Palmar-plantar Erythrodysesthesia Syndrome Research Articles

A disproportionality analysis for assessing the safety of FLT3 inhibitors using the FDA Adverse Event Reporting System (FAERS).

This pharmacovigilance analysis was conducted to assess the safety signals of FMS-related tyrosine kinase 3 (FLT3) inhibitors in a real-world setting using the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We analyzed adverse event (AE) reports related to FLT3 inhibitors submitted to the FAERS database from the first quarter of 2015 to the fourth quarter of 2022. Disproportionality analysis was used to identify AEs of FLT3 inhibitors in the FAERS database. A total of 55,393 AE reports were identified, of which 5938, 44,013, and 5442 were attributed to midostaurin, sorafenib, and gilteritinib, respectively, as primary suspects. Compared to the full database, significant safety signals at the system organ class level were observed for midostaurin (blood and lymphatic system disorders and hepatobiliary disorders), sorafenib (skin and subcutaneous tissue disorders and hepatobiliary disorders), and gilteritinib (investigations, blood and lymphatic system disorders, infections and infestations, and hepatobiliary disorders). All the drugs studied were associated with hepatobiliary disorders. The most prominent AEs associated with midostaurin, sorafenib, and gilteritinib were cytopenia, palmar-plantar erythrodysesthesia syndrome, and increased blast cell count, respectively. Compared with chemotherapy, midostaurin and gilteritinib showed a higher risk of electrocardiogram QT prolongation, gastrointestinal hemorrhage, cerebral hemorrhage, and increased white blood cell count. Gilteritinib had the highest overall death percentage (30.28%), whereas sorafenib had the lowest (23.06%). Mining AE signals using the FAERS database provides a method for analyzing the safety of FLT3 inhibitors in post-marketing. We found several significant AE signals that corresponded to previous studies; however, some AE signals were not mentioned in the drug instructions. Our study could provide a direction for follow-up real-world studies to verify the results further.

Характеристика и управление нежелательными реакциями у пациентов с распространенным раком эндометрия, которые получают комбинацию ленватиниб плюс пембролизумаб

Background. Lenvatinib plus pembrolizumab significantly improved efficacy compared with chemotherapy in patients with advanced endometrial cancer (aEC) regardless of microsatellite instability status or histologic subtype, who had disease progression following prior platinum-based therapy, in Study-309/KEYNOTE-775. The safety profile of the combination was generally consistent with that of each monotherapy drug and of the combination in patients with endometrial cancer and other solid tumors. Given the medical complexity of patients with aEC, this paper aims to characterize key adverse reactions (ARs) of the combination treatment and review management strategies, providing a guide for AR management to maximize anticancer benefits and minimize treatment discontinuation. Materials and methods. In Study-309/KEYNOTE-775, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks) or chemotherapy (doxorubicin or paclitaxel). The incidence and median time to the first onset of ARs, dose modifications, and concomitant medications are described. Key ARs characterized include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight decreased, proteinuria, and palmar-plantar erythrodysesthesia syndrome. Results. As expected, the most common any-grade key ARs included: hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders. Grades 3-4 key ARs with incidence ≥10% included: hypertension, fatigue, and weight decreased. Key ARs first occurred within approximately 3 months of treatment initiation. AR management strategies consistent with the prescribing information and the study protocol are discussed. Conclusion. Successful AR management strategies for lenvatinib plus pembrolizumab include education of the patient and entire treatment team, preventative measures and close monitoring, and judicious use of dose modifications and concomitant medications.

Characterization and Management of Adverse Reactions in Patients With Unresectable Hepatocellular Carcinoma Treated With Lenvatinib.

Advanced practice providers (APPs) play a vital role in monitoring for and managing adverse reactions (ARs). As lenvatinib ARs can resemble cirrhosis (commonly presenting with hepatocellular carcinoma [HCC]), APP input is important for timely detection and management of ARs and to promote medication adherence. The goal of this post-hoc analysis of the REFLECT trial was to characterize key ARs associated with lenvatinib, and to discuss management strategies. In REFLECT, patients with unresectable HCC were randomized to either daily lenvatinib (12 mg/day for patients who weighed ≥ 60 kg or 8 mg/day for those < 60 kg) or sorafenib 400 mg twice daily. Adverse events in the lenvatinib arm were grouped into ARs (hypertension, fatigue, palmar-plantar erythrodysesthesia syndrome, proteinuria, and decreased appetite) per the United States Prescribing Information (USPI) for lenvatinib. Key ARs in the lenvatinib arm (n = 476) generally occurred within months of starting lenvatinib. Some cases of proteinuria, decreased appetite, and diarrhea were first reported at about 2 years of treatment. The onset of key ARs associated with lenvatinib treatment can be predicted and generally be managed (per the lenvatinib USPI and REFLECT) by withholding lenvatinib and resuming it at a reduced dose after the severity decreases. However, lenvatinib should generally be discontinued if the AR is life-threatening.

Characterization and Management of Adverse Reactions in Patients With Advanced Endometrial Cancer Receiving Lenvatinib Plus Pembrolizumab.

