Efficacy of a platinum-based chemotherapy rechallenge for platinum-sensitive recurrence after PARP inhibitor maintenance.

Objective: Platinum-free interval (PFI) is the period from the end of platinum-based chemotherapy to the date of recurrence. If the PFI is > 6 months, a platinum-based chemotherapy rechallenge is considered; however, its efficacy after poly adenosine 5'-diphosphate-ribose polymerase (PARP) inhibitor maintenance therapy is unknown. This study aimed to examine the efficacy of a platinum-based chemotherapy rechallenge after PARP inhibitor therapy. Methods: We retrospectively evaluated patients with ovarian cancer with a PFI≥6 months with PARP inhibitor maintenance therapy, receiving platinum-based chemotherapy. Duration of PARP inhibitor therapy, best response to subsequent platinum chemotherapy rechallenge, and clinical characteristics were collected from medical records. Tumor response was assessed according to RECIST 1.1. Correlations were calculated using Spearman's correlation coefficients. Results: Among the 10 included patients, seven (70 %) received PARP inhibitors after primary chemotherapy, and three (30 %) received chemotherapy for platinum-sensitive relapse. One and five patients harbored a germline BRCA1 and BRCA wild-type mutations, respectively, and two had homologous recombination proficiency. The median PFI was 303.5 (182-602) days, and PARP inhibitor therapy duration was 249 (147-570) days. Platinum chemotherapy rechallenge efficacy was complete and partial response and stable disease in one (10 %), six (60 %), and three (30 %) patients, respectively. The longer the duration of PARP inhibitor treatment, better the response to platinum agents (Spearman correlation coefficient 0.284, p = 0.0288). Conclusion: Platinum-based chemotherapy rechallenge is reasonable for patients with platinum-sensitive disease, using the traditional PFI cutoff of 6 months, even when the PFI is obtained with a maintenance PARP inhibitor.

Preliminary results from ASCENT-J02: a phase 1/2 study of sacituzumab govitecan in Japanese patients with advanced solid tumors.

BACKGROUND: Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate approved outside Japan for second-line and later metastatic triple-negative breast cancer (mTNBC), based on the ASCENT study (NCT02574455). We report SG safety and efficacy in an open-label, phase 1/2 bridging study in Japanese patients with advanced solid tumors (ASCENT-J02; NCT05101096; jRCT2031210346). METHODS: Phase 1 was a standard 3 + 3 design. Patients received intravenous SG 6 mg/kg, escalating to 10 mg/kg, on Days 1 and 8 per 21-day cycle; primary endpoints were safety, incidence of dose-limiting toxicity/toxicities (DLTs), and determination of the recommended phase 2 dose (RP2D). In the multicohort phase 2 study, patients in the mTNBC cohort with previously treated disease received SG at the RP2D; primary endpoint was independent review committee (IRC)-assessed objective response rate (ORR; RECIST v1.1). Safety was a secondary endpoint. RESULTS: In phase 1 (N = 15), one DLT (grade 3 elevated transaminases) occurred with SG 10 mg/kg; RP2D was SG 10 mg/kg regardless of UGT1A1 status. In phase 2, 36 patients with mTNBC received SG 10 mg/kg. At median follow-up of 6.1 months, IRC-assessed ORR was 25.0% (95% CI 12.1-42.2; P = 0.0077). Median progression-free survival was 5.6 months (95% CI 3.9-not reached [NR]); median overall survival was NR. No treatment-emergent adverse events led to discontinuation or death. CONCLUSIONS: SG RP2D was established as 10 mg/kg in Japanese patients. SG showed efficacy in Japanese patients with previously treated mTNBC, a manageable safety profile, and no new safety signals, consistent with the previous ASCENT study.

Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study.

