Zongertinib (BI 1810631), an irreversible HER2 TKI, spares EGFR signaling and improves therapeutic response in preclinical models and patients with HER2-driven cancers.

Mutations in HER2 occur in 2-4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2 mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent anti-tumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of antibody-drug conjugates and KRASG12C inhibitors, without causing obvious toxicities. The preclinical efficacy of zongertinib translates in objective responses in patients with HER2-dependent tumors, including cholangiocarcinoma (SDC4-NRG1 fusion) and breast cancer (V777L HER2 mutation) thus supporting the ongoing clinical development of zongertinib.

Association between lorlatinib blood concentration and adverse events and clinical impact of dose modification.

OBJECTIVES: Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, causes distinct adverse events (AEs), including hyperlipidemia and central nervous system (CNS) disorders. Although dose modifications are recommended to manage these AEs, whether dose modifications can achieve optimal blood lorlatinib concentrations and reduce the incidence of lorlatinib-induced AEs remains unclear. Therefore, we investigated the association between lorlatinib exposure and AEs in each patient. MATERIALS AND METHODS: We retrospectively reviewed patients with advanced ALK-rearranged non-small cell lung cancer treated with lorlatinib between November 2018 and July 2022. Serum lorlatinib concentrations were assessed using high-performance liquid chromatography-tandem mass spectrometry. All AEs were evaluated using the Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median age of the 55 eligible patients was 59 years (range: 23-79 years). All patients were administered lorlatinib after first line ALK-tyrosine kinase inhibitor failure. Grade ≥ 3 AEs occurred in 25 patients (25/55, 45 %), including hyperlipidemia in 17 (17/55, 31 %), CNS disorders in 7 (7/55, 13 %), and edema in 6 (6/55, 11 %). Dose modification was required in 23 patients (23/55, 42 %). Among the 36 patients with available data on serum lorlatinib levels at day 28 (±14) and no drug dose modifications, lorlatinib serum concentrations were significantly higher in patients with grade ≥ 3 AEs than in those without AEs (median: 462 ng/mL vs. 177 ng/mL, p < 0.01). In eight patients with data on serial lorlatinib serum concentrations following dose modifications, lorlatinib serum concentrations were effectively reduced, facilitating the ongoing administration of lorlatinib. Additionally, no significant difference was observed in the landmark analysis of progression-free survival between patients with dose modification within the first 16 weeks and those without (median: 24.8 months vs. 10.1 months, p = 0.46). CONCLUSION: Dose modification of lorlatinib was associated with successful management of AEs and decreased serum concentration of lorlatinib.

Pharmacokinetics, safety, and efficacy of an alternative dosing regimen of sasanlimab in participants with advanced NSCLC and other malignancies.

Background: Sasanlimab (PF-06801591), a humanized immunoglobulin G4 monoclonal antibody, binds to programmed cell death protein-1 (PD-1), preventing ligand (PD-L1) interaction. Objectives: To evaluate pharmacokinetics (PK), safety, tolerability, and efficacy of two subcutaneous sasanlimab dosing regimens. Design: An open-label study consisting of phases Ib and II. Phase Ib: non-randomized, dose escalation, and expansion study in Asian participants with advanced malignancies. Phase II: conducted globally in participants with non-small-cell lung cancer with PD-L1 positive or PD-L1 status unknown tumors; participants were randomized 1:2 to receive subcutaneous sasanlimab 300 mg once every 4 weeks (300 mg-Q4W) or 600 mg once every 6 weeks (600 mg-Q6W). Methods: Primary endpoint in phase Ib: dose-limiting toxicity (DLT) occurring in first treatment cycle; in phase II: C trough and AUC. Results: A total of 155 participants (phase Ib, n = 34; phase II, n = 121) received sasanlimab. Phase Ib: no DLT reported. Phase II: ratio of adjusted geometric mean for AUCtau was 231.2 (90% CI, 190.1-281.2) and C trough was 111.5 (90% CI, 86.3-144.0) following 600 mg-Q6W (test) versus 300 mg-Q4W (reference). Phase Ib: grade 3 treatment-related adverse events (TRAEs) occurred in 1/4 (25%) and 3/12 (25%) participants treated in 300 mg-Q4W dose escalation and expansion cohorts, respectively. Phase II: grade 3 TRAEs occurred in 3/41 (7.3%) and 3/80 (3.8%) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively; no grade 4/5 TRAEs. Phase II: confirmed objective response was observed in 11/41 (26.8% (95% CI, 14.2-42.9)) and 12/80 (15.0% (95% CI, 8.0-24.7)) participants treated with 300 mg-Q4W and 600 mg-Q6W, respectively. Conclusions: Phase Ib regimens were considered safe with no DLTs reported. In phase II, 600 mg-Q6W regimen criteria were met for AUCtau and C trough metrics to support PK-based extrapolation of efficacy of alternative regimen. Regimens were well tolerated, showing anti-tumor activity in participants with advanced solid tumors. Administration of sasanlimab at a dose of 600 mg-Q6W subcutaneously may serve as a convenient alternative to 300 mg-Q4W administration. Trial registration: NCT04181788 (ClinicalTrials.gov); 2019-003818-14 (EudraCT).