Lenvatinib plus pembrolizumab significantly improved efficacy compared with chemotherapy in patients with advanced endometrial cancer (aEC) regardless of microsatellite instability status or histologic subtype, who had disease progression following prior platinum-based therapy, in Study-309/KEYNOTE-775. The safety profile of the combination was generally consistent with that of each monotherapy drug and of the combination in patients with endometrial cancer and other solid tumors. Given the medical complexity of patients with aEC, this paper aims to characterize key adverse reactions (ARs) of the combination treatment and review management strategies, providing a guide for AR management to maximize anticancer benefits and minimize treatment discontinuation. In Study-309/KEYNOTE-775, patients received lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously every 3 weeks) or chemotherapy (doxorubicin or paclitaxel). The incidence and median time to the first onset of ARs, dose modifications, and concomitant medications are described. Key ARs characterized include hypothyroidism, hypertension, fatigue, diarrhea, musculoskeletal disorders, nausea, decreased appetite, vomiting, stomatitis, weight decreased, proteinuria, and palmar-plantar erythrodysesthesia syndrome. As expected, the most common any-grade key ARs included: hypothyroidism, hypertension, fatigue, diarrhea, and musculoskeletal disorders. Grades 3-4 key ARs with incidence ≥10% included: hypertension, fatigue, and weight decreased. Key ARs first occurred within approximately 3 months of treatment initiation. AR management strategies consistent with the prescribing information and the study protocol are discussed. Successful AR management strategies for lenvatinib plus pembrolizumab include education of the patient and entire treatment team, preventative measures and close monitoring, and judicious use of dose modifications and concomitant medications. NCT03517449.

A phase 1b study of E7386, a CREB-binding protein (CBP)/β-catenin interaction inhibitor, in combination with lenvatinib in patients with advanced hepatocellular carcinoma.

4075 Background: E7386, a novel oral anticancer agent, inhibits β-catenin binding to its transcriptional co-activator, CBP, thus modulating Wnt/β-catenin signaling. The objectives of the dose-escalation part in this phase 1b study were to assess safety, tolerability, pharmacokinetics (PK), biomarkers, and preliminary efficacy of E7386 combined with lenvatinib in patients with advanced hepatocellular carcinoma (HCC) or other solid tumors. Here, we present the results from the HCC subpart. Methods: In cycle 0, E7386 was administered orally in escalating doses once daily (QD) or twice daily (BID) for 5 or 6 consecutive days. From cycle 1 day 1, E7386 QD or BID, combined with daily oral lenvatinib (8 mg in patients with body weight of &lt;60 kg or 12 mg in patients with body weight ≥60 kg), were administered on a continuous schedule in 28-day cycles in the HCC subpart. Adverse events (AEs) were graded using CTCAE v5.0. Prophylactic antiemetics were not allowed during the dose-limiting toxicities (DLT) evaluation period but were permitted after the occurrence of nausea and vomiting. Tumor response was assessed by investigators using mRECIST (Lencioni and Llovet, 2010). PK and biomarker analyses were conducted using samples collected at defined time points. Results: As of the cutoff date (9 December 2022), 25 patients had been treated in the HCC subpart with E7386 dose ranges from 10 to 80 mg QD and from 60 to 120 mg BID. Among 3 patients in the E7386 120 mg BID cohort, grade 3 maculopapular rash (in 1 patient) and grade 5 acute kidney injury (in 1 patient) DLTs were observed. No DLTs were observed in other cohorts. The most common treatment-emergent AEs (TEAEs; any grade) across all cohorts were nausea (n=19; 76.0%), vomiting (n=15; 60.0%), constipation (n=13; 52.0%), palmar-plantar erythrodysesthesia syndrome (n=12; 48.0%), diarrhea (n=11; 44.0%), and proteinuria (n=10; 40.0%). The most common grade ≥3 TEAEs (≥5% of patients) were proteinuria (n=5; 20.0%) and aspartate aminotransferase level increased (n=2; 8.0%). Nausea and vomiting were well controlled by a 5HT3 antagonist. Among the 25 treated patients, 9 (36.0%) partial responses (PRs) were observed, including 3 PRs in 10 patients who had received lenvatinib as a prior regimen. Cmax and AUC for E7386 increased with increasing E7386 dose. Conclusions: E7386 100 mg BID, in combination with lenvatinib (8 or 12 mg based on bodyweight) QD, was determined as the recommended phase 2 dose, and was deemed tolerable and manageable with antiemetic administration. The combination showed promising activity in patients with HCC, including those pretreated with lenvatinib. Clinical trial information: NCT04008797 .

Preliminary safety and efficacy of tinengotinib tablets as monotherapy and combination therapy in advanced solid tumors: A phase Ib/II clinical trial.

3019 Background: Tinengotinib is a spectrum-selective multi-kinase inhibitor that targets cell proliferation, angiogenesis, and immune-oncology pathways by inhibiting Aurora kinases A/B, Janus kinases (JAK), and receptor tyrosine kinases (FGFRs, VEGFRs). Tinengotinib has shown preliminary efficacy in prostate cancer (PC), hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC), triple-negative BC (TNBC) and cholangiocarcinoma (CCA) in Phase (Ph) 1 trial. Here we present the preliminary safety, pharmacokinetics (PK), and efficacy of tinengotinib in a Ph Ib/II trial. Methods: Eligible patients (pts) with advanced or metastatic solid tumors were assigned to: Arm A (tinengotinib 12 mg QD), Arm B (tinengotinib 8/10/12 mg QD in combination with 100 mg/m2 Abraxane, HER2- BC); Arm C PK Run-in (tinengotinib 5/8/10/12 mg QD, or 4/6 mg BID). Objectives include safety (CTCAE v5.0) and tolerability, PK profile, efficacy (RECIST v1.1) and exploratory biomarker(s). Results: As of 30 Jan 2023, 157 pts with solid tumors were enrolled and treated. In monotherapy (Arm A and Arm C, N=153), median age was 62.5 years (23-83), 56% were female, 69% had ≥ 3 prior lines of therapy. In combination (Arm B, N=4), median age was 40 years (25-46), 100% were female, 100% had ≥3 prior lines of therapy. The treatment-related AEs (TRAE) in monotherapy arms were reported in 110 (71.9%) pts. 53 (34.6%) were Grade (G) 1-2, 55 (35.9%) were G3, 2 (1.3%) were G4, no G5 was observed; the most common TRAEs were hypertension (29.4%), stomatitis (20.9%), diarrhea (16.3%), nausea (13.7%) and palmar-plantar erythrodysesthesia syndrome (12.4%). In the combination arm, 4 treated pts at dose level 1 experienced G3 TRAEs, and the most common TRAEs were neutropenia (75%), stomatitis (50%), hyponatremia (50%), hypokalemia (50%) and hypertension (50%). In 108 efficacy-evaluable pts of monotherapy arms, the overall response rate (ORR) and disease control rate (DCR) were 16% and 60%, respectively. The ORR in PC, HR+/HER2- BC, TNBC and CCA were 50% (5/10), 40% (2/5), 50% (3/6) and 20% (3/15), respectively. Preliminary PK analysis showed a linear increase on exposure in terms of geometric mean Cmax,ss and AUC0-24h,ss from 5 mg QD to 12 mg QD. No significant difference in exposure was observed in QD vs BID. Conclusions: Tinengotinib monotherapy was well-tolerated. The tolerability assessment in combination with chemotherapy is underway. The PK results may support dose recommendation for subsequent trials. Encouraging anticancer activity of tinengotinib monotherapy were observed in pts with heavily pre-treated solid tumors, including PC, HR+/HER2- BC, TNBC and CCA. The ongoing Ph II study of tinengotinib continues to evaluate clinical benefit and safety in pts with PC. Clinical trial information: NCT04742959 .