BACKGROUND: Patients with unfavourable subset cancer of unknown primary (CUP) have a poor prognosis when treated with standard platinum-based chemotherapy. Whether first-line treatment guided by comprehensive genomic profiling (CGP) can improve outcomes is unknown. The CUPISCO trial was designed to inform a molecularly guided treatment strategy to improve outcomes over standard platinum-based chemotherapy in patients with newly diagnosed, unfavourable, non-squamous CUP. The aim of the trial was to compare the efficacy and safety of molecularly guided therapy (MGT) versus standard platinum-based chemotherapy in these patients. This was to determine whether the inclusion of CGP in the initial diagnostic work-up leads to improved outcomes over the current standard of care. We herein report the primary analysis. METHODS: CUPISCO was a phase 2, prospective, randomised, open-label, active-controlled, multicentre trial done at 159 sites in 34 countries outside the USA. Patients with central eligibility review-confirmed disease (acceptable histologies included adenocarcinoma and poorly differentiated carcinoma) and an Eastern Cooperative Oncology Group performance status of 0 or 1, evaluated by CGP, who reached disease control after three cycles of standard first-line platinum-based chemotherapy were randomly assigned 3:1 via a block-stratified randomisation procedure to MGT versus chemotherapy continuation for at least three further cycles. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03498521, and follow-up is ongoing. FINDINGS: From July 10, 2018, to Dec 9, 2022, 636 (42%) of 1505 screened patients were enrolled. Median follow-up in the treatment period was 24·1 months (IQR 11·6-35·6). Of 438 patients who reached disease control after induction chemotherapy, 436 were randomly assigned: 326 (75%) to the MGT group and 110 (25%) to the chemotherapy group. Median progression-free survival in the intention-to-treat population was 6·1 months (95% CI 4·7-6·5) in the MGT group versus 4·4 months (4·1-5·6) in the chemotherapy group (hazard ratio 0·72 [95% CI 0·56-0·92]; p=0·0079). Related adverse event rates per 100-patient-years at risk were generally similar or lower with MGT versus chemotherapy. INTERPRETATION: In patients with previously untreated, unfavourable, non-squamous CUP who reached disease control after induction chemotherapy, CGP with subsequent MGTs resulted in longer progression-free survival than standard platinum-based chemotherapy. On the basis of these results, we recommend that CGP is performed at initial diagnosis in patients with unfavourable CUP. FUNDING: F Hoffmann-La Roche.

Efficacy of Trametinib in Neurofibromatosis Type 1-Associated Gastrointestinal Stromal Tumors: A Case Report.

Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST.

Outcomes in Nonmetastatic Hormone Receptor-Positive HER2-Negative Pure Mucinous Breast Cancer: A Multicenter Cohort Study.

BACKGROUND: Although considered a favorable subtype, pure mucinous breast cancer (PMBC) can recur, and evidence for adjuvant therapy is limited. We aimed to compare outcomes of nonmetastatic PMBC with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) to address these uncertainties. METHODS: Individual patient-level data from 6 centers on stage I-III hormone receptor-positive and HER2-negative PMBC, IDC, and ILC were used to analyze recurrence-free interval (RFI), recurrence-free survival (RFS), and overall survival (OS), and to identify prognostic factors for PMBC. RESULTS: Data from 20,684 IDC cases, 1,475 ILC cases, and 943 PMBC cases were used. Median follow-up was 6.6 years. Five-year RFI, RFS, and OS for PMBC were 96.1%, 94.9%, and 98.1%, respectively. On multivariable Cox regression, PMBC demonstrated superior RFI (hazard ratio [HR], 0.59; 95% CI, 0.43-0.80), RFS (HR, 0.70; 95% CI, 0.56-0.89), and OS (HR, 0.71; 95% CI, 0.53-0.96) compared with IDC. ILC showed comparable outcomes to IDC. Fewer than half (48.7%) of recurrences in PMBC were distant, which was a lower rate than for IDC (67.3%) and ILC (80.6%). In contrast to RFI, RFS events were driven more by non-breast cancer deaths in older patients. Significant prognostic factors for RFI among PMBC included positive lymph node(s) (HR, 2.42; 95% CI, 1.08-5.40), radiotherapy (HR, 0.44; 95% CI, 0.23-0.85), and endocrine therapy (HR, 0.25; 95% CI, 0.09-0.70). No differential chemotherapy associations with outcomes were detected across PMBC subgroups by nodal stage, tumor size, and age. A separate SEER database analysis also did not find any association of improved survival with adjuvant chemotherapy in these subgroups. CONCLUSIONS: Compared with IDC, PMBC demonstrated superior RFI, RFS, and OS. Lymph node negativity, adjuvant radiotherapy, and endocrine therapy were associated with superior RFI. Adjuvant chemotherapy was not associated with better outcomes.

Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study.

BACKGROUND: Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations. METHODS: In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting. FINDINGS: Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis. INTERPRETATION: Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting. FUNDING: AstraZeneca and Daiichi Sankyo.

PD-1 inhibition with retifanlimab and/or arginase inhibition with INCB001158 in Japanese patients with solid tumors: A phase I study.

BACKGROUND: Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors. METHODS: Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients. RESULTS: Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy. CONCLUSION: Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients.

Genomic Landscape of Circulating Tumor DNA in Patients With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Treated With Abemaciclib: Data From the SCRUM-Japan Cancer Genome Screening Project.

PURPOSE: To understand the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) treated with abemaciclib + endocrine therapy (ET). METHODS: Blood samples for ctDNA and/or tissue samples were collected from abemaciclib-treated patients with HR+/HER2- MBC enrolled in the SCRUM-Japan MONSTAR-SCREEN project. Blood samples were collected before abemaciclib initiation (baseline) and at disease progression/abemaciclib discontinuation (post abemaciclib treatment). Clinical and genomic characteristics including neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]) were assessed at baseline. Genomic alterations in ctDNA were compared in paired baseline and post abemaciclib treatment samples. RESULTS: All patients (N = 97) were female (median age, 57 years [IQR, 50-67]). In baseline ctDNA (n = 77), PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequently mutated genes. Baseline tissue samples (n = 79) showed similar alteration frequencies. Among patients with baseline ctDNA data, 30% had received previous ET. ESR1 alteration frequency (35% v 8%; P < .01), median shedding rate (3 v 2), and maximum somatic VAF (4 v 0.8; both P < .05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), PIK3CA and ESR1 alteration frequencies were higher after abemaciclib treatment than at baseline, though not statistically significant. Among the post-treatment alterations, those newly acquired were detected most frequently in FGF3/4/19 (18%); PIK3CA, TP53, CCND1, and RB1 (all 15%); and ESR1 (12%). CONCLUSION: We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2- MBC. The data provide insights that could help optimize treatment strategies in this population.

English version of Japanese Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) issued by the Japan Society of Clinical Oncology.

The Japan Society of Clinical Oncology Clinical Practice Guidelines 2022 for gastrointestinal stromal tumor (GIST) have been published in accordance with the Minds Manual for Guideline Development 2014 and 2017. A specialized team independent of the working group for the revision performed a systematic review. Since GIST is a rare type of tumor, clinical evidence is not sufficient to answer several clinical and background questions. Thus, in these guidelines, we considered that consensus among the experts who manage GIST, the balance between benefits and harms, patients' wishes, medical economic perspective, etc. are important considerations in addition to the evidence. Although guidelines for the treatment of GIST have also been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO), there are some differences between the treatments proposed in those guidelines and the treatments in the present guidelines because of the differences in health insurance systems among countries.

Molecular and clinicopathological features of KIT/PDGFRA wild-type gastrointestinal stromal tumors.

