Irreversible pan-ErbB Inhibitor Research Articles

Real-world outcomes associated with afatinib use in patients with solid tumors harboring NRG1 gene fusions

ObjectivesNeuregulin-1 (NRG1) fusions may drive oncogenesis via constitutive activation of ErbB signaling. Hence, NRG1 fusion-driven tumors may be susceptible to ErbB-targeted therapy. Afatinib (irreversible pan-ErbB inhibitor) has demonstrated activity in individual patients with NRG1 fusion-positive solid tumors. This study collected real-world data on demographics, clinical characteristics, and clinical outcomes in this patient population. Materials and MethodsIn this retrospective, multicenter, non-comparative cohort study, physicians in the US-based Cardinal Health Oncology Provider Extended Network collected data from medical records of patients with NRG1 fusion-positive solid tumors who received afatinib (afatinib cohort) or other systemic therapies (non-afatinib cohort) in any therapy line. Objectives included demographics, clinical characteristics, and outcomes (overall response rate [ORR], progression-free survival [PFS], and overall survival [OS]). ResultsPatients (N = 110) with a variety of solid tumor types were included; 72 received afatinib, 38 other therapies. In the afatinib cohort, 70.8 % of patients received afatinib as second-line treatment and Eastern Cooperative Oncology Group performance status (ECOG PS) was 2–4 in 69.4 % at baseline. In the non-afatinib cohort, 94.7 % of patients received systemic therapy as first-line treatment and ECOG PS was 2–4 in 31.6 % at baseline. In the afatinib cohort, ORR was 37.5 % overall (43.8 % when received as first-line therapy); median PFS and OS were 5.5 and 7.2 months, respectively. In the non-afatinib cohort, ORR was 76.3 %; median PFS and OS were 12.9 and 22.6 months, respectively. ConclusionThis study provides real-world data on the characteristics of patients with NRG1 fusion-positive solid tumors treated with afatinib or other therapies; durable responses were observed in both groups. However, there were imbalances between the cohorts, and the study was not designed to compare outcomes. Further prospective/retrospective trials are required.

Abstract 4017: TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models

Abstract Patients with brain tumors and metastases have poor prognosis and overall survival rates despite the advancements in neurosurgery, radiotherapy, and chemotherapy. Genomic alterations in HER2 are present in brain metastases of breast cancer (BC; ~20%) and non-small cell lung cancer (NSCLC; 13-20%), and EGFR alterations occur frequently in glioblastoma multiforme (GBM; >50%). Despite the advancements in standard of care options, optimal treatment management for these patients remains an unmet medical need. Recent evidence suggests activity of systemic therapy for immune and targeted therapies in the brain, including agents targeting HER2/EGFR. HER2-targeted tyrosine kinase inhibitors lapatinib, neratinib, and tucatinib and the HER2-targeted antibodies trastuzumab and pertuzumab, in combination with chemotherapy, have been shown to improve survival of patients with HER2 overexpressing BC in the presence of brain metastases. The limited penetration of these compounds into the CNS, however, limits their efficacy. TAS2940 is an irreversible pan-ErbB inhibitor with greater brain-penetrability than poziotinib, tucatinib, and neratinib. Here, we demonstrate that TAS2940 induces downregulation of phosphorylated HER2/EGFR, reduces tumor burden, and promotes a significant increase in survival in intracranial xenograft mouse models with HER2-amplification (BC), HER2-Exon20 insertion mutation (NSCLC), and EGFR-amplification (GBM). These promising preclinical data highlight potential novel therapeutic strategies for patients with EGFR-aberrant GBM and brain metastases harboring HER2/EGFR alterations, and may help support the advancement of the ongoing first-in-human clinical trial (NCT04982926) for TAS2940 in solid tumors with EGFR and/or HER2 alterations. Citation Format: Jing Han, Mikhila Mahendra, Poojabahen Gandhi, Joseph R. Daniele, Caroline C. Carrillo, Benjamin J. Bivona, Ningping Feng, John V. Heymach, Funda Meric-Bernstam, Kei Oguchi, Shinji Mizuarai, Timothy P. Heffernan, Christopher P. Vellano, Joseph R. Marszalek. TAS2940 inhibits intracranial tumor growth and prolongs survival in HER2-aberrant and EGFR-amplified patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4017.