A phase 2 study of HMPL-453, a selective FGFR tyrosine kinase inhibitor (TKI), in patients with previously treated advanced cholangiocarcinoma containing FGFR2 fusions.

e16118 Background: Patients (pts) with advanced cholangiocarcinoma (CCA) who progressed on or after 1L chemotherapy have few treatment options. FGFR2 fusions or rearrangements occur in 10–16% of pts in global and 6.14% in Chinese pts with intrahepatic cholangiocarcinoma (iCCA), and may predict tumor susceptibility to FGFR inhibitors. HMPL-453 is a novel, selective tyrosine kinase inhibitor against FGFR1, 2, and 3. Here, we report results from an open-label, multi-cohort, single-arm phase 2 study (NCT04353375). Methods: Pts with histologically or cytologically confirmed locally advanced or metastatic iCCA with FGFR2 fusions who were treated at least one previous line of systemic therapy were eligible and included in this analysis. They received 21-day cycles of HMPL-453 orally with 150 mg (QD, cohort 1) or 300 mg (QD, 2w on/1w off, cohort 2) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Results: At data cutoff (Sep 21, 2022), a total of 25 iCCA pts (12 in cohort 1, 13 in cohort 2) were enrolled and treated with HMPL-453. Median age was 51 yrs (range 28-76) and 12 (48%) were male. All pts had received ≥1 prior treatment line and 21 (84%) had received previous gemcitabine-based chemotherapy. The median follow-up duration was 12 months (mos) and 4.1 mos for cohort 1 and cohort 2, respectively. Of 22 evaluable pts (12 in cohort 1 and 10 in cohort 2) who had at least one post-baseline tumor assessment, the best overall response by investigator assessment was confirmed partial response in seven (31.8%) pts and stable disease in an additional 12 pts (54.5%), resulting in a disease control rate (DCR) of 86.4%. Specifically, in cohort 2 the confirmed ORR was 50% (95% CI, 18.7%–81.3%) and DCR was 90% (95% CI, 55.5%–99.7%). Duration of response was not reached in either cohort. Median progression-free survival was 5.7 (95% CI, 2.6, NR) mos in cohort 1 and not yet mature in cohort 2. Of all pts, 23 (92%) experienced ≥1 treatment-related adverse events (TRAEs). The most common TRAEs (any grade) were diarrhea (56%), dry mouth (44%), and blood phosphorus increased (44%). The common Gr ≥3 TRAEs (≥5% pts) were decreased neutrophil count (8%), nail toxicity (8%) and palmar-plantar erythrodysesthesia syndrome (8%). Compared to cohort 1, pts in cohort 2 experienced a lower incidence of Gr ≥3 TRAEs (23.1% vs 58.3%), less dose interruption/reduction (32.0% vs 41.7%) and less treatment discontinuation (0.0% vs 16.7%) due to TRAE. Based on the better safety profile and preliminary efficacy, 300mg, QD, 2w on/1w off was chosen as the recommended phase 2 dose (RP2D). Conclusions: HMPL-453 showed promising efficacy, particularly in RP2D regimen (300 mg, QD, 2w on/1w off) and acceptable toxicity in pts with previously-treated advanced iCCA and FGFR fusions. These results warrant further study in pts with advanced iCCA. Clinical trial information: NCT04353375 .

The safety and efficacy of donafenib combined with anti-PD-1 antibody as adjuvant therapy for patients (pts) with hepatocellular carcinoma (HCC): Updated results of a phase 2 study.

