Worse Treatment-related Adverse Events Research Articles

Emerging chemotherapy-based treatments in anaplastic thyroid cancer: an updated analysis of prospective studies.

For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively. For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs). Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%). Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations.

Preclinical evaluation and phase 1 study of the PI3Kα/δ inhibitor TQ-B3525 in Chinese patients with advanced cancers.

Phosphatidylinositol 3-kinase (PI3K) inhibitors transformed management of various malignancies. This study preclinically characterized TQ-B3525 (dual PI3Kα/δ inhibitor) and assessed the recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics in relapsed or refractory (R/R) lymphoma or advanced solid tumors (STs). Oral TQ-B3525 was given at eight dose levels on a 28-day cycle. Primary end points were dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and safety. TQ-B3525 showed high selectivity and suppressed tumor growth. Between June 12, 2018, and November 18, 2020, 80 patients were enrolled (63 in dose-escalation cohort; 17 in dose-expansion cohort). Two DLTs occurred in two (two of 63, 3.2%) DLT-evaluable patients; MTD was not identified. TQ-B3525 at 20 mg once daily was selected as RP2D. Grade 3 or worse treatment-related adverse events mainly included hyperglycemia (16.3%), neutrophil count decreased (15.0%), and diarrhea (10.0%). Two (2.5%) treatment-related deaths were reported. Sixty patients with R/R lymphoma and 11 advanced STs demonstrated objective response rates of 68.3% and 9.1%, disease control rates of 91.7% and 54.6%, median progression-free survivals of 12.1 and 1.1 months; median overall survivals were not reached. TQ-B3525 exhibited rapid absorption and a nearly proportional increase in exposure. Acceptable safety and promising efficacy support further investigation of TQ-B3525 (20 mg once daily) for R/R lymphoma.

Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial

ObjectiveTo evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy.DesignRandomised, double blind,...

Abstract PO3-02-12: Dalpiciclib combination with letrozole as neoadjuvant therapy for HR-positive HER2-negative breast cancer: a single-arm, prospective exploratory clinical study

Abstract Background: CDK4/6 inhibitors effectively block tumor cells from progressing from the G1 phase to the S phase, thereby interrupting the cell cycle progression and inhibiting tumor cell proliferation. Dalpiciclib is a novel CDK4/6 inhibitor developed independently in China, which has been approved for use in combination with fulvestrant for the treatment of HR-positive/HER2-negative recurrent or metastatic breast cancer in patients who have experienced disease progression after prior endocrine therapy, or in combination with aromatase inhibitors as initial treatment for HR-positive/HER2-negative locally advanced or metastatic breast cancer patients. This study aims to explore the efficacy and safety of dalpiciclib in combination with letrozole as neoadjuvant therapy for HR-positive, HER2-negative breast cancer. Methods: This is a single-arm, open-label study that enrolled female breast cancer patients with early or locally advanced HR-positive, HER2-negative tumors and an ECOG performance status of 0 to 1. After enrollment, patients first received 4 cycles of dalpiciclib (150mg po qd, d1-21, q4w) in combination with letrozole as neoadjuvant therapy. Breast MRI was performed every 2 cycles, and treatment response was evaluated according to the RECIST 1.1 criteria. If patients achieved a confirmed complete response (CR) or partial response (PR) after 4 cycles, they would continue to receive an additional 4 cycles of dalpiciclib in combination with letrozole treatment. If the treatment response was stable disease (SD) or disease progression (PD), the investigator might modify other treatment regimens based on the individual circumstances of the subjects. The primary endpoint was residual cancer burden (RCB 0/I), and the secondary study endpoints were objective response rate (ORR), complete cell cycle arrest (CCCA, C1D15 Ki67≤2.7%) rate and safety. This study is registered at the Chinese Clinical Trial Registry Centre (registration No. ChiCTR2200057104). Results: From April 2022 to June 2023, a total of 38 patients were screened and enrolled in the study. All patients had ER ≥ 50%, and 84% (32/38) had Ki67 ≥ 88%. Among the 21 patients who completed the assessment after 4 cycles, the overall response rate (ORR) was 81% (17/21). Additionally, among the 22 patients who underwent C1D15 biopsy and Ki67 analysis, 55% (12/22) had C1D15 Ki67 ≤ 2.7%. After completing 8 cycles of neoadjuvant treatment with the combination of dalpiciclib and letrozole,12 patients underwent surgery. The postoperative RCB scores were as follows: 1 patient had RCB (0-I), and 11 patients had RCB (II-III). The most common adverse event was decreased neutrophil count (25/38 [66%]). Among the 38 patients, 16 (42%) experienced grade 3 or worse treatment-related adverse events. There were no occurrences of grade 4 or worse adverse events. Conclusions: The combination of dalpiciclib and letrozole has shown efficacy in downstaging and shrinking tumors in patients with early or locally advanced HR-positive/HER2-negative breast cancer. Patients who exhibit a positive response in the assessment after 4 cycles may consider it as a viable option for chemo-free neoadjuvant treatment. Citation Format: Jingruo Li, Yuanting Gu, Chuang Du, Jianhua Zhang, Yingying Zhang, Linfeng Zhang, Nan Wang, Lin Li, Fang Wang, Pengwei Lv, Hong Zong, Xinhong Pei, Bingjian Xue, Yan Wang, Dongcheng Gao. Dalpiciclib combination with letrozole as neoadjuvant therapy for HR-positive HER2-negative breast cancer: a single-arm, prospective exploratory clinical study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-02-12.