Approximately 10% of gastrointestinal stromal tumors (GISTs) harbor reportedly no KIT and PDGFRA mutations (wild-type GISTs). The clinicopathological features and oncologic outcomes of wild-type GISTs based on molecular profiles are unknown. We recruited 35 wild-type GIST patients from the two registry studies of high-risk GISTs between 2012 and 2015 and primary GISTs between 2003 and 2014. Molecular profiling of wild-type GISTs was performed by targeted next-generation sequencing (NGS) using formalin-fixed paraffin-embedded tumor samples. Among 35 wild-type GISTs, targeted NGS analysis detected NF1, SDH, or BRAF mutation: 16 NF1-GISTs with various NF1 mutations, 12 SDH-GISTs (4 with SDHA mutations, 4 with SDHB mutations, and 4 with SDHB-negative staining), and 5 BRAF-GISTs with the V600E mutation. Two GISTs showed no mutations based on our targeted NGS analysis. Additional gene mutations were infrequent in primary wild-type GISTs and found in TP53, CREBBP, CDKN2A, and CHEK2. Most NF1-GISTs were located in the small intestine (N = 12; 75%) and showed spindle cell features (N = 15; 94%) and multiple tumors (N = 6, 38%) with modest proliferation activities. In contrast, SDH-GISTs were predominantly found in the stomach (N = 11; 92%), exhibiting epithelioid cell (N = 6; 50%) and multiple (N = 6, 50%) features. The overall survival of patients with SDH-GISTs appeared to be better than that of BRAF-GISTs (p = 0.0107) or NF1-GISTs (p = 0.0754), respectively. In conclusion, major molecular changes in wild-type GISTs include NF1, SDH, and BRAF. NF1-GISTs involved multifocal spindle cell tumors in the small intestine. SDH-GISTs occurred in young patients and were multifocal in the stomach and clinically indolent.

A Learning Program for Treatment Recommendations by Molecular Tumor Boards and Artificial Intelligence.

Importance: Substantial heterogeneity exists in treatment recommendations across molecular tumor boards (MTBs), especially for biomarkers with low evidence levels; therefore, the learning program is essential. Objective: To determine whether a learning program sharing treatment recommendations for biomarkers with low evidence levels contributes to the standardization of MTBs and to investigate the efficacy of an artificial intelligence (AI)-based annotation system. Design, Setting, and Participants: This prospective quality improvement study used 50 simulated cases to assess concordance of treatment recommendations between a central committee and participants. Forty-seven participants applied from April 7 to May 13, 2021. Fifty simulated cases were randomly divided into prelearning and postlearning evaluation groups to assess similar concordance based on previous investigations. Participants included MTBs at hub hospitals, treating physicians at core hospitals, and AI systems. Each participant made treatment recommendations for each prelearning case from registration to June 30, 2021; participated in the learning program on July 18, 2021; and made treatment recommendations for each postlearning case from August 3 to September 30, 2021. Data were analyzed from September 2 to December 10, 2021. Exposures: The learning program shared the methodology of making appropriate treatment recommendations, especially for biomarkers with low evidence levels. Main Outcomes and Measures: The primary end point was the proportion of MTBs that met prespecified accreditation criteria for postlearning evaluations (approximately 90% concordance with high evidence levels and approximately 40% with low evidence levels). Key secondary end points were chronological enhancements in the concordance of treatment recommendations on postlearning evaluations from prelearning evaluations. Concordance of treatment recommendations by an AI system was an exploratory end point. Results: Of the 47 participants who applied, 42 were eligible. The accreditation rate of the MTBs was 55.6% (95% CI, 35.3%-74.5%; P < .001). Concordance in MTBs increased from 58.7% (95% CI, 52.8%-64.4%) to 67.9% (95% CI, 61.0%-74.1%) (odds ratio, 1.40 [95% CI, 1.06-1.86]; P = .02). In postlearning evaluations, the concordance of treatment recommendations by the AI system was significantly higher than that of MTBs (88.0% [95% CI, 68.7%-96.1%]; P = .03). Conclusions and Relevance: The findings of this quality improvement study suggest that use of a learning program improved the concordance of treatment recommendations provided by MTBs to central ones. Treatment recommendations made by an AI system showed higher concordance than that for MTBs, indicating the potential clinical utility of the AI system.

Clinical practice guidelines for molecular tumor markers, 2nd edition review part 1.