e16202 Background: Adjuvant therapy may have an important role in decreasing recurrence rates and improve survival in selected pts with HCC following surgical resection. However, there is no standard treatment options or strategies. This study aimed to investigate the safety and efficacy of donafenib combined with anti-PD-1 antibody as adjuvant therapy for HCC pts with high risks of recurrence. Methods: This prospective, open-label, single-arm study planned to enroll 30 pts who had undergone radical surgery and were diagnosed as HCC confirmed by histology or cytology with any of the following risk factors: a) Microvascular invasion (MVI); b) Satellite nodules in specimens; c) &gt;3 tumor nodules; d) Portal vein tumor thrombosis (excluded main portal vein invasion). Donafenib combined with anti-PD-1 antibody was initiated at 4 to 8 weeks after surgical resection and continued for up to six months. The primary endpoint was the cumulative 1-year recurrence-free survival rate (RFSR). The secondary endpoints were recurrence-free survival (RFS), overall survival, and safety. Results: As of December 31st, 2022, a total of 23 pts received donafenib plus anti-PD-1 antibody (toripalimab) with a mean follow-up of 7.6 months (safety set). The most common risk factor was MVI (91%). 20 pts were included in efficacy set (three pts were excluded due to ineligibility), of whom 16 pts had one risk factor and four had two. Intrahepatic recurrence occurred in 3 pts (15%) and no extrahepatic metastasis or death was reported. The RFSR at one year was 83.0% (90%CI, 61.6%-93.1%) in all the pts from efficacy set, 81.9% (90%CI, 59.6%-92.6%) and 92.3% (90%CI, 66.0%-98.5%) in pts with MVI and MVI-low risk, and 85.1% (90%CI, 59.6%-95.1%) in pts with only one risk factor. The median RFS was not reached. The incidence of grade 3 adverse events related to donafenib and/or toripalimab was 52.2% (12/23). No pts had grade 4/5 adverse events. Adverse events leading to withdrawal of any and both treatments occurred in six (26.1%) and one (4.3%) pts, respectively. The most common grade 3 treatment-related adverse events (occurred in more than one patient) were palmar-plantar erythrodysesthesia syndrome (17.4%), rash (17.4%), alanine aminotransferase increased (13.0%), and aspartate aminotransferase increased (8.7%). Conclusions: These results were consistent with earlier reports. The combination of donafenib and toripalimab may be a promising adjuvant therapy for pts with MVI, satellite nodules or multiple tumor after hepatectomy. No safety issues were noted. Clinical trial information: NCT04418401 . [Table: see text]

CASSIOPE: A prospective noninterventional study of cabozantinib treatment following prior vascular endothelial growth factor (VEGF) -targeted therapy in patients with advanced renal cell carcinoma (aRCC).

4529 Background: Cabozantinib is a tyrosine kinase inhibitor approved as monotherapy for aRCC in the USA, and as first-line therapy for patients with intermediate or poor risk aRCC, or after previous VEGF-targeted therapy in Europe. In the METEOR trial, a substantial proportion of patients required cabozantinib dose modifications. We report a real-world study of cabozantinib use for aRCC. Methods: CASSIOPE was a non-interventional prospective cohort study (conducted Apr 2018–May 2022; NCT03419572). Enrollment spanned 11 European countries (91 sites) where cabozantinib is marketed for aRCC. Patients had aRCC and had received ≥ 1 prior VEGF-targeted therapy (excluding cabozantinib). Decision to initiate cabozantinib was made prior to enrolment. The primary endpoint was cabozantinib usage (dose interruptions, reductions or discontinuations due to AEs) in the second- (2L) or later- (≥ 3L) line settings. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and tolerability. Data were analyzed descriptively for patients with safety follow-up after ≥ 1 cabozantinib dose. Results: In total, 679 patients were included (73.0% male; median [range] age 67.0 [29–93] yrs; 85.7% clear-cell aRCC; 80.3% prior nephrectomy). Median (range) observation period was similar for 2L (n = 335; 8.51 [0.2–15.4] mo) and ≥ 3L cabozantinib (n = 343; 9.26 [0.0–15.0] mo). Usage data are shown. For the overall population, ORR (95% CI) and median (95% CI) PFS according to local assessment were 21.9% (17.5%–26.9%) and 7.8 (6.3–8.7) mo for 2L cabozantinib, and 38.0% (32.7%–43.5%) and 8.7 (7.6–9.6) mo for ≥ 3L cabozantinib. Median OS (95% CI) was 13.0 (12.6–not calculated [NC]) mo for 2L, and 17.1 (13.8–NC) mo for ≥ 3L cabozantinib. Most patients (90.4%) reported treatment-related AEs (Grade 1, 71.1%; Grade 2, 70.3% of patients), most commonly any grade diarrhea (52.4%), palmar-plantar erythrodysesthesia syndrome (27.2%), decreased appetite (25.5%), hypertension (21.9%), asthenia (21.6%), fatigue (20.5%) and nausea (20.3%). Conclusions: In this real-world study, tolerability of ≥ 2L cabozantinib was consistent with the METEOR trial safety profile: cabozantinib dose modifications due to AEs were common, but discontinuation rates due to AEs were substantially less frequent. Cabozantinib activity was maintained across lines. Clinical trial information: NCT03419572 . [Table: see text]

Phase I/II study to evaluate penpulimab combined with anlotinib and epirubicin in the first-line treatment of soft tissue sarcoma: Updated.