Pivekimab sunirine (IMGN632), a novel CD123-targeting antibody–drug conjugate, in relapsed or refractory acute myeloid leukaemia: a phase 1/2 study

Pivekimab sunirine (IMGN632) is a first-in-class antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload. CD123 is overexpressed in several haematological malignancies, including acute myeloid leukaemia. We present clinical data on pivekimab sunirine in relapsed or refractory acute myeloid leukaemia. This first-in-human, phase 1/2 dose-escalation and dose-expansion study enrolled participants aged 18 years or older at nine hospitals in France, Italy, Spain, and the USA with CD123+ haematological malignancies (Eastern Cooperative Oncology Group performance status of 0-1); participants reported here were in a cohort of participants with acute myeloid leukaemia who were refractory to or had relapsed on one or more previous treatments for acute myeloid leukaemia. The 3 + 3 dose-escalation phase evaluated two dosing schedules: schedule A (once every 3 weeks, on day 1 of a 3-week cycle) and fractionated schedule B (days 1, 4, and 8 of a 3-week cycle). The dose-expansion phase evaluated two cohorts: one cohort given 0·045 mg/kg of bodyweight (schedule A) and one cohort given 0·090 mg/kg of bodyweight (schedule A). The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Antileukaemia activity (overall response and a composite complete remission assessment) was a secondary endpoint. The study is ongoing and registered with ClinicalTrials.gov, NCT03386513. Between Dec 29, 2017, and May 27, 2020, 91 participants were enrolled (schedule A, n=68; schedule B, n=23). 30 (44%) of schedule A participants were female and 38 (56%) were male; 60 (88%) were White, six (9%) were Black or African American, and two (3%) were other races. Pivekimab sunirine at doses of 0·015 mg/kg to 0·450 mg/kg in schedule A was administered in six escalating doses with no maximum tolerated dose defined; three dose-limiting toxicities were observed (reversible veno-occlusive disease; 0·180 mg/kg, n=1 and 0·450 mg/kg, n=1; and neutropenia; 0·300 mg/kg, n=1). Schedule B was not pursued further on the basis of comparative safety and antileukaemia findings with schedule A. The recommended phase 2 dose was selected as 0·045 mg/kg once every 3 weeks. At the recommended phase 2 dose (n=29), the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (three [10%]), infusion-related reactions (two [7%]), and anaemia (two [7%]). Treatment-related serious adverse events occurring in 5% or more of participants treated at the recommended phase 2 dose were febrile neutropenia (two [7%]) and infusion-related reactions (two [7%]). Among 68 participants who received schedule A, one death (1%) was considered to be treatment-related (cause unknown; 0·300 mg/kg cohort). At the recommended phase 2 dose, the overall response rate was 21% (95% CI 8-40; six of 29) and the composite complete remission rate was 17% (95% CI 6-36; five of 29). Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia. ImmunoGen.

Sunvozertinib for patients in China with platinum-pretreated locally advanced or metastatic non-small-cell lung cancer and EGFR exon 20 insertion mutation (WU-KONG6): single-arm, open-label, multicentre, phase 2 trial