Phase I Study of Simlukafusp Alfa (FAP-IL2v) with or without Atezolizumab in Japanese Patients with Advanced Solid Tumors.

PURPOSE: The aim of the study was to evaluate the safety/tolerability and pharmacokinetics of simlukafusp alfa (FAP-IL2v), an immunocytokine containing an anti-fibroblast activation protein-α (FAP) antibody and an IL2 variant, administered alone or with the PDL1 inhibitor atezolizumab, in Japanese patients with advanced solid tumors. PATIENTS AND METHODS: In this phase 1, open-label, dose-escalation study, patients received i.v. FAP-IL2v at 10 or 15/20 mg alone or 10 mg when combined with i.v. atezolizumab. The primary objectives were identification of dose-limiting toxicities (DLT), recommended dose, and maximum tolerated dose, and evaluation of the safety/tolerability and pharmacokinetics of FAP-IL2v alone and combined with atezolizumab. RESULTS: All 11 patients experienced adverse events (AE) during FAP-IL2v treatment. Although most AEs were of mild severity, four treatment-related AEs led to study treatment discontinuation in two patients: one with infusion-related reaction, hypotension, and capillary leak syndrome, and the other with increased aspartate aminotransferase. No AE-related deaths occurred. One DLT (grade 3 hypotension) occurred in a patient receiving FAP-IL2v 15/20 mg alone. The recommended dose and maximum tolerated dose could not be determined. The pharmacokinetics of FAP-IL2v remained similar with or without atezolizumab. The study was terminated early as FAP-IL2v development was discontinued because of portfolio prioritization (not for efficacy/safety reasons). CONCLUSIONS: This study describes the safety/tolerability of FAP-IL2v 10 mg alone and in combination with atezolizumab in Japanese patients with advanced solid tumors; one DLT (hypotension) occurred with FAP-IL2v 15/20 mg. However, dose escalation of FAP-IL2v was not conducted because of early study termination. SIGNIFICANCE: This phase I study assessed the safety/tolerability and PK of simlukafusp alfa alone or combined with atezolizumab in Japanese patients with advanced solid tumors. No notable differences in PK were noted with the combination versus simlukafusp alfa alone; however, high-dose simlukafusp alfa treatment was associated with recombinant IL2-related toxicity, despite the drug's FAP targeting and IL2Rßγ-biased IL2 variant design.

Impact of Durvalumab on the Duration and Complexity of Corticosteroid Therapy for Pneumonitis After Chemoradiotherapy.