11569 Background: Anthracycline-based chemotherapy regimens are the cornerstone of first-line treatment of recurrent/metastatic unresectable soft tissue sarcoma(STS)，while the efficacy was not satisfactory (the median PFS: 4-8 months). Anti -angiogenesis TKI hypothetically can improve the efficacy of chemotherapy by remodeling the immunosuppressive TME. We conducted this trial to explore the safety and efficacy of PD-1 antibody Penpulimab(P) plus anlotinib(A) and epirubicin(E) in the first-line treatment of STS. The results of the phase I study were reported (2022 ESMO), We updated the latest efficacy and safety data. Methods: This ongoing phase I/II, open-lable trial (ChiCTR2100048014) enrolled patients (pts) aged 16-75 years old with pathologically confirmed metastatic or unresectable locally advanced STS. Pathologic types are moderately sensitive or above to anthracycline chemotherapy. Pts who met the inclusion criteria were treated with phase I dose results (E 60 mg/m2 + A 10 mg and P 200 mg；E: IV, D1-3, Q3W, A: PO, QD, D1-14, Q3W, P: IV, Q3W ) for a total of 6 treatment cycles (3 weeks each). A+P was maintained for 2 years until progressive disease or unacceptable toxicity. The primary endpoint was PFS(progression-free survival ) and secondary endpoints were ORR(objective response rate), DCR(disease control), OS(overall survival), 2-year OS and PFSR at 3 and 6 months. The response to treatment was evaluated according to RECIST vesion 1.1. In addition,adverse events were evaluated by CTCAE v5.0. Results: From September 2021 to December 2022, 32 pts (14 males and 18 females) were enrolled with the median age is 53.5 (range 29-73) years old. Pathological types included liposarcoma (DDLPS 14, PLS 1, n = 15), undifferentiated sarcoma (n = 4), leiomyosarcoma (n = 5), angiosarcoma (n = 3), fibrosarcoma (n = 2), and others (n = 3). At the data cut off date on December 20, 2022, Median follow-up time was 3.5 months （range 0.03-15.38）, Median PFS was 10.55 months [95%CI 4.60, 14.59]. Median OS was not reached. The PFS at 3 months and 6 months was 86.76%, 68.16%, respectively. and the OS at 12 months was 92.64%. 24 pts were eligible for the evaluation of tumor response, the objective response rate (ORR) was 12.50% (4/24) and the disease control rate (DCR) was 68.75% (14/24). The incidence of treatment-related adverse events of grade 3 was 31.25%, with a higher incidence of hypertriglyceridemia (9.38%), Neutrophil count decreased (6.25%) , palmar-plantar erythrodysesthesia syndrome (6.25%), febrile neutropenia (6.25%), respectively. The incidence of Severity Adverse Event was 12.5%. 50 pts are expected to be enrolled in the study, and the data will be mature after the follow-up is completed. Conclusions: Penpulimab(P) plus anlotinib(A) and epirubicin(E) has shown encouraging activity as firsy-line treatment for STS, which significantly prolong the PFS with well tolerance. Clinical trial information: ChiCTR2100048014 .

A phase IV study to evaluate the safety of fruquintinib in Chinese real-world clinical practice.

e15568 Background: Fruquintinib is a highly selective, potent, oral tyrosine kinase inhibitor of VEGFR-1, -2, and -3, which was approved in China for 3L mCRC patients based on results of FRESCO study (NCT02314819). In addition, FRESCO-2 (NCT04322539) demonstrated a consistent efficacy and safety profile of Fruquintinib in more heavily treated mCRC worldwide patients. This Phase IV study aims to evaluate the safety of Fruquintinib in real-world clinical practice in China. Methods: This is a prospective, multicenter, phase IV study, to evaluate a real-world safety of Fruquintinib in China. Patients who are within the first cycle of Fruquintinib treatment or plan to use Fruquintinib within 1 week can be enrolled into this study. Three visits are scheduled, including the day of consent, 1 month after consent, and 6 months after consent or 30 days after the last dose (whichever occurs first). The primary endpoint is the collected AE. Results: From April 2019 to Feb 2022, a total of 3005 patients from 96 study sites received at least one dose of fruquintinib and were enrolled in the safety analysis set (SS). The median age of the patients was 60, of which 1053 patients (35.0%) were ≥65.In SS, a total of 1923 patients (64.0%) started Fruquintinib at 5 mg/day. The median relative dose intensity was 85.3%; the median exposure time was 2.7months. In SS, 2291 patients (76.2%) reported TEAEs; 1901 patients (63.3%) reported investigator assessed fruquintinib-related TEAEs.718 patients (23.9%) reported ≥Grade3 TEAEs; 418 patients (13.9%) reported investigator assessed fruquintinib-related ≥Grade3 TEAEs. 330 patients (11.0%) reported SAE; 86 patients (2.9%) reported investigator assessed fruquintinib-related SAE. 169 patients (5.6 %) reported TEAEs leading to death;8 patients (0.3%) reported investigator assessed fruquintinib-related TEAEs leading to death. The most frequent fruquintinib-related TEAEs(＞10%）include palmar-plantar erythrodysesthesia syndrome (PPES,19.4%)，hypertension (15.6%) &amp; fatigue (10.1%); the most frequent Fruquintinib-related≥Grade 3 TEAE (≥1%）include hypertension (6.4%) &amp; PPES (2.2%); The most frequent fruquintinib-related TEAE (≥5%) leading to dose modification was PPES (5.4%). Conclusions: The results are consistent with the fruquintinib safety profile observed in existing clinical studies. No new or significant safety signals were identified. Clinical trial information: NCT04005066 .

Efficacy and safety of anlotinib-based chemotherapy for locally advanced or metastatic anaplastic thyroid carcinoma.

Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies with no effective treatment. In this study, we investigated the efficacy and safety of anlotinib-based chemotherapy as first-line therapy for ATC. Locally advanced or metastatic (LA/M) ATC patients who never received antitumor treatment of any sort were eligible for this study. The patients received 2-6 cycles anlotinib12mg on days 1-14 per 21 days. Chemotherapy regimens consisted of paclitaxel, capecitabine, or paclitaxel plus carboplatin/capecitabine. The end points including Objective Response Rate (ORR), Disease Control Rate (DCR), Progression-Free Survival (PFS), and Disease Specification Survival (DCS) were analyzed. A total of 25 patients were enrolled. 1 patient achieved a Complete Response (CR) and 14 patients achieved Partial Response (PR). The best ORR was 60.0%, and the DCR was 88.0%. The median PFS was 25.1 weeks, and the median DCS was 96.0 weeks. Approximately 56% (14 patients) had at least one Adverse Event (AE) of any grade. Most AEs were well tolerated. The most common AEs was palmar-plantar erythrodysesthesia syndrome (28.0%). Anlotinib-based chemotherapy as first-line therapy is a safe and effective intervention for the treatment of LA/M ATC patients.