Abstract P2-01-07: Combination of pyrotinib with trastuzumab, taxanes and platinum as neoadjuvant therapy in patients with HER2-positive early or locally advanced breast cancer: a multicenter phase II trial

Abstract Background: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine have shown clinically and statistically meaningful progression-free survival and overall survival benefits with acceptable tolerability in patients with HER2-positive metastatic breast cancer in phase 3 trials. In this study, we assessed the efficacy and safety of neoadjuvant pyrotinib plus trastuzumab, taxanes and platinum in women with HER2-positive early or locally advanced breast cancer. Methods: In this multicenter, single-arm, phase II trial (ChiCTR2000039286), treatment-naive patients with early or locally advanced (T2-3, N0-3, M0) breast cancer received pyrotinib 400 mg once daily, plus trastuzumab (8 mg/kg loading dose and 6 mg/kg maintenance dose), docetaxel (75 mg/m2) or nab-paclitaxel (125 mg/m2), and carboplatin (AUC=5-7) on day 1 of each 21-day cycle for 6 cycles before surgery. All patients also received 1-year adjuvant pyrotinib combined with trastuzumab after surgery. The primary endpoint of the study was total pathological complete response (tpCR, ypT0/is ypN0) rate. The secondary endpoints were breast pathological complete response (bpCR) rate, objective response rate, adverse events (AEs) and invasive disease-free survival. Results: Between October 2020 and March 2022, a total of 35 patients were enrolled from 7 sites. By the data cut-off date on June 29, 2022, two patients withdrew from the study, and one received other anti-tumor therapies. Thirty-two patients received neoadjuvant therapy and surgery (modified intention-to-treat [mITT] population), and 30 of whom completed the 6-cycle neoadjuvant therapy (per-protocol [PP] population). The local pathologist-assessed tpCR rate was 59.4% (19/32) and 60.0% (18/30) in the mITT and PP populations, and bpCR rate was 65.6% (21/32) and 66.7% (20/30) in the mITT and PP populations, respectively. The tpCR rate was 68.8% (11/16) among patients with hormone receptor-negative disease and 50.0% (8/16) among those with hormone receptor-positive disease in the mITT population. Of 30 patients with preoperative imaging assessments, 26 (86.7%) achieved an objective response. Treatment-related AEs (TRAEs) were reported in 34 (97.1%) of 35 patients, with the most common being diarrhea (82.9%) and platelet decreased (48.6%). The most common grade ≥3 TRAEs were diarrhea (25.7%), platelet decreased (8.6%), neutropenia (8.6%), vomiting (5.7%), and alanine aminotransferase increased (5.7%). No grade 4 or 5 diarrhea events occurred. Conclusions: This study showed similar efficacy with previous reports, neoadjuvant pyrotinib plus trastuzumab-based chemotherapy exhibits promising efficacy and manageable toxicity in patients with HER2-positive early or locally advanced breast cancer. Citation Format: Hao Zhou, Lei Wang, Lei Wang, Zhaoji Guo. Combination of pyrotinib with trastuzumab, taxanes and platinum as neoadjuvant therapy in patients with HER2-positive early or locally advanced breast cancer: a multicenter phase II trial [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 P2-01-07.

Pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2-positive gastric cancer or solid tumors: Safety and efficacy results from a phase Id trial.