INTRODUCTION: It is unclear how the duration and tapering pattern of corticosteroid therapy for pneumonitis changed after the introduction of durvalumab consolidation therapy. METHODS: We retrospectively evaluated the medical records of patients diagnosed with nonsmall cell lung cancer who received chemoradiotherapy between January 2014 and December 2020. RESULTS: Data for 135 patients treated before durvalumab approval and 100 patients treated with durvalumab after its approval were analyzed. In both groups, more than 70% were male, with a median age of 66 y. Approximately 85% were smokers, and the most common tumor histology was adenocarcinoma. Most patients were treated with doses of 60 and 66 Gy (n = 127 [94%] vs. n = 95 [95%]). Among the patients treated with durvalumab, 57%, 38%, and 5% had grade 1, grade 2, and grade 3 pneumonitis; none had grade 4 or 5 pneumonitis. Patients treated with durvalumab exhibited a longer duration of corticosteroid therapy for pneumonitis (17 wk; range: 2-88 wk) than patients not treated with durvalumab (7 wk; range: 0.4-21 wk; P < 0.001). Pneumonitis relapse was more frequent in patients treated with durvalumab (n = 8; 23%) than in patients not treated with durvalumab (n = 2; 7%). Among the 8 patients treated with durvalumab, 2 had recurrent pneumonitis, 1 could not terminate corticosteroids. CONCLUSIONS: Our data show that durvalumab prolongs the duration of corticosteroid therapy and increases the complexity of corticosteroid tapering patterns. This study can help manage pneumonitis caused by immune checkpoint inhibitors and other drugs used after chemoradiotherapy in routine practice and clinical trials.

Phase I study of the safety and clinical activity of the interleukin-8 inhibitor AMY109 combined with atezolizumab in patients with advanced solid cancers.

BACKGROUND: Immunosuppressive conditions within the tumor microenvironment (TME) can allow tumors to evade the immune system, including by hampering programmed death ligand 1 (PD-L1) inhibitor activity. Interleukin (IL)-8 contributes to immunosuppression and fibrosis in the TME. AMY109, a humanized anti-IL-8 monoclonal antibody, reduced fibrosis and decreased immunosuppressive cells in tumor tissue in animals. Combining AMY109 with atezolizumab (anti-PD-L1 antibody) may enhance its antitumor effects by making the TME more favorable to PD-L1 inhibition. METHODS: This multicenter, open-label, dose-escalation study evaluated the safety, pharmacokinetics, and clinical activity of AMY109 plus atezolizumab in patients with previously treated advanced solid tumors and Eastern Cooperative Oncology Group performance status 0 or 1. Patients received AMY109 (2-45 mg/kg) plus atezolizumab (1200 mg) intravenously every 3 weeks in part 1, and AMY109 (15-45 mg/kg) plus atezolizumab (1200 mg) in part 2. Primary endpoints were the dose-limiting toxicity (DLT), safety, and pharmacokinetics of AMY109 and atezolizumab in Part 1, and safety and antitumor activity per investigator-assessed Response Evaluation Criteria in Solid Tumors 1.1 in part 2. Exploratory analyses of peripheral and tumor biomarker were conducted. RESULTS: Overall, 38 patients (18 in part 1 and 20 in part 2) were enrolled. Part 1 showed no DLTs and a dose-proportional increase in AMY109 exposure over 2-45 mg/kg, with no apparent change in mean atezolizumab serum concentrations across AMY109 dosing. Plasma IL-8 concentration accumulation was seen in all dose cohorts after AMY109 initiation. Grade 1-3 treatment-related adverse events (AEs) occurred in 21 of 38 patients (55%). Treatment-related serious AEs occurred in two patients (5%). No AEs led to treatment withdrawal. Partial responses (PRs) occurred in 2 of 38 patients; the confirmed objective response rate was 5%. These patients had uterocervical and pancreatic cancer, respectively, and had been treated for >500 days at the cut-off date: one had received 45 mg/kg of AMY109 throughout, and the other received 30 mg/kg of AMY109 until cycle 5, then 45 mg/kg thereafter. CONCLUSIONS: With no DLTs, AMY109 plus atezolizumab was well tolerated in patients with advanced solid tumors, with no new safety signals. AMY109 showed a dose-proportional increase in exposure. The PRs in two patients were durable.

The remarkable antitumor efficacy of corticosteroid treatment in patients with refractory thymomas.