Regorafenib plus nivolumab in patients with mismatch repair-proficient/microsatellite stable metastatic colorectal cancer: a single-arm, open-label, multicentre phase 2 study

Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80mg/day was administered orally for 3 weeks on/1 week off (increased to 120mg/day if 80mg/day was well tolerated) with intravenous nivolumab 480mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months' follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4-15.9; p=0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0-not evaluable) and 1.8 months (95% CI 1.8-2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Bayer/Bristol Myers Squibb.

Abstract P4-01-10: Evaluating the safety of tucatinib in combination with trastuzumab and capecitabine for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer in a real-world setting

Abstract Background: Tucatinib, a highly selective tyrosine kinase inhibitor (TKI) for human epidermal growth factor 2 (HER2) receptor, received FDA approval in combination with trastuzumab and capecitabine for metastatic HER2-positive breast cancer based on the HER2CLIMB trial. While the efficacy data is promising, the tucatinib-containing triplet regimen is associated with significant toxicity and many drug-drug interactions (DDIs). The toxicity profile of tucatinib in regards to adverse events (AEs) and DDIs has not been reported outside of the HER2CLIMB trial. Additionally, with the development of many new HER2 targeted therapies including antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan, efficacy in regards to therapy sequence is still unknown. Here, we describe the safety and efficacy of tucatinib in a real-world setting. Methods: This single-center, retrospective, cohort study included patients (pts) with a diagnosis of HER2- positive locally advanced or metastatic breast cancer pts that were newly initiated on tucatinib therapy at the Duke Breast Oncology Clinic following FDA approval from April 17, 2020 to June 9, 2021. Pts were evaluated for the pre-specified outcomes for the duration of tucatinib therapy, until progression of disease, or for at least 6 months follow-up. AEs reviewed included palmar-plantar erythrodysesthesia syndrome (PPE), diarrhea, fatigue, rash, anemia, thrombocytopenia, neutropenia, nausea, vomiting, mucositis, hepatotoxicity, and nephrotoxicity, defined according to the Common Terminology Criteria for Adverse Events (CTCAE) grading criteria. Overall response was categorized as complete response, partial response, stable disease, or progressive disease, defined according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, at first staging after therapy initiation. The overall response rate was stratified by prior standard therapies, pts who did not receive capecitabine therapy with tucatinib, and the presence or absence of brain metastases. Results: A total of 23 pts (N=23) were included in the cohort, 52% of which had brain metastases and 9% with leptomeningeal disease. Pts had a median of 3 prior lines of therapy in the metastatic setting including: lapatinib (9%), neratinib (30%), trastuzumab deruxtecan (13%), trastuzumab emtansine (74%). All pts experienced AEs, most of which were mild or moderate severity. The most common AEs reported were fatigue (70%), PPE (61%), nausea (61%), and anemia (61%). Severe AEs occurred in 6 pts (26%) with grade 3 or 4 hepatotoxicity in 13%. Only 2 pts discontinued therapy due to AEs (grade 4 hepatoxicity, grade 2 fatigue). Due to capecitabine intolerance, 13% received tucatinib and trastuzumab doublet therapy. There were 9 pts (39%) that experienced a DDI with tucatinib requiring therapy modification or close monitoring. At first staging, partial response was seen in 26% while 35% demonstrated stable disease and 30% progressive disease. Pts with previous neratinib therapy demonstrated a partial response of 14% and a stable disease response of 29%. No pts with previous trastuzumab deruxtecan or omission of capecitabine therapy experienced a partial or stable disease response. Conclusions: The rate of AEs were similar in a real-world setting compared to the HER2CLIMB trial with a lower rate of severe adverse events, however, a higher rate of hepatotoxicity. Given the high rate of drug interactions identified with tucatinib, concurrent medications should be reviewed for appropriate therapy adjustments and monitoring. Additional data is needed in regards to sequencing and impact on therapy efficacy. Citation Format: Heather Moore, Carey Anders, Sarah L. Sammons, Alaattin Erkanli, Alice Parish, Christina DiCola. Evaluating the safety of tucatinib in combination with trastuzumab and capecitabine for human epidermal growth factor 2 (HER2)-positive metastatic breast cancer in a real-world setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-10.

Cabozantinib in Japanese patients with advanced hepatocellular carcinoma: Final results of a multicenter phase II study.

Cabozantinib showed a favorable benefit-risk profile in Japanese patients with advanced hepatocellular carcinoma (HCC) in an open-label, phase II study (NCT03586973). This analysis presents cumulative data to final database lock. Patients with previously treated, advanced HCC received cabozantinib 60mg/day. Progression-free survival (PFS) and tumor response rates in prior-sorafenib and sorafenib-naïve cohorts were assessed by independent radiology committee (IRC) and an investigator. Liver function was evaluated by albumin-bilirubin (ALBI) score. Median cabozantinib exposure was 5.6months. In the prior-sorafenib cohort (n=20), median PFS was 7.4months per IRC assessment and 5.6months per investigator assessment. In the sorafenib-naïve cohort (n=14), median PFS was 3.6 and 4.4months per IRC and investigator assessment, respectively. Six-month PFS rate per IRC and investigator assessment in the prior-sorafenib cohort was 59.8% and 49.5%, respectively, and in the sorafenib-naïve cohort was 16.7% and 35.7%, respectively. Disease control rate by both IRC and investigator assessment was 85.0% in the prior-sorafenib cohort and 64.3% in the sorafenib-naïve cohort. Median overall survival (Kaplan-Meier estimate) was 19.3 and 9.9months in the prior-sorafenib and sorafenib-naïve cohort, respectively. Mean ALBI score remained relatively constant in patients able to continue treatment. The most frequent adverse events were palmar-plantar erythrodysesthesia syndrome, diarrhea, hypertension, and decreased appetite. No new safety concerns were identified. Cabozantinib showed efficacy and a manageable safety profile in Japanese patients with advanced HCC.

