2.9-15.2 months).

Conclusions

In this real-world cohort of advanced CSCC patients, cemiplimab demonstrated to be well-tolerated, achieving an objective clinical response in 50% of patients, even in elderly patients with severe comorbidities. Their outcome was comparable to the results of prospective clinical trials.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L.A. Devriese: Non-Financial Interests, Institutional, Advisory Role: BMS; Non-Financial Interests, Institutional, Advisory Role: Merck; Non-Financial Interests, Institutional, Advisory Role: MSD. J.B.A.G. Haanen: Non-Financial Interests, Institutional, Advisory Role: Achilles Therapeutics; Non-Financial Interests, Institutional, Advisory Role: Aimm; Non-Financial Interests, Institutional, Advisory Role: BioNTech; Non-Financial Interests, Institutional, Advisory Role: BMS; Non-Financial Interests, Institutional, Advisory Role: Gadeta; Non-Financial Interests, Institutional, Advisory Role: Immunocore; Non-Financial Interests, Institutional, Advisory Role: Ipsen; Non-Financial Interests, Institutional, Advisory Role: MSD; Non-Financial Interests, Institutional, Advisory Role: Merck Serono; Non-Financial Interests, Institutional, Advisory Role: Molecular Partners; Non-Financial Interests, Institutional, Advisory Role: Neogene Therapeutics; Non-Financial Interests, Institutional, Advisory Role: Novartis; Non-Financial Interests, Institutional, Advisory Role: Pfizer; Non-Financial Interests, Institutional, Advisory Role: Roche/Genentech; Non-Financial Interests, Institutional, Advisory Role: Sanofi; Non-Financial Interests, Institutional, Advisory Role: Seattle Genetics; Non-Financial Interests, Institutional, Advisory Role: Third Rock Ventures; Financial Interests, Institutional, Research Grant: Amgen; Financial Interests, Institutional, Research Grant: BioNTech; Financial Interests, Institutional, Research Grant: BMS; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Novartis. All other authors have declared no conflicts of interest.

Background

Ovarian cancer (OC) is the most lethal gynecologic cancer. BRCA1/2 genetic testing has a significant impact on OC prevention and treatment, but the role of other genes in hereditary OC is less understood. In this study we analyzed wild-type BRCA1/2 OC patients (pts) registered in our clinic.

Methods

Observational study characterizing the molecular contribution of non-BRCA1/2 genes to hereditary cancer. Survival outcomes were calculated by the Kaplan Meier method.

Results

Between January 2000 to December 2020, 5233 index pts consented in genetic testing, 502 (9.6%) of whom had OC diagnosis. Of these, 176 pts (35%) underwent BRCA1/2 testing only, while 326 pts consented in multigene panel testing (MGPT). BRCA1/2 detection rate was 17% (86/502), while the detection rate for non-BRCA genes was 28/ 326 (8,6%). Wild-type BRCA1/2 OC pathogenic variants (PV), were diagnosed in RAD51D, RAD51C, CHEK2, ATM, TP53 (low allelic fraction in an advanced pt with fallopian tube carcinoma), BRIP1 and MUTYH genes (Table). Median age at diagnosis of non-BRCA OC pts with a PV identified was 57,5 yrs (34-73). For a median follow-up of 42.7 months (7.9-254.2), 14 (50%) pts had recurrent disease and 5 (17.9%) pts died. Median progression free survival was 29.3 months (7.9-110.8) and median OS was 155.25 months (127-182). No significant difference was observed in OS between wild-type BRCA1/2 OC and the hereditary non-BRCA1/2 subgroup (p = 0.097). Survival differences between index BRCAmt and the hereditary non-BRCA OC were also non-significant(p=0.204). Table: 770P