368 Background: Pyrotinib (an irreversible pan-ErbB inhibitor, RP2D 400mg qd) monotherapy showed limited efficacy in patients with HER2 positive GC. In pyrotinib-resistant PDX models, pyrotinib combined with SHR6390 (a novel oral CDK4/6 inhibitor, RP2D 150mg qd) showed encouraging anti-tumor activity. A phase Id trial was conducted to evaluate the safety of pyrotinib combined with SHR6390 in refractory advanced HER2 positive gastric cancer or solid tumors (NCT03480256). Methods: This study followed a “3+3” design. Patients (Pts) received pyrotinib (qd, d1-28; q4w) combined SHR6390 (qd, d1-21; q4w) at dose of 400/100mg (cohort A), 400/125mg (cohort B), 400/150mg (cohort C), 400/175mg (cohort D) until disease progression or intolerable toxicity. The primary endpoint was safety and MTD. Results: From Aug. 2018 to Jul. 2022, 25 pts (GC, n=19; CRC, n=4; others, n=2) were enrolled with 19 pts experiencing prior anti-HER2 regimens. In cohort A (n=6), 1 patient withdrew consent. No DLT was observed. However, ≥G3 hematological toxicities were commonly reported, including neutropenia (G4, lasting< 3 days, n=2), anemia (G3, n=1) and thrombocytopenia (G3, n=1). After SMC discussion, another 3 dose levels (cohort E, 320/100mg; cohort F, 400/75mg; cohort G, 320/75mg) were designed for safety consideration. One DLT (G4 neutropenia, lasting≥3 days) was observed in cohort E (n=6). In cohort F (n=7), no DLT was observed. One patient did not finish the DLT assessment for clinical PD, and one had clinical PD after DLT assessment without radiologic confirmation. The ORR of cohort A, E, F was 60.0% (3/5), 33.3% (2/6), 40.0% (2/5). To determine RP2D, 6 pts were included in cohort B. One DLT was observed with G4 neutropenia lasting ≥3 days. One patient suffered G3 thrombocytopenia. The ORR was 33.3% (2/6). Although MTD was not reached, the remaining cohort (G, C and D) would not be continued based on the current data. In all, the most common AEs were leukopenia (100%), neutropenia (95.8%), anemia (91.7%) and thrombocytopenia (66.7%), diarrhea (79.2%) and mucositis (33.3%). The most common G3-4 AEs included leukopenia (41.7%), neutropenia (41.7%), anemia (12.5%) and diarrhea (12.5%). The overall ORR was 40.9%, with median PFS and OS of 3.88 (95%CI 3.46, 4.30) and 11.14 (95%CI 4.50, 17.78) months, respectively. Among GC patients (n=18), 16 pts finished efficacy assessment, 8 pts achieved PR (5 pts having prior anti-HER2 regimens) and 7 achieved SD, with ORR and DCR of 50.0% and 93.8%, respectively. The median PFS was 3.88 months (95%CI 3.59, 4.17) and the median OS was 12.48 months (95%CI 3.82, 21.1). Considering the safety profile and efficacy trend, the RP2D was defined as pyrotinib 400mg+SHR6390 100mg. Conclusions: Pyrotinib combined with SHR6390 showed acceptable safety profile and encouraging efficacy. Further expansion would be conducted at the dose level of cohort A. Clinical trial information: NCT03480256 .

Neoadjuvant pyrotinib, trastuzumab, and docetaxel for HER2-positive breast cancer (PHEDRA): a double-blind, randomized phase 3 trial

BackgroundPyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine has survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer. We further assessed addition of pyrotinib to trastuzumab and docetaxel in the neoadjuvant setting.MethodsIn this multicenter, double-blind, phase 3 study (PHEDRA), treatment-naive women with HER2-positive early or locally advanced breast cancer were randomly assigned (1:1) to receive four neoadjuvant cycles of oral pyrotinib or placebo (400 mg) once daily, plus intravenous trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg) and docetaxel (100 mg/m2) every 3 weeks. The primary endpoint was the total pathological complete response (tpCR; ypT0/is and ypN0) rate per independent central review.ResultsBetween Jul 23, 2018, and Jan 8, 2021, 355 patients were randomly assigned, 178 to the pyrotinib group and 177 to the placebo group. The majority of patients completed four cycles of neoadjuvant treatment as planned (92.7% and 97.7% in the pyrotinib and placebo groups, respectively). The tpCR rate was 41.0% (95% CI 34.0 to 48.4) in the pyrotinib group compared with 22.0% (95% CI 16.6 to 28.7) in the placebo group (difference, 19.0% [95% CI 9.5 to 28.4]; one-sided P < 0.0001). The objective response rate per investigator was 91.6% (95% CI 86.6 to 94.8) in the pyrotinib group and 81.9% (95% CI 75.6 to 86.9) in the placebo group after the neoadjuvant treatment, resulting in an increase of 9.7% (95% CI 2.7 to 16.6). The most common grade 3 or worse adverse events were diarrhea (79 [44.4%] in the pyrotinib group and nine [5.1%] in the placebo group), neutropenia (33 [18.5%] and 36 [20.3%]), and decreased white blood cell count (29 [16.3%] and 24 [13.6%]). No deaths were reported during neoadjuvant treatment.ConclusionsThe primary endpoint of the study was met. Neoadjuvant pyrotinib, trastuzumab, and docetaxel significantly improved the tpCR rate compared with placebo, trastuzumab, and docetaxel, with manageable toxicity, providing a new option for HER2-positive early or locally advanced breast cancer.Trial registrationClinicalTrials.gov, NCT03588091

TAS2940, a novel brain-penetrable pan-ERBB inhibitor, for tumors with HER2 and EGFR aberrations.

Genetic alterations in human epidermal growth factor receptor type 2 (HER2)/epidermal growth factor receptor (EGFR) are commonly associated with breast and lung cancers and glioblastomas. Cancers with avian erythroblastosis oncogene B (ERBB) deregulation are highly metastatic and can cause primary brain tumors. Currently, no pan-ERBB inhibitor with remarkable brain penetration is available. Here, TAS2940, a novel irreversible pan-ERBB inhibitor with improved brain penetrability, was evaluated for its efficacy against several ERBB aberrant cancer models. The selectivity of TAS2940 was evaluated by enzymatic kinase assays. The inhibitory effects of TAS2940 against ERBB genetic alterations were examined using MCF10A cells expressing various HER2 or EGFR mutations and other generic cell lines harboring deregulated ERBB expression. In vivo efficacy of TAS2940 was examined following oral treatment in subcutaneous or intracranial xenograft cancer models. TAS2940 was highly potent against cells harboring HER2/EGFR alterations. TAS2940 could selectively inhibit phosphorylation of targets and the growth of cancer cells with ERBB aberrations in vitro. TAS2940 also inhibited tumor growth in xenograft mouse models with ERBB aberrations: HER2 amplification, HER2/EGFR exon 20 insertions, and EGFR vIII mutation. TAS2940 was effective in the intracranial xenograft models of HER2/EGFR cancers and improved the survival of these mice. TAS2940 has promising therapeutic effects in preclinical study against cancers harboring HER2/EGFR mutations, especially metastatic and primary brain tumors. Our results highlight potential novel strategies against lung cancers with brain metastases harboring HER2/EGFR exon 20 insertions and glioblastomas with EGFR aberrations.

Pyrotinib-based therapy for patients with HER2-positive breast cancer: A multicenter, real-world study.