Sunvozertinib is an oral, irreversible, and selective tyrosine kinase inhibitor that has a favourable safety profile and encouraging antitumour activity, as shown in phase 1 studies of patients with heavily pretreated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation (exon20ins). We aimed to assess the antitumour efficacy of sunvozertinib in patients with platinum-pretreated locally advanced or metastatic NSCLC with EGFR exon20ins. WU-KONG6 is a single-group, open-label, multicentre phase 2 trial of sunvozertinib monotherapy, conducted across 37 medical centres in China. We enrolled adult patients with pathologically or cytologically confirmed locally advanced or metastatic NSCLC whose tumour tissue carried an EGFR exon20ins mutation. All patients had received at least one line of previous systemic therapy, with at least one line containing platinum-based chemotherapy. The primary endpoint was objective response rate (ORR), as assessed by the independent review committee. The ORR was defined as the percentage of patients who achieved complete or partial response, confirmed by two separate assessments with at least 4-week time interval, until disease progression or initiation of any new anti-cancer therapy. Enrolled patients received sunvozertinib 300 mg once daily until meeting discontinuation criteria per the protocol. Patients who received at least one dose of treatment and were evaluable for efficacy analysis were included in the primary analysis, and all patients who received at least one dose of treatment were included in the safety analysis. This study is registered with ChinaDrugTrials.org, CTR20211009, and ClinicalTrials.gov, NCT05712902, and efficacy and safety follow-up are ongoing. Between July 19, 2021, and May 6, 2022, 104 patients were enrolled. At data cutoff (Oct 17, 2022), the last enrolled patient had been followed up for about 6 months. Among 97 patients evaluable for efficacy analysis, 59 (61%) patients achieved tumour response, with a confirmed ORR of 61% (95% CI 50-71). All tumour responses were partial responses. Tumour responses were observed irrespective of age, sex, smoking history, EGFR exon20ins subtypes, brain metastasis at baseline, previous lines of therapy, and history of onco-immunotherapy. In total, 19 death events occurred over a median follow-up period of 7·6 months (IQR 6·1-9·4). Sunvozertinib was well tolerated at 300 mg once daily. The most common grade 3 or worse treatment-related adverse events were blood creatine phosphokinase increased (18 [17%] of 104), diarrhoea (eight [8%]), and anaemia (six [6%]). The most common serious treatment-related adverse events were interstitial lung disease (five [5%] of 104), anaemia (three [3%]), vomiting (two [2%]), nausea (two [2%]) and pneumonia (two [2%]). In this phase 2 study, sunvozertinib demonstrated antitumour efficacy in patients with platinum-based chemotherapy pretreated NSCLC with EGFR exon20ins, with a manageable safety profile. A multinational randomised, phase 3 study of sunvozertinib versus platinum-doublet chemotherapy in EGFR exon20ins NSCLC is ongoing (NCT05668988). Dizal Pharmaceutical.

Systemic therapy with or without local intervention for oligometastatic oesophageal squamous cell carcinoma (ESO-Shanghai 13): an open-label, randomised, phase 2 trial

The efficacy of local therapy for patients with oligometastatic oesophageal squamous cell carcinoma is unclear. We aimed to assess the efficacy of local plus systemic therapy compared with systemic therapy alone in patients with oligometastatic oesophageal squamous cell carcinoma. The ESO-Shanghai 13 trial was a randomised, open-label, multicentre, phase 2 trial. Patients (aged ≥18 years) were recruited from six hospitals in China with histological confirmation of oligometastatic oesophageal squamous cell carcinoma with a controlled primary tumour and one to four metastatic lesions. Eligible patients were randomly assigned via a computer-generated schedule in a 1:1 ratio to receive either systemic therapy alone (ie, systemic therapy only group) or combined systemic and local therapy (ie, systemic and local therapy group). The systemic therapy regimens in both groups were at the discretion of the investigator and included chemotherapy alone, anti-PD-1 antibodies alone, or chemotherapy plus anti-PD-1 antibodies. Local therapy-radiotherapy, surgery, or thermal ablation-was delivered to all metastatic lesions for patients in the systemic and local therapy group. Randomisation was balanced dynamically on three factors: the number of disease sites, the lines of systemic therapy, and the location of the metastases. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, defined as the time from randomisation to progression or death from any cause in the intention-to-treat population. The safety population included all patients who had undergone random assignment and at least one of the intended therapies. This trial is registered with ClinicalTrials.gov, NCT03904927. The trial is ongoing but closed to new participants. 116 patients were screened for enrolment between March 5, 2019, and Sept 16, 2021, and 104 patients who met the eligibility criteria were randomly assigned to the systemic and local therapy group (n=53) or the systemic therapy only group (n=51). 20 (38%) patients in the systemic plus local therapy group and 23 (45%) patients in the systemic therapy only group received anti-PD-1 antibody-based systemic therapy; three patients in the systemic and local therapy group did not receive systemic therapy. At a median follow-up of 30·5 months (IQR 24·7-37·8), median progression-free survival was 15·3 months (95% CI 10·1-20·5) in the systemic and local therapy group versus 6·4 months (5·2-7·6) in the systemic therapy only group (stratified hazard ratio 0·26 [95% CI 0·16-0·42]; stratified log rank p<0·0001). Grade 1-2 acute oesophagitis was more common in the systemic and local therapy group than in the systemic therapy only group (10 [19%] vs one [2%] patients; p=0·036). The number of patients who had grade 3 or worse treatment-related adverse events was similar between groups (25 [47%] vs 21 [41%]; p=0·538), with the most common adverse events being leukocytopenia (17 [32%] vs 18 [35%]) and neutropenia (19 [36%] vs 20 [39%]). Treatment-related deaths occurred in two patients in the systemic and local therapy group and one patient in the systemic therapy only group. The addition of local treatment for metastases could significantly improve progression-free survival among patients with oligometastatic oesophageal squamous cell carcinoma being treated with systemic therapy. Our findings suggest that combining local and systemic therapy could be a treatment option for patients with oligometastatic oesophageal squamous cell carcinoma, but further support from phase 3 trials is required. Science and Technology Commission of Shanghai Municipality, National Nature Science Foundation of China, and Shanghai Municipal Health Commission. For the Chinese translation of the abstract see Supplementary Materials section.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial

Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. Akeso Biopharma. For the Chinese translation of the abstract see Supplementary Materials section.

OncoVee™-MiniPDX-guided anticancer treatment for HER2-negative intermediate-advanced gastric cancer patients: a single-arm, open-label phase I clinical study

BackgroundChemotherapy is the main treatment strategy for patients with advanced HER2-negative gastric cancer (GC); yet, many patients do not respond well to treatment. This study evaluated the sensitivity of a mini patient-derived xenograft (MiniPDX) animal model in patients with HER2-negative intermediate-advanced GC.MethodsIn this single-arm, open-label clinical study, we consecutively recruited patients with HER2-negative advanced or recurrent GC from September 2018 to July 2021. Tumor tissues were subjected to MiniPDX drug sensitivity tests for screening individualized anti-tumor drugs; appropriate drug types or combinations were selected based on drug screening results. The primary endpoints were progression-free survival (PFS) and safety, and the secondary endpoints were overall survival (OS) and objective response rate (ORR).ResultsA total of 17 patients were screened, and 14 eligible patients were included.The median follow-up time was 9 (2–34) months. The median PFS time was 14.1 (2–34) months, the median OS time was 16.9 (2–34) months, ORR was 42.9% (6/14), and DCR was 92.9% (13/14). The most common treatment-related adverse events (TRAE) were fatigue (14 (100%)), anorexia (13 (93%)) and insomnia (12 (86%)), and the most common grade 3 or worse TRAE was fatigue (6 (43%)), and anorexia (6 (43%)). The occurrence rate of myelosuppression, nausea and vomiting, abnormal liver enzymes, and other grade 3–4 chemotherapy adverse reactions were relatively low, and no grade 5 treatment-related adverse events occurred.ConclusionScreening HER2-negative medium-advanced GC/GJC chemotherapy regimens and targeted drugs based on MiniPDX animal models showed good tumor activity and safety.

A rapid and durable response to larotrectinib in a patient with NTRK fusion-positive secretory carcinoma originating from the external auditory canal

For decades, no clear consensus existed on the standard treatment option for malignant tumors of the external auditory canal, an extremely rare disease. Here we report the case of a 55-year-old female patient with secretory carcinoma that originated from the left external auditory canal. Magnetic resonance imaging (MRI) at baseline showed that the tumor had extended to the medulla oblongata despite surgical and radiation treatments for more than 20 years from the initial diagnosis. Based on the results of a next-generation sequencing test of a formalin-fixed paraffin-embedded surgical specimen indicating that the tumor harbored ETV6–NTRK3 fusion, the patient was enrolled in a global basket study of larotrectinib, an oral selective tropomyosin receptor kinase (TRK) inhibitor. Three weeks after the start of larotrectinib treatment, MRI showed only small remnants of the tumor in the medulla oblongata and the patient’s headache before the treatment had disappeared. Subsequent MRI after 12 weeks of treatment confirmed the complete disappearance of the tumor. The patient repeated grade 2 flu-like symptoms related to treatment, but did not experience any other grade 2 or worse treatment-related adverse events. TRK inhibitors, such as larotrectinib, exert potent antitumor activity against neurotrophic tyrosine receptor kinase (NTRK) fusion-positive tumors in a tumor-agnostic manner. To the best of our knowledge, this is the first report on NTRK fusion-positive secretory carcinoma of the external auditory canal, and this report provides a valuable insight into the management of the extremely rare but now treatable malignancy.

Platinum-free chemotherapy in the new era of immunotherapy: A phase II study of camrelizumab combined with apatinib and albumin paclitaxel in advanced non-squamous NSCLC (CAPAP-lung).