Conclusions

RAD51C and RAD51D genes are the main contributors to hereditary wild-type BRCA1/2 OC in our cohort. The identification by MGPT of a TP53 PV with low allelic fraction raises suspicion of somatic interference. Although most pts with PV in genes other than BRCA1/2 had either relapsed or died at the time of this analysis, no differences in survival were observed between this subgroup and BRCA1/2 wild-type OC neither with BRCA1/2 OC.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The efficacy of nivolumab monotherapy has demonstrated survival benefit for patients with metastatic and recurrent esophageal squamous cell carcinoma in ATTRACTION-3 study. However, about only 20% of the patients respond to nivolumab, raising the necessity of its predictive biomarkers. Recent studies showed that gut microbiome as an important regulator of immunity, with the potential to modulate responses to immune check point inhibitors (ICIs). However, the specific functions and molecular mechanisms of each component of the complex gut microbiome remain largely unknown. Moreover, reported bacteria are different among studies. It implies that the immune-modulating effects of the gut microbiota are different according to race, geography, foods and cancer types. Furthermore, some species of oral bacteria was reported to development and presence of the intratumor bacteria was associated with poor prognosis of esophageal cancer.

Trial design

To evaluate the efficacy and the safety of nivolumab monotherapy for patients with metastatic and recurrent esophageal cancer and explore the utility of oral and gut microbiome as a potential biomarker, HGCSG2002 study has started as multicenter observational biomarker study. The patients with metastatic or recurrent esophageal squamous cell carcinoma who receive nivolumab monotherapy are eligible for this study. Nivolumab 240 mg is administered intravenously every 2 weeks. Samples of saliva and feces are collected at three point; before the initial treatment, 4 weeks after the first administration and after the finish of nivolumab treatment. The analysis with 16S rRNA gene sequences is planned to investigate bacterial diversity and taxonomic profile. The primary endpoint is overall survival, and the secondary endpoints are progression-free survival, safety and association between oral and gut microbiome and clinical outcome. A total of 25 cases are planned for registration within 2 years. This study was approved by the institutional review board of Hokkaido University Hospital (approval number: 020-0224). This study is registered with UMIN registration number: UMIN000043208.

Clinical trial identification

UMIN000043208.

Legal entity responsible for the study

Hokkaido Gastrointestinal Cancer Study Group.

Funding

Ono Pharmaceutical Co., Ltd.

Disclosure

K. Harada: Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical Company Limited; Financial Interests, Personal, Invited Speaker: Nippon Kayaku Co.,Ltd.; Financial Interests, Personal, Invited Speaker: Bayer Yakuhin, Ltd. S. Yuki: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly K.K.; Financial Interests, Personal, Invited Speaker: Takeda Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Bayer Yakuhin, Ltd; Financial Interests, Personal, Invited Speaker: Bristol-Myers Squibb Co., Ltd.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: MSD K.K.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Invited Speaker: Medical & Biological Laboratories Co., Ltd.; Financial Interests, Personal, Invited Speaker: Yakult Honsha Co., Ltd.; Financial Interests, Personal, Invited Speaker: Merck Biopharma Co., Ltd.; Financial Interests, Personal, Invited Speaker: Sanofi K.K.. Y. Tsuji: Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co. Ltd.; Financial Interests, Personal, Invited Speaker: Ono Pharmaceutical Co. Ltd.; Financial Interests, Personal, Invited Speaker: Asahi Kasei Pharma Co. Ltd.; Financial Interests, Personal, Invited Speaker: Sawai Pharmaceutical Co. Ltd.; Financial Interests, Personal, Invited Speaker: Eli Lilly Japan Co. Ltd.; Financial Interests, Personal, Invited Speaker: Merck Biopharma Co. Ltd.; Financial Interests, Personal, Invited Speaker: Nippon Kayaku Co. Ltd.; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical Co. Ltd.; Financial Interests, Personal, Invited Speaker: Bayer Co. Ltd. I. Yokota: Financial Interests, Personal, Research Grant: Japan Society for the Promotion of Science Kakenhi; Financial Interests, Personal, Research Grant: Health, Labour and Welfare Policy Research Grants; Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co,; Financial Interests, Personal, Invited Speaker: AstraZeneca plt; Financial Interests, Personal, Invited Speaker: Japan Tabacco Pharamaceutical Division; Financial Interests, Personal, Invited Speaker: Nippon Shinyaku Co. N. Sakamoto: Financial Interests, Personal, Invited Speaker: Gilead Sciences; Financial Interests, Personal, Invited Speaker: Chugai Parm; Financial Interests, Personal, Invited Speaker: Bayer AG; Financial Interests, Personal, Invited Speaker: Otsuka Pharm; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Astellas Pharma; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Research Grant: Gilead Sciences; Financial Interests, Personal, Research Grant: Eisai; Financial Interests, Personal, Research Grant: MSD; Financial Interests, Personal, Research Grant: Otsuka Pharm; Financial Interests, Personal, Research Grant: AbbVie; Financial Interests, Personal, Research Grant: Asuka Pharm. Y. Sakata: Financial Interests, Personal, Invited Speaker: Yakult Honsha; Financial Interests, Personal, Invited Speaker: Taiho Pharmaceutical; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo Co. Ltd.; Financial Interests, Personal, Invited Speaker: BMS Co; Financial Interests, Personal, Stocks/Shares: Delt-fly pharm. Y. Komatsu: Financial Interests, Personal, Research Grant: MSD; Financial Interests, Personal, Research Grant: JFMC; Financial Interests, Personal, Research Grant: NanoCarrier; Financial Interests, Personal, Research Grant: Yakult; Financial Interests, Personal, Research Grant: Mediscience; Financial Interests, Personal, Research Grant: National cancer center; Financial Interests, Personal, Research Grant: ONO; Financial Interests, Personal, Research Grant: Taiho; Financial Interests, Personal, Research Grant: Daiichi Sankyo; Financial Interests, Personal, Research Grant: IQVIA; Financial Interests, Personal, Research Grant: Chugai; Financial Interests, Personal, Invited Speaker: Ono; Financial Interests, Personal, Invited Speaker: Taiho; Financial Interests, Personal, Invited Speaker: Chugai; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Institutional, Research Grant: Eli Lilly; Financial Interests, Institutional, Research Grant: Nipro. All other authors have declared no conflicts of interest.