With advances in gene and protein analysis technologies, many target molecules that may be useful in cancer diagnosis have been reported. Therefore, the "Tumor Marker Study Group" was established in 1981 with the aim of "discovering clinically" useful molecules. Later, the name was changed to "Japanese Society for Molecular Tumor Marker Research" in 2000 in response to the remarkable progress in gene-related research. Currently, the world of cancer treatment is shifting from the era of representative tumor markers of each cancer type used for tumor diagnosis and treatment evaluation to the study of companion markers for molecular-targeted therapeutics that target cancer cells. Therefore, the first edition of the Molecular Tumor Marker Guidelines, which summarizes tumor markers and companion markers in each cancer type, was published in 2016. After publication of the first edition, the gene panel testing using next-generation sequencing became available in Japan in June 2019 for insured patients. In addition, immune checkpoint inhibitors have been indicated for a wide range of cancer types. Therefore, the 2nd edition of the Molecular Tumor Marker Guidelines was published in September 2021 to address the need to revise the guidelines. Here, we present an English version of the review (Part 1) of the Molecular Tumor Marker Guidelines, Second Edition.

Efficacy and safety of mirogabalin for chemotherapy-induced peripheral neuropathy: a prospective single-arm trial (MiroCIP study).

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a painful, dose-limiting adverse effect of commonly used chemotherapeutic agents. The purpose of this exploratory study was to evaluate the efficacy and safety of mirogabalin in patients with moderate to severe CIPN during chemotherapy and the effects of 12 weeks' intervention on chemotherapy completion and CIPN severity. METHODS: Patients experiencing moderate to severe CIPN while undergoing oxaliplatin- or taxane-containing chemotherapy for colorectal, gastric, non-small-cell lung, or breast cancer received mirogabalin at between 5 and 15 mg twice daily. The primary endpoint was change in numeric rating scale (NRS) score for pain from baseline to week 12. Secondary endpoints included NRS scores for tingling and sleep, completion of chemotherapy, severity of CIPN, and quality of life (QOL) scores. The safety endpoint was incidence of adverse events. RESULTS: Of 58 patients who consented to participation, 52 were eligible and constituted the full analysis set and safety analysis set. From baseline to week 12 (last observation carried forward [LOCF]), NRS score decreased by 30.9%: mean change (95% confidence interval [CI]), - 1.7 (- 2.4 to - 1.0) (p < 0.001). Patients with baseline NRS of ≥ 6 experienced a 44.0% reduction in score from baseline to week 12 (LOCF): mean change (95% CI), - 3.3 (- 5.0 to - 1.5) (p = 0.002). Chemotherapy was discontinued in 18 (34.6%) patients; CIPN led to discontinuation in only 2 (3.8%). There was no notable worsening of CIPN severity in terms of Common Terminology Criteria for Adverse Events grade or Modified Total Neuropathy Score-reduced, although use of pain medications during chemotherapy might cause worsening of CIPN due to underestimation of subjective symptoms. QOL score based on the EuroQol five-dimensional descriptive system did not worsen during the 12 weeks. Thirty-one percent of patients experienced adverse drug reactions, and the most common event was somnolence (13.5%). Serious adverse events and death occurred in 3 patients and 1 patient, respectively; however, they were unrelated to mirogabalin treatment. CONCLUSIONS: Intervention with mirogabalin during chemotherapy may be effective and safe for cancer patients with moderate to severe CIPN. It can contribute to completion of chemotherapy without worsening of CIPN. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs031210101, registered 20/5/2021).

The Japanese Breast Cancer Society Clinical Practice Guidelines for systemic treatment of breast cancer, 2022 edition.

The Japanese Breast Cancer Society (JBCS) Clinical Practice Guidelines for systemic treatment of breast cancer were updated to the 2022 edition through a process started in 2018. The updated guidelines consist of 12 background questions (BQs), 33 clinical questions (CQs), and 20 future research questions (FRQs). Multiple outcomes including efficacy and safety were selected in each CQ, and then quantitative and qualitative systematic reviews were conducted to determine the strength of evidence and strength of recommendation, which was finally determined through a voting process among designated committee members. Here, we describe eight selected CQs as important updates from the previous guidelines, including novel practice-changing updates, and recommendations based on evidence that has emerged specifically from Japanese clinical trials.