9034 Background: Cytotoxic chemotherapy and anti-angiogenic therapy may enhance the therapeutic efficacy of immune checkpoint inhibitors (ICIs). Platinum-containing dual-agent chemotherapy combined with ICIs is the standard first-line treatment for non-small cell lung cancer (NSCLC), however, the optimal combination regimen remains unclear. The adverse effects of platinum-based chemotherapy are relatively serious, whether platinum chemotherapy can be eliminated in the first-line treatment of non-small cell lung cancer is a hotspot and difficulty in current research. Based on these results, we initiated CAPAP-lung study, which is a single-arm, multicenter Phase II trial to evaluate the efficacy and safety of Camrelizumab in combination with apatinib and albumin paclitaxel without platinum as the first-line therapy for non-squamous non-small cell lung cancer. Methods: Patients diagnosed with ⅢB-IV non-squamous NSCLC without EGFR and ALK sensitive mutations received Camrelizumab (200mg/3w) in combination with Albumin Paclitacxel (135mg/m2, d1, d8/3w, 4-6 cycles) and Apatinib (250mg Qd po for 5 days, resting for 2 days every week). From August 2020 to February 2022, 54 of the planned 63 patients have been enrolled. The primary endpoint is progression-free survival(PFS), and secondary endpoints were overall survival (OS), duration of Response (DOR), objective response rate (ORR), and disease control rate (DCR) assessed by RECIST v1.1. This study is registered with ClinicalTrials.gov, NCT04459078 (follow-up is ongoing). Results: The data for a total of 38 patients out of 54 enrolled patients were evaluable. Median PFS was 10.97 mo (95%CI 7.1-NR).The objective response rate (ORR) and disease control rate (DCR) were 71.1% (27/38, 95%CI 53.9-84.0) and 97.4% (37/38, 95%CI 84.6-99.9), respectively. The incidence of grade 3 and worse treatment-related adverse events was acceptable, with grade 3 events in 25(46.3%) patients and grade 4 events in 3(5.6%) patients. The most common grade 3 treatment-related adverse events were decreased neutrophil count (8 [14.8%]), liver function damage (9 [16.7%]), rash (3 [5.6%]), and decreased white blood cell count (3 [5.6%]). Conclusions: Camrelizumab combined with albumin paclitaxel and apatinib showed encouraging antitumor activity with an acceptable safety profile for the first-line treatment of advanced lung adenocarcinoma. Clinical trial information: NCT04459078.

A phase I study of pharmacokinetic (PK)-driven sequential dosing of rucaparib (RUB) with irinotecan liposome (nal-IRI) and fluorouracil (5FU) in metastatic gastrointestinal (mGI) and pancreas (PANC) cancers.

563 Background: RUB is an oral PARP1,2,3 inhibitor that demonstrated efficacy in patients (pts) with ovarian and prostate cancers harboring deleterious BRCA mutations. RUB exerts synergistic anti-tumor effect with IRI preclinically though the combination has overlapping toxicities. We previously published on the population PK of nal-IRI (Adiwijaya, Ma et al, Clin Pharm Ther 2017). We conducted a phase I study to evaluate a novel sequential dosing of RUB with nal-IRI/5FU in mGI cancer pts. Methods: Eligible pts had incurable mGI cancer previously received &gt; 1 line of therapy (rx), ECOG PS 0-1, had RECIST measurable disease, adequate organ reserves and not received IRI for metastatic disease. Previous PARPi rx was excluded. The endpoints included dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile. The dose escalation utilized the 3+3 design. RUB was given oral bid on Day 4 to 13 and 18 to 27 with nal-IRI i.v. and 5FU i.v. 2400 mg/m2 over 46 hr on Day 1 and 15, every 28 day. Planned dose levels were RUB 400 mg/nal-IRI 50 mg/m2 (DL1), 400 mg/70 mg/m2 (DL2) and 600 mg/70 mg/m2 (DL3). Adverse events (AEs) were scored per CTCAE v4.03. Molecular profile was evaluated by CLIA-certified NGS testing. Results: Eighteen pts including 11 colorectal (CRC), 6 PANC, 1 gastroesophageal (GE) were enrolled and 12 were evaluable for DLTs. DL2 was not tolerable (DLT: G3 diarrhea, nausea and vomiting) and DL2A was added (RUB 600 mg/nal-IRI 50 mg/m2). DL2A enrolled 6 pts with no DLT and was determined as the MTD. Of DLT-evaluable pts, G3 and worse treatment-related AEs from all cycles were diarrhea (33%), fatigue (25%), leukopenia (25%), neutropenia (25%), anemia (8%) and nausea (8%). Four of 12 response evaluable pts had partial response: 2 CRC (1 had ATM mut), 1 PANC ( ATM mut), 1 GE ( BRCA2 mut) whilst 3 responders previously had platinum (PLA). Five pts had stable disease beyond 16 weeks (range 18.9 to 100.7 weeks), and all had prior PLA. Conclusions: The study successfully determined the MTD of RUB in combination with nal-IRI and 5FU. Encouraging efficacy was observed in PLA-treated mGI cancers including responses in those harboring ATM and BRCA alterations. The study is proceeding to evaluate the efficacy of the combination in metastatic pancreas cancer pts with and without BRCA1/2 or PALB2 alterations. Clinical trial information: NCT03337087.