BACKGROUND: Some case reports have found that corticosteroid treatments shrunk thymoma lesions remarkably after the failure of chemotherapy or surgery. However, few studies have comprehensibly evaluated the antitumor effects of corticosteroids in patients with invasive thymomas. METHODS: We reviewed the medical records of 13 consecutively enrolled patients with locally advanced or metastatic thymomas treated via corticosteroid monotherapies from January 2010 to March 2021 in our institute. A Cox's proportional hazard model and the Kaplan-Meier method were used to identify factors associated with survival. RESULTS: The median follow-up time was 26 months (range, 13-115 months). The median initial dose of corticosteroid was 0.90 mg/kg/day prednisolone equivalent (range, 0.4-1.1 mg/kg/day). Of the 13 cases, 7 (53.8%, 95% CI: 0.25-0.81) exhibited a partial response and 5 (38.5%, 95% CI: 0.14-0.68) stable disease. The median progression-free survival was 5.7 months [95% confidence interval (CI): 1.5-9.6 months]. The median overall survival was 25.3 months (95% CI: 7.1-not attained). The median duration of corticosteroid use was 3 months (range, 1-64 months). Patients with WHO subtype B thymomas exhibited a better overall response rate to corticosteroids than did patients with other disease subtypes (75%, 95% CI: 0.19-0.99). Adverse events of Grade 3 or more were not observed. CONCLUSIONS: Corticosteroids are clinically valuable for patients with thymomas.

A phase 1/1b, open-label, dose-escalation study of PD-1 inhibitor, cetrelimab alone and in combination with FGFR inhibitor, erdafitinib in Japanese patients with advanced solid tumors.

Immune checkpoint inhibitors are the leading approaches in tumor immunotherapy. The aim of the study was to establish recommended phase 2 doses (RP2Ds) of intravenous cetrelimab, a checkpoint inhibitor, alone and with oral erdafitinib in Japanese patients with advanced solid tumors. This open-label, non-randomized, dose-escalation phase 1/1b study enrolled adults with advanced solid tumors who were ineligible for standard therapy. Study was conducted in two parts: phase 1a assessed cetrelimab at three dosing levels (80 mg every 2 weeks [Q2W], 240 mg Q2W, and 480 mg Q4W); phase 1b assessed cetrelimab+erdafitinib at two dosing levels (240 mg Q2W + 6 mg once daily [QD] and 240 mg Q2W + 8 mg QD). Primary endpoint was frequency and severity of dose-limiting toxicities (DLTs) of cetrelimab ± erdafitinib. In total 22 patients (phase 1a, n = 9; phase 1b, n = 13) were enrolled. Median duration of follow-up was 8.64 months in phase 1a and 2.33 months in phase 1b. In phase 1a, DLTs weren't reported while in phase 1b, 1 patient who received 240 mg cetrelimab + 6 mg erdafitinib reported Stevens-Johnson syndrome (grade 3, immune-related). Overall, 88.9% patients in phase 1a (grade ≥ 3: 44.4%) and 100.0% in phase 1b (grade ≥ 3: 53.8%) experienced ≥ 1 treatment-related adverse events (TEAEs); 33.3% in phase 1a and 38.5% in phase 1b reported serious TEAEs, of which 11.1% patients in phase 1a and 15.4% in phase 1b had TEAEs which led to treatment discontinuation. Cetrelimab alone and in combination with erdafitinib showed manageable safety in Japanese patients with advanced solid tumors. RP2Ds were determined as 480 mg cetrelimab Q4W for monotherapy, and cetrelimab 240 mg Q2W + erdafitinib 8 mg QD for combination therapy.

A molecular glue RBM39-degrader induces synthetic lethality in cancer cells with homologous recombination repair deficiency.

E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. To identify biomarkers of the antitumor efficacy of E7820, we treated patient-derived xenograft (PDX) mouse models established from 42 patients with solid tumors. The overall response rate was 38.1% (16 PDXs), and tumor regression was observed across various tumor types. Exome sequencing of the PDX genome revealed that loss-of-function mutations in genes of the homologous recombination repair (HRR) system, such as ATM, were significantly enriched in tumors that responded to E7820 (p = 4.5 × 103). Interestingly, E7820-mediated double-strand breaks in DNA were increased in tumors with BRCA2 dysfunction, and knockdown of BRCA1/2 transcripts or knockout of ATM, ATR, or BAP1 sensitized cancer cells to E7820. Transcriptomic analyses revealed that E7820 treatment resulted in the intron retention of mRNAs and decreased transcription, especially for HRR genes. This induced HRR malfunction probably leads to the synthetic lethality of tumor cells with homologous recombination deficiency (HRD). Furthermore, E7820, in combination with olaparib, exerted a synergistic effect, and E7820 was even effective in an olaparib-resistant cell line. In conclusion, HRD is a promising predictive biomarker of E7820 efficacy and has a high potential to improve the prognosis of patients with HRD-positive cancers.