Prognostic impact of adjuvant endocrine therapy for estrogen receptor-positive and HER2-negative T1a/bN0M0 breast cancer.

PURPOSE: Mammography screening has increased the detection of subcentimeter breast cancers. The prognosis for estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative T1a/bN0M0 breast cancers is excellent; however, the necessity of adjuvant endocrine therapy (ET) is uncertain. METHODS: We evaluated the effectiveness of adjuvant ET in patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer who underwent surgery from 2008 to 2012. Standard ET was administrated after surgery. The primary endpoint was the cumulative incidence of distant metastasis. All statistical tests were 2-sided. RESULTS: Adjuvant ET was administered to 3991 (83%) of the 4758 eligible patients (1202 T1a [25.3%] and 3556 T1b [74.7%], diseases). The median follow-up period was 9.2 years. The 9-year cumulative incidence of distant metastasis was 1.5% with ET and 2.6% without ET (adjusted subdistribution hazard ratio [sHR], 0.54; 95% CI, 0.32-0.93). In multivariate analysis, the independent risk factors for distant metastasis were no history of ET, mastectomy, high-grade, and lymphatic invasion. The 9-year overall survival was 97.0% and 94.4% with and without ET, respectively (adjusted HR, 0.57; 95% CI, 0.39-0.83). In addition, adjuvant ET reduced the incidence of ipsilateral and contralateral breast cancer (9-year rates; 1.1% vs. 6.9%; sHR, 0.17, and 1.9% vs. 5.2%; sHR, 0.33). CONCLUSIONS: The prognosis was favorable in patients with ER-positive and HER2-negative T1a/bN0M0 breast cancer. Furthermore, adjuvant ET reduced the incidence of distant metastasis with minimal absolute risk difference. These findings support considering the omission of adjuvant ET, especially for patients with low-grade and no lymphatic invasion disease.

Safety of immune checkpoint inhibitors after proton beam therapy in head and neck mucosal melanoma: a case series.

Proton beam therapy (PBT) has shown promising efficacy in treating locally advanced head and neck mucosal melanoma despite its poor prognosis. Although PBT may improve the efficacy of subsequent immune checkpoint inhibitors (ICIs), the safety of ICIs in patients who have previously received PBT has not been established. Hence, this study evaluated the safety of ICIs in patients who had recurrent mucosal melanoma after PBT. Between April 2013 and June 2022, we retrospectively reviewed the medical records of patients diagnosed with cutaneous or mucosal melanoma at the National Cancer Center Hospital East. Seven patients were treated with ICIs after their head and neck mucosal melanoma (HNMM) recurred after PBT. Four of the seven patients experienced grade immune-related adverse events (irAEs). Due to irAE in the irradiation field, two patients had grade 3 hypopituitarism. Other grade 3 or higher irAEs included an increase in serum alanine aminotransferase in two patients and gastritis in one, and two patients discontinued ICI due to the irAEs. All irAEs were resolved with appropriate management. Although administering ICIs after PBT may increase the risk of irAEs, especially in the irradiation field, they appear manageable. These findings could help in the development of a treatment strategy for locally advanced HNMM that includes PBT and subsequent ICIs.

Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with DNA mismatch repair deficient (dMMR) tumors, third edition.

BACKGROUND: Clinical trials have reported the efficacy of immune checkpoint inhibitors in the treatment of mismatch repair-deficient (dMMR) advanced solid tumors. The accumulated evidence of tumor agnostic agent has been made since PD-1 inhibitor was approved and used in clinical practice. Therefore, we have revised the guideline "Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition". METHODS: Clinical questions regarding medical care were formulated for patients with dMMR advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO and the public comments among all societies' members were done. RESULTS: The current guideline describes two clinical questions and eight recommendations for whom, when, and how MMR status should be tested. CONCLUSION: In this guideline, the committee proposed eight recommendations for performing MMR testing properly to select patients who are likely to benefit from immunotherapy.