1040 Background: Pyrotinib, an irreversible pan-ErbB inhibitor, has been approved for the treatment of HER2-positive advanced breast cancer in China. Real-world data is instructive for effect evaluation and application of the drug in clinical practice. Herein, this study was conducted to evaluate the effectiveness and safety of pyrotinib-based therapy in patients with HER2-positive breast cancer in the real-world setting. Methods: In this retrospective, multicenter, real-world study, data of patients with HER2-positive breast cancer who received pyrotinib-based therapy from 19 sites were reviewed. Disease characteristics, prior therapies, and treatment patterns were summarized. Progression-free survival (PFS) and the incidence of diarrhea were analyzed. Results: Between September 2018 and June 2021, a total of 378 patients with HER2-positive advanced breast cancer were included. Of 378 patients, 47.4% had hormone receptor (HR)-positive disease, 41.3% had HR-negative disease, and 11.4% had unknown HR status. Brain, lung, liver, and bone metastases were found in 24.9%, 35.7%, 31.7%, and 33.1% of all cases, respectively. Most of patients (83.1%) were trastuzumab-exposed, 12.7% were pertuzumab-exposed, and 8.2% had been treated with lapatinib or neratinib before receiving pyrotinib. Pyrotinib plus chemotherapy (211 [55.8%]) was the most commonly used regimen, followed by pyrotinib monotherapy (115 [30.4%]), pyrotinib plus trastuzumab and chemotherapy (29 [7.7%]), other regimens (18 [4.8%]), and unknown regimen (5 [1.3%]). Standard dose (400 mg once daily) was used in 256 (67.7%) patients. With a median follow-up duration of 20.5 months, the median PFS was 13.0 months (95%CI, 12.0-14.0). Further analyses showed that the median PFS did not differ in subgroups by age (≥65 or &lt; 65 years), HR status (positive or negative), brain metastasis (yes or no), lung metastasis (yes or no), liver metastasis (yes or no), bone metastasis (yes or no), prior exposure to trastuzumab (yes or no), treatment regimen (pyrotinib monotherapy or combination therapy). Significant variance was discovered between sufficient dosage group and non-sufficient group (13.2 months vs 10.93 months, p= 0.028). The survival advantage of sufficient dosage was also evident in brain metastasis cases (14.4 months vs 8.3 months, p= 0.043).The most common adverse event was diarrhea (85.7%), and grade ≥3 diarrhea occurred in 18.5% of patients. Diarrhea was the leading cause for does reduction of pyrotinib. Conclusions: The PFS data in our study was similar to previous clinical trials referring to HER2-positive advanced breast cancer treated with pyrotinib. Cases with brain metastasis also displayed a satisfactory survival result. Sufficient dosage is of great importance for prolonged survival, prevention of diarrhea may efficiently avoid does reduction and guarantee the drug efficacy.

Abstract P5-18-06: Proactive diarrhea management improved tolerability of pyrotinib in combination with trastuzumab and docetaxel in patients with HER2+ early or locally advanced breast cancer: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study