Background

This dose-finding study of osimertinib aimed to investigate the safety, pharmacokinetics (PK), and recommended dose (RD) for EGFR-mutated non-small cell lung carcinoma (NSCLC) patients with impaired renal function and low body weight.

Methods

NSCLC patients with activated EGFR mutations, regardless of T790M mutation, were allocated into the following four cohorts according to renal function and body weight: cohort A, normal renal function (eGFR ≥ 50 mL/min/1.73 m²) and normal body weight (≥ 45 kg); cohort B, moderate renal dysfunction (eGFR = 30-50 mL/min/1.73 m²); cohort C, low body weight (< 45 kg); and cohort D, severe renal dysfunction (eGFR < 30 mL/min/1.73 m² or undergoing dialysis). We evaluated the PK and safety in cohort A as the control group. Cohorts B, C, and D consisted of two parts, dose-escalation using a standard 3 + 3 design and expansion. The starting dose of osimertinib in cohorts A, B, and C was 80 mg once daily, while for cohort D, it was 40 mg once daily. For PK analysis, serial blood samples were collected on days 1 and 15, and pre-dose blood samples were collected on days 29 and 56.

Results

Thirty eligible patients with EGFR-mutated NSCLC were enrolled in eight institutions in Japan. In cohort A, one patient discontinued osimertinib therapy on day six due to an exacerbation of chronic obstructive pulmonary disease. Twenty-nine patients were evaluated for PK and safety (N=12 for A, N=8 for B, N=8 for C, and N=1 for D). In the dose-escalation part, no DLT was observed, and the RD was determined to be 80 mg once in cohorts B and C. Due to the poor accrual, only one patient was included in cohort D. Four serious adverse events occurred in this study, and two considered to be related to osimertinib (heart failure grade 3 in cohort B and ILD grade 3 in cohort C). The PK parameters of osimertinib in cohorts A, B, and C were similar. However, the toxicity of any grade occurred more frequently in cohorts B and C than in cohort A.

Conclusions

The RD of osimertinib was determined to be 80 mg once for patients with moderate renal function (cohort B) and low body weight (cohort C). Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in cohorts B and C than in cohort A.

Clinical trial identification

UMIN000033301.

Editorial acknowledgement

Editage for English language editing.

Legal entity responsible for the study

The authors.

Funding

This research was supported by AMED under Grant Number JP20ck0106464h0003.