The effect of anti-PD-1/PD-L1 antibodies combined with VEGF receptor tyrosine kinase inhibitors versus bevacizumab in unresectable hepatocellular carcinoma.

Immune checkpoint inhibition (ICI) plus bevacizumab (BEV) is the standard first-line treatment for unresectable hepatocellular carcinoma (uHCC). We aimed to assess the efficacy and safety of ICI plus bevacizumab and ICI plus receptor tyrosine kinase inhibitor (TKI) in this patient population. This retrospective single-institution study enrolled 94 patients with uHCC who received ICI plus TKI or bevacizumab as the first-line treatment. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR) were used to evaluate treatment efficacy. RECIST v1.1 criteria were used to calculate the objective clinical response. Common Terminology Criteria for Adverse Events were used to report and categorize adverse events. By the last follow-up interview on May 15, 2022, there were 57 deaths, and 19 patients did not develop disease progression. Thirty patients received sintilimab/atezolizumab plus bevacizumab (ICI + BEV group), and 64 received ICI plus TKI (ICI + TKI group). The median OS was 430 days (95% CI, 266-NA) in the ICI+TKI group and 498 days (95% CI, 349-NA) in the ICI+BEV group (HR, 1.20; 95% CI, 0.69-2.07; P = 0.52). There was no significant difference between the two groups in the median PFS (182 vs. 221 days, P=0.67). In the ICI+TKI group, the ORR and DCR were 28.1% and 67.2%, respectively. In the ICI+BEV group, the ORR and DCR were 26.7% and 66.7%, respectively. The overall incidence of adverse events was similar between the two groups. Palmar-plantar erythrodysesthesia syndrome (23[36%]) occurred only in the ICI + TKI group. Patients who received ICI+BEV were more prone to upper gastrointestinal bleeding (2 [7%]), with one patient with grade 4 requiring emergency DSA treatment. This study found that ICI+TKI and ICI+BEV as first-line treatments were similar in OS, PFS, and tumor response in uHCC. Different populations are suitable for different regimens because of the different adverse events.

Real-World Study Evaluating Safety and Effectiveness of Axitinib in Korean Patients with Renal Cell Carcinoma after Failure of One Prior Systemic Therapy.

This post-marketing surveillance (PMS) study was conducted to monitor the usage of axitinib (Inlyta) in clinical practice of Korean patients with advanced renal cell carcinoma (RCC) with disease progression during or after a prior systemic therapy in real world. In this multicenter, observational study, patients indicated for oral axitinib 5 mg twice daily as second-line therapy for advanced RCC were followed up under routine clinical practices, and their safety and effectiveness outcomes were collected. Between 2012 and 2021, 125 patients were enrolled, and data from 111 patients were analyzed. Median age was 65 years (range, 30 to 84 years), 81% was male, and 110 (99%) had clear cell RCC. The median daily dose of axitinib was 10 mg (range, 4.36 to 15.95 mg) with a median administration period of 5.6 months (range, 15 to 750 days). Eighty-three percentage of patients experienced any grade of adverse events, 71% of which were related to study treatment, including diarrhea (36%), hypertension (21%), stomatitis (17%), decreased appetite (14%), palmar-plantar erythrodysesthesia syndrome (12%), and asthenia (11%). Most adverse events were generally well tolerated and manageable, with 13% of grade ≥ 3. Axitinib dose reduction was required in 20% of the adverse events and discontinuation in 8%. Median progression-free survival was 12.4 months (95% confidence interval [CI], 9.6 to 18.9). Objective responses were observed in 30% of patients (95% CI, 21 to 39) with 4% of complete response and 26% of partial response. No new safety signal was found in the present PMS study of Korean RCC patients. Axitinib showed consistent outcomes in terms of effectiveness and safety confirming that the drug is a valid option for second-line therapy in patients with advanced RCC in a real-world setting.

Antitumor activity of lurbinectedin in combination with oral capecitabine in patients with metastatic breast cancer

Preclinical studies showed a synergistic effect for 5-fluorouracil and lurbinectedin against solid tumors. This phase I trial evaluated a combination of capecitabine plus lurbinectedin in patients with selected advanced solid tumors. Results in patients with relapsed metastatic breast cancer (MBC) are described. Patients received capecitabine daily on day (D)1-D14 combined with lurbinectedin on D1, D8 or D1 every 3 weeks (q3w) intravenously, following a standard 3+ 3 escalation design and expansion at the recommended dose (RD). Of the 81 enrolled patients, 28 had relapsed MBC: 20 with hormone receptor (HR)-positive tumors and 8 with triple-negative tumors; 3 treated in the D1,D8 schedule and 25 in the D1 schedule. The RD was capecitabine 1650 mg/m2 daily on D1-D14 plus lurbinectedin 2.2 mg/m2 on D1 q3w. Sixteen confirmed responses and two prolonged disease stabilizations (≥6 months) were observed [overall response rate (ORR)/clinical benefit rate (CBR)= 57%/64% at all dose levels; 47%/60% at the RD]. Twelve responses and both prolonged stabilizations occurred in HR-positive tumors (ORR/CBR= 60%/70% at all dose levels, 56%/78% at the RD). Four responses were found in triple-negative tumors (ORR and CBR= 50% at all dose levels; 33% at the RD). Myelotoxicity was reversible and manageable at the RD; most non-hematological toxicities were mild/moderate. No episodes of febrile neutropenia or severe palmar-plantar erythrodysesthesia syndrome occurred. No major pharmacokinetic drug-drug interaction was found between lurbinectedin, capecitabine or capecitabine metabolites. The capecitabine/lurbinectedin combination showed encouraging clinical activity in relapsed MBC, especially in HR-positive tumors. Toxicity was manageable at the RD. Further development is warranted in relapsed MBC.