A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor.

PURPOSE: To evaluate DS-6157a, an antibody-drug conjugate targeting G protein-coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST). PATIENTS AND METHODS: In this phase I multicenter, open-label, multiple-dose study, patients with previously treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the MTD. Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy. RESULTS: A total of 34 patients enrolled. DS-6157a was well tolerated, with DLTs in 4 patients (11.8%) at doses of 6.4 mg/kg, 9.6 mg/kg, and 12.8 mg/kg; the MTD was determined to be 6.4 mg/kg. Treatment-emergent adverse events (TEAE) grade ≥3 occurred in 17 patients (50.0%), including decreased platelet count (23.5%), anemia (20.6%), decreased neutrophil count (14.7%), and decreased white blood cell count (11.8%). Four patients (11.8%) experienced serious adverse events related to DS-6157a. Six patients died with 5 due to disease progression and 1 due to DS-6157a-related TEAE. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response. Plasma concentrations and exposure of intact DS-6157a, DXd, and total anti-GPR20 antibody all demonstrated a dose-dependent profile. No treatment-emergent ADAs were observed. CONCLUSIONS: Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild-type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.

Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of immunotherapy in patients with high tumor mutational burden tumors.

The development of novel antitumor agents and accompanying biomarkers has improved survival across several tumor types. Previously, we developed recommendations for tumor-agnostic treatments in patients with solid tumors with DNA mismatch repair deficient or neurotrophic receptor tyrosine kinase fusions. Recently, immune checkpoint inhibitors have shown efficacy in patient with tumor mutation burden-high (TMB-H) solid tumors and have been established as a third tumor-agnostic agent, making it necessary to develop the guideline prioritized for these patients. Clinical questions regarding medical care were formulated for patients with TMB-H advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by Japan Society of Clinical Oncology (JSCO), Japanese Society of Medical Oncology (JSMO), and Japanese society of pediatric hematology/oncology (JSPHO) voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. The current guideline describes three clinical questions and seven recommendations for whom, when, and how TMB should be tested, and what is recommended for patients with TMB-H advanced solid tumors. In this guideline, the committee proposed seven recommendations for performing TMB testing properly to select patients who are likely to benefit from immunotherapy.

Japanese Society of Medical Oncology/Japan Society of Clinical Oncology/Japanese Society of Pediatric Hematology/Oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors.

BACKGROUND: Clinical trials have reported the efficacy of tropomyosin receptor kinase (TRK) inhibitors against neurotrophic receptor tyrosine kinase (NTRK) fusion gene-positive advanced solid tumors. The accumulated evidence of tumor-agnostic agent has made since TRK inhibitors were approved and used in clinical practice. Therefore, we have revised the 'Japan Society of Clinical Oncology (JSCO)/Japanese Society of Medical Oncology (JSMO)-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese Society of Pediatric Hematology/Oncology (JSPHO)'. METHODS: Clinical questions regarding medical care were formulated for patients with NTRK fusion-positive advanced solid tumors. Relevant publications were searched by PubMed and Cochrane Database. Critical publications and conference reports were added manually. Systematic reviews were performed for each clinical question for the purpose of developing clinical recommendations. The committee members identified by JSCO, JSMO, and JSPHO voted to determine the level of each recommendation considering the strength of evidence, expected risks and benefits to patients, and other related factors. Thereafter, a peer review by experts nominated from JSCO, JSMO, and JSPHO, and the public comments among all societies' members was done. RESULTS: The current guideline describes 3 clinical questions and 14 recommendations for whom, when, and how NTRK fusion should be tested, and what is recommended for patients with NTRK fusion-positive advanced solid tumors. CONCLUSION: The committee proposed 14 recommendations for performing NTRK testing properly to select patients who are likely to benefit from TRK inhibitors.