Efficacy and Safety of the MDM2-p53 Antagonist Brigimadlin (BI 907828) in Patients with Advanced Biliary Tract Cancer: A Case Series.

Background: In patients with advanced biliary tract cancer (BTC), first-line chemotherapy plus immunotherapy has improved outcomes; however, second-line options that reflect the disease's molecular heterogeneity are still needed. One emerging target is MDM2, amplified in ~5-8% of BTC cases. Methods: This is a subset analysis of two ongoing Phase Ia/Ib trials assessing patients treated with brigimadlin (BI 907828; a highly potent, oral MDM2-p53 antagonist) ± ezabenlimab (PD-1 inhibitor) ± BI 754111 (anti-LAG-3; n = 1). Results: Results from 12 patients with BTC are shown (monotherapy: n = 6/combination: n = 6). Six patients achieved partial response (monotherapy: n = 2/combination: n = 4), four had stable disease; responses were durable. Brigimadlin had a manageable safety profile. Seven patients had dose reductions due to adverse events, but no treatment-related adverse events led to treatment discontinuation. Conclusion: Brigimadlin demonstrated anti-tumor activity in patients with advanced MDM2-amplified BTC, and warrants further investigation.

Biliary tract carcinoma (BTC) is a cancer that affects the bile ducts which are part of the digestive system. Usually, the first treatment for advanced BTC (ie cannot be removed surgically and/or has spread) is chemotherapy in combination with immunotherapy. However, if chemotherapy does not work, or stops working, there are few treatment options available in second-line. Accordingly, intensive research is ongoing to try and find effective drugs. One potential medicine, called brigimadlin (or BI 907828), is a tablet that activates a molecule in tumor cells called p53. The normal function of p53 is to kill cells when they first start to become cancerous. However, if p53 is turned off by genetic mutations, or other mechanisms, then cancer can develop. Although p53 is rarely mutated in BTC tumors, it is inactivated by another molecule called MDM2 which is usually present at abnormally high levels in BTC. Brigimadlin prevents interaction between MDM2 and p53. This activates p53 and causes the cancer to die. Two clinical trials are currently assessing brigimadlin in a range of cancers, including BTC, with the aim of identifying a safe dose that can be examined in more detail in larger trials. So far, 12 patients with BTC have been treated. The patients' tumors significantly shrank in six of these patients and remained stable in a further four patients. Side effects were as expected and could be tolerated by pausing treatment or lowering the dose. These results show that brigimadlin should be tested further in patients with advanced BTC.

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.

Safety, tolerability, pharmacokinetics, and antitumor activity of adavosertib in Japanese patients with advanced solid tumors: A phase I, open-label study.

INTRODUCTION: We aimed to assess the safety, pharmacokinetic profile, and antitumor activity of adavosertib monotherapy in Japanese patients with advanced solid tumors. MATERIALS AND METHODS: This was a single-center, open-label, phase I study with two consecutive cohorts (250 mg and 200 mg cohorts). Patients received adavosertib at 250 mg or 200 mg, orally once daily for 5 days on and 2 days off for Weeks 1 and 2 of a 21-day cycle. RESULTS: Dose-limiting toxicities (Grade 3 febrile neutropenia) occurred in 2/6 patients in the 250 mg cohort. None of the three patients in the 200 mg cohort developed dose-limiting toxicities. The most frequent treatment-emergent adverse event was nausea (250 mg: 83.3 %; 200 mg: 100.0 %). Median time to peak drug concentration was 4.03 and 2.08 h after the first dose and 2.82 and 1.90 h after multiple dosing in the 250 and 200 mg cohorts, respectively; respective mean terminal elimination half-lives were 7.36 and 7.30 h (first dose) and 10.55 and 8.88 h (multiple dosing). Systemic exposure increased in a slightly more than dose-proportional manner. No RECIST v1.1 response was observed. Disease control rate was 0 % and 33.3 % in the 250 and 200 mg cohorts, respectively. One patient (33.3 %) in the 200 mg cohort showed a best overall response of stable disease at ≥ 8 weeks; the rest showed progressive disease. CONCLUSIONS: Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04462952.