423P Fruquintinib plus sintilimab in refractory repair-proficient (pMMR)/microsatellite stable (MSS) metastatic colorectal cancer (mCRC): Preliminary clinical results and biomarker analyses from a phase II study

Addition of immune checkpoint inhibitor to anti-angiogenesis inhibitors is expected to have the potential to improve efficacy in pMMR/MSS refractory mCRC. This study aimed to evaluate the efficacy and safety of fruquintinib plus sintilimab in refractory mCRC, and to explore the potential biomarker associated with efficacy and prognosis. This is a prospective, single arm phase II trial (NCT04695470). Patients with pMMR/MSS mCRCs who had failed with at least 2 lines of standard therapy including bevacizumab were treated with fruquintinib (5mg/day, orally, d1-14, Q3w) plus sintilimab (sintilimab 200mg, intravenous infusion, d1, Q3w). The primary endpoint was the 6-month PFS rate, and secondary endpoints included ORR, PFS, OS and safety, with biomarker analyses from ctDNA being the exploratory endpoint. Between Sep 18, 2020 and Apr 19, 2022, 55 patients (pts) were enrolled. 43 pts with a follow-up time of at least 3 months (median 9.8 m) were included in this analysis. The median age was 57 (IQR, 34-73); 69% were male. 7 pts achieved PR and 26 achieved SD, the ORR was 16% (95% CI, 7%-31%), and DCR was 77% (95% CI, 61%-88%). Pts with liver metastases had lower ORR than those without (7.1% vs 33.3%, P=0.0398). The 6-month PFS rate was 31% with a median PFS of 4.1 m and an estimated OS of 13.3 m, respectively. The present of liver metastasis was associated with shorter PFS (4.1 vs 6.4 m, P=0.0364). The most common adverse events were proteinuria (53.4%), palmar-plantar erythrodysesthesia syndrome (46.5%) and hypothyroidism (37.2%). 18.6% of the pts had grade 3 or 4 treatment-related adverse events. The median bTMB was 11.35 muts/Mb (IQR: 5.03-177.85muts/Mb). No statistically significant differences in ORR and PFS were observed according to bTMB status. Three pts with MYC amplification in ctDNA seemed to have worse PFS (1.3 m, 1.3 m, 2.1 m) and OS (3.0 m, 3.7 m, 5.4 m). Fruquintinib plus sintilimab showed promising efficacy and favorable safety profile in refractory MSS mCRC. MYC amplification identified by ctDNA sequencing seemed to associate with poor prognosis, which warrants future study.

MODUL cohort 2: an adaptable, randomized, signal-seeking trial of fluoropyrimidine plus bevacizumab with or without atezolizumab maintenance therapy for BRAFwt metastatic colorectal cancer

BackgroundMODUL is an adaptable, signal-seeking trial designed to test novel agents in predefined patient subgroups in first-line metastatic colorectal cancer (mCRC).Patients and methodsPatients with measurable, unresectable, previously untreated mCRC received induction with ≤8 cycles of FOLFOX + bevacizumab followed by randomization to maintenance treatment comprising control [fluoropyrimidine (FP)/bevacizumab: 5-fluorouracil 1600-2400 mg/m2 46-h intravenous (i.v.) infusion day 1 q2 weeks plus leucovorin 400 mg/m2 2-h infusion i.v. day 1 q2 weeks or capecitabine 1000 mg/m2 b.i.d. orally days 1-14 every 21 days; bevacizumab 5 mg/kg 15-30-min i.v. infusion q2 weeks] or experimental treatment in one of four biomarker-driven cohorts. In patients with BRAF wild-type (BRAFwt) tumors (cohort 2), experimental treatment was FP/bevacizumab + atezolizumab (800 mg 60-min i.v. infusion q2 weeks). Primary efficacy endpoint was progression-free survival (PFS; intent-to-treat population). Enrollment is complete; efficacy and safety findings from cohort 2 are presented.ResultsFour hundred and forty-five patients with BRAFwt mCRC were randomized (2 : 1) to maintenance in cohort 2. At a median follow-up of 10.5 months, PFS outcome hypothesis was not met [hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.72-1.17; P = 0.48]; overall survival (OS) was immature. At a median follow-up of 20.3 months (2-year survival follow-up), PFS benefit was also not met (HR 0.95; 95% CI 0.77-1.18; P = 0.666); OS HR with nearly two-thirds of patients with events was 0.83 (95% CI 0.65-1.05; P = 0.117). No new safety signals were identified. The most common grade ≥3 treatment-emergent adverse events (TEAEs) for experimental versus control arms were hypertension (6.1% versus 4.2%), diarrhea (3.1% versus 2.1%), and palmar-plantar erythrodysesthesia syndrome (1.0% versus 2.5%). Four patients experienced TEAEs with fatal outcome, two were study treatment-related: hepatic failure (experimental arm) and large intestine perforation (control arm; bevacizumab-related).ConclusionsAdding atezolizumab to FP/bevacizumab as first-line maintenance treatment after FOLFOX + bevacizumab induction for BRAFwt mCRC did not improve efficacy outcomes.