Disclosure

T. Hase: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Kyowa Kirin; Financial Interests, Personal, Other, Honoraria (Lecture fee): Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria (Lecture fee): Nippon Kayaku; Financial Interests, Personal, Other, Honoraria (Lecture fee): Novartis Pharma; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical; Financial Interests, Institutional, Principal Investigator: AstraZeneca; Financial Interests, Institutional, Principal Investigator: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator: Novartis Pharma; Financial Interests, Institutional, Research Grant: Taiho Pharmaceutical. Y. Fujiwara: Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Ono Pharmaceutical; Financial Interests, Personal, Advisory Board: Otsuka Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria (Lecture fee): Novartis. R.A. Makihara: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Novartis; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eisai; Financial Interests, Personal, Other, Honoraria (Lecture fee): Taiho Pharmaceutical. N. Hashimoto: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Boehringer Ingelheim; Financial Interests, Personal, Other, Honoraria (Lecture fee): GlaxoSmithKline; Financial Interests, Personal, Other, Honoraria (Lecture fee): Novartis; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim. Y. Tsubata: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca K.K.; Financial Interests, Personal, Other, Honoraria (Lecture fee): Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical Co., Ltd.; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical Co., Ltd.; Financial Interests, Personal, Funding: Pfizer Health Research Foundation. T. Takahashi: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): MSD; Financial Interests, Personal, Other, Honoraria (Lecture fee): Pfizer Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Boehringer Ingelheim Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Roche Diagnostics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical; Financial Interests, Institutional, Research Grant: Eli Lilly Japan; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: MSD; Financial Interests, Institutional, Research Grant: Pfizer Japan; Financial Interests, Institutional, Research Grant: Boehringer Ingelheim Japan; Financial Interests, Institutional, Research Grant: Amgen. H. Kobayashi: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly; Financial Interests, Personal, Other, Honoraria (Lecture fee): Taiho Pharmaceutical. Y. Shinno: Financial Interests, Personal, Other, Honoraria (Lecture fee): Pfizer; Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca. K. Goto: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca K.K.; Financial Interests, Institutional, Research Grant: AstraZeneca K.K.; Financial Interests, Personal, Advisory Board: AstraZeneca K.K. Y. Hosomi: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly Japan; Financial Interests, Personal, Other, Honoraria (Lecture fee): Taiho Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria (Lecture fee): Kyowa Kirin. K. Watanabe: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Taiho Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical; Financial Interests, Personal, Other, Honoraria (Lecture fee): MSD; Financial Interests, Personal, Other, Honoraria (Lecture fee): Pfizer; Financial Interests, Personal, Other, Honoraria (Lecture fee): Boehringer Ingelheim. S. Kitazono: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai Pharmaceutical Co., Ltd.; Financial Interests, Personal, Other, Honoraria (Lecture fee): Daiichi Sankyo; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono Pharmaceutical Co. N. Yamamoto: Financial Interests, Personal, Other, Honoraria (Lecture fee): AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Chugai; Financial Interests, Personal, Other, Honoraria (Lecture fee): Chugai; Financial Interests, Personal, Advisory Board: Cimic; Financial Interests, Personal, Other, Honoraria (Lecture fee): Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Other, Honoraria (Lecture fee): Eli Lilly; Financial Interests, Personal, Other, Honoraria (Lecture fee): Ono; Financial Interests, Personal, Advisory Board: Otsuka; Financial Interests, Personal, Other, Honoraria (Lecture fee): Pfizer; Financial Interests, Personal, Other, Honoraria (Lecture fee): Sysmex; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: AbbVie; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Astellas; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Bayer; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: BMS; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Boehringer Ingelheim; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Chiome Bioscience; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Chugai; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Eisai; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Eli Lilly; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: GSK; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Janssen Pharma; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Kyowa Hakko Kirin; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Merck; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: MSD; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Novartis; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Ono; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Otsuka; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Pfizer; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Sumitomo Dainippon; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Taiho; Financial Interests, Institutional, Principal Investigator, Principal Investigator in industry sponsored trial: Takeda. All other authors have declared no conflicts of interest.