Clinical significance of inter-assay discrepancy in PD-L1 evaluation for the efficacy of pembrolizumab in advanced NSCLC with high PD-L1 expression.

INTRODUCTION: Programmed cell death ligand-1 (PD-L1) expression is a predictive biomarker for the efficacy of anti-programmed cell death receptor-1/PD-L1 antibodies in advanced non-small cell lung cancer (NSCLC). Although several assays have been approved for evaluating PD-L1 expression status, inter-assay discordance has been observed between some assays. The clinical significance of these discrepancies is still unclear. METHODS: We retrospectively reviewed treatment-naïve NSCLC patients whose PD-L1 expression was evaluated using both 22C3 and SP142 assays. Among those, efficacy analysis was performed for patients with PD-L1 tumor proportion score (TPS) ≥ 50 % (22C3), who had received first-line pembrolizumab monotherapy. Additionally, transcriptome analysis was conducted in the available tumors with TPS ≥ 50 % to investigate the distinct immune profiles that accompany inter-assay discordance. RESULTS: In total, 611 patients were eligible. Among 198 patients with TPS ≥ 50 %, 91 (46 %) had tumor cell score ≤ 1 (SP142, i.e., inter-assay discrepancy). In the 52 patients who received first-line pembrolizumab monotherapy, treatment efficacy was significantly lower in patients with the discrepancy than that in those without (objective response rate: 18 % vs. 83 %, p < 0.001; median progression-free survival [months]: 3.2 vs. 8.3, p < 0.001). Transcriptome analysis revealed significantly more CD274 splice variants with aberrant 3'-terminal sequences in tumors with the inter-assay discrepancy than in those without. CONCLUSION: The inter-assay discrepancy in the PD-L1 status of tumor cells between the 22C3 and SP142 assays, reflecting an imbalance in the CD274 splice variants, could be a biomarker for primary resistance against pembrolizumab monotherapy in high PD-L1-expressing NSCLCs.

Long-term follow-up and exploratory analysis of lenvatinib in patients with metastatic or recurrent thymic carcinoma: Results from the multicenter, phase 2 REMORA trial.

OBJECTIVES: The main objective of this report was to detail the long-term follow-up data from the REMORA study, which investigated the safety and efficacy of lenvatinib in patients with thymic carcinoma. In addition, an exploratory analysis of the association between relative dose intensity (RDI) and the efficacy of lenvatinib is presented. MATERIALS AND METHODS: The single-arm, open-label, phase 2 REMORA study was conducted at eight Japanese institutions. Forty-two patients received oral lenvatinib 24 mg once daily in 4-week cycles until the occurrence of intolerable adverse events or disease progression. The REMORA long-term follow-up data were evaluated, including overall survival (OS). RDI was calculated by dividing the actual dose administered to the patient by the standard recommended dose. This trial is registered on JMACCT (JMA-IIA00285) and on UMIN-CTR (UMIN000026777). RESULTS: The updated median OS was 28.3 months (95 % confidence interval [CI]: 17.1-34.0 months), and the OS rate at 36 months was 35.7 % (95 % CI: 21.7 %-49.9 %). When grouped by RDI of lenvatinib, the median OS was 38.5 months (95 % CI: 31.2-not estimable) in patients with ≥ 75 % RDI and 17.3 months (95 % CI: 13.4-26.2 months) in patients with < 75 % RDI (hazard ratio 0.46 [95 % CI: 0.22-0.98]; P = 0.0406) at 8 weeks. Patients who maintained their lenvatinib dose over 8 weeks had a higher objective response rate than patients whose doses were reduced (75.0 % vs 29.4 %; P = 0.0379). No new safety concerns or treatment-related deaths were reported, and lenvatinib had a tolerable safety profile. CONCLUSION: This follow-up report updated OS in patients with metastatic or recurrent thymic carcinoma. A higher RDI of lenvatinib at 8 weeks could be associated with improved outcomes.