A multicenter randomized phase III study of albumin-bound paclitaxel combined with S-1 (AS) versus oxaliplatin combined with S-1 (SOX) for first-line treatment of advanced gastric cancer (GAPSO study).

282 Background: Albumin-bound paclitaxel has been proven to be an active agent in advanced gastric cancer, and was approved by PMDA Japan for use as a second-line treatment of advanced gastric cancer. The aim of this study was to evaluated the efficacy and safety of AS and SOX in the first-line treatment of advanced gastric cancer. Methods: Patients diagnosed with unresectable locally advanced, recurrent or metastatic human epidermal growth factor receptor type 2 (HER2)-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma were randomized (1:1) to either AS group (albumin-bound paclitaxel 260mg/m2 d1 or 130mg/m2 d1, 8; S-1 40 mg [BSA &lt; 1.25 m2], 50 mg [1.25 ≤ BSA &lt; 1.50 m2] and 60 mg [BSA ≥1.50 m2] b.i.d. d1-14, every 3wks) or SOX group (oxaliplatin 130mg/m2 d1; S-1 40 mg [BSA &lt; 1.25 m2], 50 mg [1.25 ≤ BSA &lt; 1.50 m2] and 60 mg [BSA ≥1.50 m2] b.i.d. d1-14, every 3wks). Primary endpoint was progression-free survival (PFS), secondary endpoints included overall survival (OS), objective response rate (ORR) and safety. Results: Between March 2019 and March 2021, 96 patients were enrolled and 85 patients (AS group, n = 43; SOX group, n = 42) who received at least one dose of study drug and had at least one postbaseline efficacy evaluation were included in the final analysis. 34 (79.0%) patients in the AS group and 35 (83.3%) in the SOX group had discontinued treatment. Of these 85 patients, 78.8% had two or more organs involved, 61.2% had peritoneal dissemination, and more than 1/4 had massive ascites. Patient demographics and disease characteristics were generally balanced between arms. With median follow-up 15.4 months (95% CI, 8.8-21.9), the median PFS of AS group vs. SOX group was 9.2 vs.5.1 months (HR = 0.58 [95% CI 0.36-0.96], p = 0.034); and the median OS was 14.4 vs. 15.4 months (HR = 0.73 [95%CI 0.40-1.34], p = 0.375). Tumor response was assessable in 33 patients according to RECIST V1.1 in both cohorts, the ORR and DCR were similar in AS vs. SOX arm (ORR: 54.5% vs. 51.5%, P = 0.805; DCR: 78.8% vs. 78.8%, P = 1.000). The main grade 3 or worse treatment-related adverse events were neutropenia (30.2% vs 23.8%), Leucopenia (11.6% vs 11.9%) and peripheral sensory neuropathy (4.7% vs 7.1%) in AS and SOX group. The study was planned to be adjusted, due to the widespread use of immunotherapy in first-line treatment of gastric cancer. Conclusions: The results of this study indicated that in previously untreated patients with unresectable locally advanced, recurrent or metastatic HER2-negative gastric or GEJ adenocarcinoma, AS achieved better PFS than SOX, with an inadequate power. The toxicities were controllable and consistent with previously reported. Clinical trial information: NCT03801668.

Camrelizumab plus apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma (CAP 02): a single-arm, open-label, phase 2 trial

Camrelizumab, an anti-PD-1 antibody, has shown moderate efficacy in oesophageal squamous cell carcinoma. Apatinib, a selective inhibitor of VEGFR2, has a synergistic effect with immunotherapy. We aimed to assess the combination of camrelizumab and apatinib as second-line treatment for advanced oesophageal squamous cell carcinoma. This single-arm, open-label, phase 2 study was conducted at eight centres in China. Eligible patients were aged 18-75 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had unresectable locally advanced, locally recurrent, or metastatic oesophageal squamous cell carcinoma, and had progressed after or were intolerant to first-line chemotherapy. Patients received intravenous camrelizumab 200 mg once every 2 weeks plus oral apatinib 250 mg once daily for a 28-day cycle until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was investigator-assessed confirmed objective response rate. Efficacy was analysed in patients who had received at least one dose of study drug, and safety was analysed in patients who received the study drug and had at least one post-baseline safety assessment. The study of this cohort is complete and this trial is registered with ClinicalTrials.gov, number NCT03736863. Between Dec 5, 2019, and Feb 10, 2021, 52 patients were enrolled and included in analyses. At data cutoff (June 20, 2021), median follow-up was 7·5 months (IQR 4·0-11·2). 18 (34·6%, [95% CI 22·0-49·1]) of 52 patients had a confirmed objective response. 23 (44%) of 52 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or worse treatment-related adverse events were increased aspartate aminotransferase (10 [19%]), increased gamma-glutamyltransferase (10 [19%]), and increased alanine aminotransferase (five [10%]). No treatment-related deaths occurred. Camrelizumab combined with apatinib showed promising activity and manageable toxicity, and might be a potential second-line treatment option for patients with advanced oesophageal squamous cell carcinoma. Another cohort of this study, enrolling patients previously treated with first-line immunotherapy, is ongoing. Jiangsu Hengrui Pharmaceuticals.

Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial

Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1-2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma. In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509. Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7-28·0) for the nivolumab group and 13·4 months (5·7-25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9-18·4) with nivolumab and 14·7 months (11·9-17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72-1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related. First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks. Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

Anlotinib Alone or in Combination With Temozolomide in the Treatment of Recurrent High-Grade Glioma: A Retrospective Analysis.

Background: Anlotinib is a multi-target anti-angiogenic agent. This retrospective study aimed to evaluate the efficacy and safety of anlotinib alone or in combination with temozolomide for the treatment of recurrent high-grade glioma. Materials and Methods: The clinical data of patients with recurrent high-grade glioma treated with anlotinib alone or in combination with temozolomide in our cancer center were collected and analyzed. Treatment response was evaluated according to the response assessment for neuro-oncology criteria. Progression-free survival, progression-free survival at 6 months, overall survival, and overall survival at 12 months were evaluated by Kaplan–Meier method and compared by log-rank test. Results: Between August 2019 and December 2020, 31 patients with recurrent high-grade glioma (21 of grade 4 and 10 of grade 3) were enrolled in this study. Seventeen patients received anlotinib alone and 14 received anlotinib plus temozolomide. All patients were heavily treated, the median lines of previous treatments were 2, and the median Karnofsky score was 60. At the data cutoff date, the median progression-free survival was 4.5 months and the progression-free survival at 6 months was 43.5%. The median overall survival was 7.7 months, and the overall survival at 12 months was 26.7%. The progression-free survival at 6 months and the overall survival at 12 months for 21 patients with grade 4 glioma was 40.2 and 27.9%, respectively. The tumor objective response rate was 41.9% in all patients and 33.3% in patients with grade 4 glioma. No grade 3 or worse treatment-related adverse events were recorded during the treatment. Conclusion: Anlotinib alone or in combination with temozolomide showed encouraging efficacy and favorable tolerability in patients with recurrent high-grade glioma who had been heavily treated.

ESMO World Congress on Gastrointestinal Cancer 2021.

Ghassan K Abou-Alfa (Memorial Sloan Kettering Cancer Center, New York, NY, USA) presented the results of a global phase 2 study of the investigational PD-1 antibody tislelizumab in patients with previously treated unresectable hepatocellular carcinoma. 249 patients were enrolled and received tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint, overall response rate by independent review committee, was 13·3% (95% CI 9·3–18·1), with 33 patients achieving an overall response (three complete responses and 30 partial responses). Median duration of response was not reached. The safety profile was as expected and manageable. Grade 3 or worse treatment-related adverse events were recorded in 36 (14%) patients, the most common of which was increased aspartate aminotransferase (in seven [3%] patients) and there were no treatment-related deaths.

Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial

Locally advanced or metastatic urothelial carcinoma is generally incurable and has scarce treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy. Enfortumab vedotin is an antibody-drug conjugate directed at Nectin-4, a protein highly expressed in urothelial carcinoma. We aimed to evaluate the efficacy and safety of enfortumab vedotin in the post-immunotherapy setting in cisplatin-ineligible patients. EV-201 is a multicentre, single-arm, phase 2 study of enfortumab vedotin in patients with locally advanced or metastatic urothelial carcinoma previously treated with PD-1 or PD-L1 inhibitors. Cohort 2 included adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status score of 2 or less who were considered ineligible for cisplatin at enrolment and who had not received platinum-containing chemotherapy in the locally advanced or metastatic setting. Enfortumab vedotin was given intravenously at a dose of 1·25 mg/kg on days 1, 8, and 15 of every 28-day cycle. The primary endpoint was confirmed objective response rate per Response Evaluation Criteria in Solid Tumours version 1.1 assessed by blinded independent central review. Efficacy and safety were analysed in all patients who received at least one dose of enfortumab vedotin. EV-201 is an ongoing study and the primary analysis is complete. This study is registered with Clinicaltrials.gov, NCT03219333. Between Oct 8, 2017, and Feb 11, 2020, 91 patients were enrolled at 40 sites globally, of whom 89 received treatment. Median follow-up was 13·4 months (IQR 11·3-18·9). At data cutoff (Sept 8, 2020), the confirmed objective response rate was 52% (46 of 89 patients; 95% CI 41-62), with 18 (20%) of 89 patients achieving a complete response and 28 (31%) achieving a partial response. 49 (55%) of 89 patients had grade 3 or worse treatment-related adverse events. The most common grade 3 or 4 treatment-related adverse events were neutropenia (eight [9%] patients), maculopapular rash (seven [8%] patients), and fatigue (six [7%] patients). Treatment-related serious adverse events occurred in 15 (17%) patients. Three (3%) patients died due to acute kidney injury, metabolic acidosis, and multiple organ dysfunction syndrome (one [1%] each) within 30 days of first dose and these deaths were considered by the investigator to be related to treatment; a fourth death from pneumonitis occurred more than 30 days after the last dose and was also considered to be related to treatment. Treatment with enfortumab vedotin was tolerable and confirmed responses were seen in 52% of cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma who were previously treated with PD-1 or PD-L1 inhibitors. These patients have few treatment options, and enfortumab vedotin could be a promising new therapy for a patient population with a high unmet need. Astellas Pharma Global Development and Seagen.

Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study

Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population. This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2·0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10·0 months (IQR 6·1-13·0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatment-related adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. Genmab, Seagen, Gynaecologic Oncology Group, and European Network of Gynaecological Oncological Trial Groups.

Camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in chemotherapy-naive patients with advanced non-squamous non-small-cell lung cancer (CameL): a randomised, open-label, multicentre, phase 3 trial

Immunotherapy combined with chemotherapy has been shown to be efficacious as treatment for advanced non-squamous non-small-cell lung cancer (NSCLC) without targetable genetic aberrations; however, there is scarce evidence of the effectiveness of the combinations in the Asian population. We evaluated camrelizumab plus chemotherapy against non-squamous NSCLC in China. We did a randomised, open-label, multicentre, phase 3 trial (CameL) in 52 hospitals in China for patients with non-squamous NSCLC without EGFR and ALK alteration. Eligible patients were aged 18-70 years and had no previous systemic chemotherapy, Eastern Cooperative Oncology Group performance status of 0 or 1, and at least one measurable lesion per Response Evaluation Criteria in Solid Tumors (version 1.1). Patients were randomly assigned (1:1) to receive 4-6 cycles of carboplatin (area under curve 5 mg/mL per min) plus pemetrexed (500 mg/m2) with or without camrelizumab (200 mg) every 3 weeks, followed by maintenance therapy with camrelizumab plus pemetrexed or pemetrexed alone. Medication was administered intravenously on day 1 of each 3-week treatment cycle. Randomisation was done using a centralised interactive web-response system with the block size randomly generated as four or six and stratified by sex and smoking history. The two primary endpoints were progression-free survival per blinded independent central review, in all patients and in patients who were PD-L1 positive. Primary analysis was done in the full analysis set that included all randomly assigned patients who received at least one dose of the study treatment. Herein, due to the primary endpoint being met at the interim analysis, we reported the findings of prespecified interim analysis, which only included confirmatory statistical testing for progression-free survival in all patients. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT03134872 (follow-up is ongoing). Between May 12, 2017, and June 6, 2018, of the 419 patients who were randomly assigned, seven did not receive assigned treatment and 412 received either camrelizumab plus chemotherapy (n=205) or chemotherapy alone (n=207). At interim analysis, median follow-up duration was 11·9 months (IQR 9·0-14·9). Progression-free survival in this interim analysis was significantly prolonged with camrelizumab plus chemotherapy than with chemotherapy alone (median 11·3 months [95% CI 9·6-15·4] vs 8·3 months [6·0-9·7]; hazard ratio 0·60 [0·45-0·79]; one-sided p=0·0001). Most common grade 3 or worse treatment-related adverse events were decreased neutrophil count (78 [38%] patients in the camrelizumab plus chemotherapy group vs 63 [30%] patients in the chemotherapy alone group), decreased white blood cell count (40 [20%] vs 30 [14%]), anaemia (38 [19%] vs 23 [11%]), and decreased platelet count (34 [17%] vs 24 [12%]). Serious treatment-related adverse events occurred in 74 (36%) patients in the camrelizumab plus chemotherapy group and 27 (13%) patients in the chemotherapy alone group. The primary endpoint was met at the interim analysis, showing a statistically significant and clinically meaningful improvement in progression-free survival with camrelizumab plus carboplatin and pemetrexed versus chemotherapy alone in all patients, supporting camrelizumab plus carboplatin and pemetrexed as a first-line treatment option for Chinese patients with advanced non-squamous NSCLC without EGFR and ALK alterations. The trial is being continued to collect long-term outcomes in all patients and carry out confirmatory statistical testing for progression-free survival in the PD-L1-positive population. Jiangsu Hengrui Medicine.