Efficacy and safety of chemoimmunotherapy in advanced non-small cell lung cancer patients with antibiotics-induced dysbiosis: a propensity-matched real-world analysis.

PURPOSE: The gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed. METHODS: We retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared. RESULTS: Of 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49-1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44-1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%). CONCLUSION: Antibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC.

Clinical management, monitoring, and prophylaxis of adverse events of special interest associated with datopotamab deruxtecan.

Antibody drug conjugates (ADCs) are an emerging class of treatments designed to improve efficacy and decrease toxicity compared with other systemic therapies through the selective delivery of cytotoxic agents to tumor cells. Datopotamab deruxtecan (Dato-DXd) is a novel ADC comprising a topoisomerase I inhibitor payload and a monoclonal antibody directed to trophoblast cell-surface antigen 2 (TROP2), a protein that is broadly expressed in several types of solid tumors. Dato-DXd is being investigated across multiple solid tumor indications. In the ongoing, first-in-human TROPION-PanTumor01 phase I study (ClinicalTrials.gov: NCT03401385), encouraging and durable antitumor activity and a manageable safety profile was demonstrated in patients with advanced/metastatic hormone receptor-positive/human epidermal growth factor receptor2-negative breast cancer (HR+/HER2- BC), triple-negative breast cancer (TNBC), and non-small cell lung cancer (NSCLC). Improved understanding of the adverse events (AEs) that are associated with Dato-DXd and their optimal management is essential to ensure safe and successful administration. Interstitial lung disease/pneumonitis, infusion-related reactions, oral mucositis/stomatitis, and ocular surface events have been identified as AEs of special interest (AESIs) for which appropriate prevention, monitoring, and management is essential. This article summarizes the incidence of AESIs among patients with HR+/HER2- BC, TNBC, and NSCLC reported in TROPION-PanTumor01. We report our recommendations for AESI prophylaxis, early detection, and management, using experience gained from treating AESIs that occur with Dato-DXd in clinical trials.

Identification of barriers to implementation of precision oncology in patients with rare cancers.

Established treatment options for rare cancers are limited by the small number of patients. The current comprehensive genomic profiling (CGP) testing might not fully exploit opportunities for precision oncology in patients with rare cancers. Therefore, we aimed to explore the factors associated with CGP testing utility in rare cancers and identify barriers to implementing precision oncology. Patients who underwent CGP testing at our institution between September 2019 and June 2021 were enrolled in this retrospective study. Based on their results, the patients received molecularly targeted drugs or immune checkpoint inhibitors. Univariate and multivariate analyses evaluated the association between patient characteristics and the proportion of patients receiving molecularly targeted drugs. Overall, 790 patients underwent CGP testing. Among them, 333 patients with rare cancers were identified, of whom 278 (83.5%) had actionable genomic alterations, 127 (38.1%) had druggable genomic alterations, and 25 (7.5%) received genomically matched therapy. The proportion of patients receiving molecularly targeted drugs was significantly higher among those with treatment options with evidence levels A-D (8.7%) than those without treatment options with evidence levels A-D (2.9%). A potential barrier to CGP testing utility in rare cancers is the limited number of molecularly targeted drugs with clinical evidence. We propose that CGP testing be performed in patients with rare cancers who have treatment options with evidence levels A-D to maximize CGP testing utility in real-world practice.

KEYNOTE-434 part B: A phase 1 study evaluating the combination of epacadostat, pembrolizumab, and chemotherapy in Japanese patients with previously untreated advanced non-small-cell lung cancer.

BACKGROUND: Pembrolizumab plus epacadostat (indoleamine 2,3-dioxygenase-1 inhibitor) was well tolerated in Japanese patients with advanced solid tumors in part A of the nonrandomized, open-label, phase 1 KEYNOTE-434 study (NCT02862457). We report results from part B, which evaluated epacadostat plus pembrolizumab and chemotherapy in Japanese patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Eligible patients aged ≥ 20 years had histologically or cytologically confirmed stage IIIB or IV NSCLC with no prior systemic therapy, and ECOG performance status of 0 or 1. Patients received epacadostat 100 mg orally twice-daily, pembrolizumab 200 mg intravenously every-3-weeks for ≤ 35 cycles, and 4 cycles of chemotherapy (cohort 1: cisplatin plus pemetrexed, non-squamous; cohort 2: carboplatin plus pemetrexed, non-squamous; cohort 3: carboplatin plus paclitaxel, squamous or non-squamous). Primary endpoint was incidence of dose-limiting toxicities (DLTs). Following unfavorable results from other studies, a protocol amendment removed epacadostat from the treatment combination. RESULTS: Of 19 patients, 7 were enrolled in cohort 1, and 6 each in cohorts 2 and 3. Median follow-up was 13.7 (range, 4.2-27.8) months. Five of 17 (29%) DLT-evaluable patients experienced ≥ 1 DLT (cohort 1, n = 1; cohorts 2 and 3, n = 2 each); most commonly maculopapular rash (grade 3, n = 3) and increased alanine aminotransferase (grade 2, n = 1; grade 3, n = 2). All patients experienced treatment-related adverse events (AEs); 58% experienced grade 3 or 4 treatment-related AEs. Objective response rate was 47%. CONCLUSION: The combination of epacadostat plus pembrolizumab and chemotherapy was found to be tolerable in Japanese patients with advanced NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02862457.

Dabrafenib and trametinib administration in patients with BRAF V600E/R or non-V600 BRAF mutated advanced solid tumours (BELIEVE, NCCH1901): a multicentre, open-label, and single-arm phase II trial.

Background: BRAF V600 mutations are common in melanoma, thyroid, and non-small-cell lung cancers. Despite dabrafenib and trametinib being standard treatments for certain cancers, their efficacy across various solid tumours remains unelucidated. The BELIEVE trial assessed the efficacy of dabrafenib and trametinib in solid tumours with BRAF V600E/R or non-V600 BRAF mutations. Methods: Between October 1, 2019, and June 2022, at least 50 patients with measurable and seven without measurable diseases examined were enrolled in a subcohort of the BELIEVE trial (NCCH1901, jRCTs031190104). BRAF mutated solid tumour cases other than BRAF V600E mutated colorectal cancer, melanoma, and non-small cell lung cancer cases were included. Patients with solid tumours received dabrafenib (150 mg) twice daily and trametinib (2 mg) once daily until disease progression or intolerable toxicity was observed. The primary endpoint was overall response rate (ORR), and secondary endpoints included progression-free survival (PFS), 6-month PFS, and overall survival (OS). Bayesian analysis was performed using a prior distribution with a 30% expected response rate [Beta (0.6, 1.4)]. Findings: Fourty-seven patients with measurable disease, mainly with the BRAF V600E mutation (94%), and three others with non-V600E BRAF mutations (V600R, G466A, and N486_P490del) were enrolled. The primary sites included the thyroid gland, central nervous system, liver, bile ducts, colorectum, and pancreas. The confirmed ORR was 28.0%; the expected value of posterior distribution [Beta (14.6, 37.4)] was 28.1%, although the primary endpoint was achieved, not exceeding an unexpectedly high response rate of 60% obtained using Bayesian analysis. The disease control rate (DCR) was 84.0%. The median PFS was 6.5 months (95% confidence interval [CI]; 4.2-7.2 months, 87.8% at 6 months). Responses were observed across seven tumour types. Median OS was 9.7 months (95% CI, 7.5-12.2 months). Additional patients without measurable diseases had a median PFS of 4.5 months. Adverse events (AEs) were consistent with previous reports, with 45.6% of patients experiencing grade ≥3 AEs. Interpretation: This study reported promising efficacy against BRAF V600-mutant tumours. Dabrafenib and trametinib would offer a new therapeutic option for rare cancers, such as high-grade gliomas, biliary tract cancer, and thyroid cancer. Funding: This study was funded by the Japan Agency for Medical Research and Development (22ck0106622h0003) and a Health and Labour Sciences Research Grant (19EA1008).