Abstract Background: Diarrhea is a common side effect of many anti-cancer treatments, including chemotherapeutic agents, tyrosine kinase inhibitors, and pelvic radiotherapy. PHEDRA was a randomized, double-blind, multicenter, phase 3 study comparing the efficacy and safety of adding pyrotinib (an irreversible pan-ErbB inhibitor) to trastuzumab and docetaxel (pyrotinib arm) vs placebo, trastuzumab, and docetaxel (placebo arm) as neoadjuvant treatment in women with HER2+ early or locally advanced breast cancer (ClinicalTrials.gov: NCT03588091). We conducted this exploratory analysis to evaluate the effectiveness of proactive diarrhea management (PDM) according to the recommendation from independent data monitoring committee. Methods: Between July 23, 2018 and January 8, 2021, 355 patients were enrolled and randomized, of whom 212 and 143 patients were randomized before and after the implementation of PDM strategy. The diarrhea management strategy was strengthened with the early identification and proactive management of diarrhea, including use of loperamide as first choice of antidiarrheal agents and strict application of loperamide recommended dose (4 mg initially and an additional 2 mg following each diarrhea stool, not exceeding 16 mg/day). Primary prophylaxis with loperamide was not allowed. The incidence, severity, onset, and duration of diarrhea were summarized. The data cutoff date was April 30, 2021. Results: Of all 178 patients with pyrotinib arm, there were 43 (40.6%) and 56 (77.8%) patients applied loperamide as the first choice of antidiarrheal agents before and after the PDM implementation, respectively. The incidence of grade 3 diarrhea has decreased from 50.0% before the PDM implementation to 36.1% after the PDM implementation (Table 1). During neoadjuvant treatment period, grade 3 diarrhea mainly occurred during the first cycle of treatment for both treatment arms (C1: 20.8%), showing a sharp decreased trend during the following cycles (C2: 8.7%; C3: 5.4%; C4: 4.5%). Furthermore, among patients with pyrotinib arm, the incidences of grade 3 diarrhea in the first, second cycle and thereafter were lower in patients enrolled after the implementation of PDM than those enrolled before the PDM implementation (C1: 29.2%. vs 44.3%; C2: 10.1% vs 21.8%; C3: 7.2% vs 14.1%; C4: 4.5% vs 11.1%). Among patients with pyrotinib, compared with those enrolled before the PDM implementation, the median duration per diarrhea episode (4 days [IQR, 2-9] vs 2 days [1-5]), median duration per grade 3 diarrhea episode (2 days [IQR, 2-3] vs 2 days [1-2]), and median cumulative duration of grade 3 diarrhea (6 days [IQR, 3-9] vs 2 [2-5] days) were shortened in those enrolled after the PDM implementation. During neoadjuvant treatment period, 31 (17.4%) patients experienced diarrhea leading to pyrotinib dose reduction, and only 1 (0.6%) patient discontinued study treatment due to diarrhea in the pyrotinib arm. Conclusion: Pyrotinib tolerability was improved with PDM, which reduced the incidence and duration of grade 3 diarrhea. Grade 3 diarrhoea occurred mainly during the first cycle of treatment and reduced in the second cycle and thereafter. Diarrhea in the pyrotinib group was characterized by early onset and short duration and was generally manageable. Table 1.Characteristics of treatment-emergent diarrheaBEFORE the implementation of PDMAFTER the implementation of PDMPyrotinib+Trastuzumab+Docetaxel(N=106)Placebo+Trastuzumab+Docetaxel(N=106)Pyrotinib+Trastuzumab+Docetaxel(N=72)Placebo+Trastuzumab+Docetaxel(N=71)Diarrhea incidence, n (%)All grade106 (100.0)57 (53.8)72 (100.0)36 (50.7)Grade 112 (11.3)32 (30.2)7 (9.7)28 (39.4)Grade 241 (38.7)18 (17.0)39 (54.2)6 (8.5)Grade 353 (50.0)7 (6.6)26 (36.1)2 (2.8)Cycle 147 (44.3)4 (3.8)21 (29.2)2 (2.8)Cycle 222 (21.8)2 (1.9)7 (10.1)0Cycle 314 (14.1)05 (7.2)0Cycle 411 (11.1)2 (1.9)3 (4.5)0Grade 4 or 50000Median time to the first onset, days (IQR)All grade4 (2 to 5)7 (4 to 28)3 (2 to 4)6 (5 to 12)Grade 39 (5 to 11)16 (7 to 24)9 (6 to 12)11 (6 to 16)Median duration per diarrhea episode, days (IQR)All grade4 (2 to 9)2 (2 to 4)2 (1 to 5)2 (1 to 3)Grade 32 (2 to 3)2 (2 to 2)2 (1 to 2)1 (1 to 1)Median cumulative duration, days (IQR)Grade 36 (3 to 9)2 (2 to 3)2 (2 to 5)1 (1 to 1)Median time since the first onset to recovery, days (IQR)All grade7 (3 to 12)2 (2 to 4)3 (1 to 10)2 (1 to 4)Note: PDM, proactive diarrhea management; IQR, interquartile range. Citation Format: Benlong Yang, Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Fei Wu, Shulin Liu, Xiang Lin, Jianjun Zou. Proactive diarrhea management improved tolerability of pyrotinib in combination with trastuzumab and docetaxel in patients with HER2+ early or locally advanced breast cancer: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-06.

Abstract PD8-08: Pyrotinib in combination with trastuzumab and docetaxel as neoadjuvant treatment for HER2-positive early or locally advanced breast cancer (PHEDRA): A randomized, double-blind, multicenter, phase 3 study

Abstract Background: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine have shown clinically and statistically meaningful progression free survival and overall survival benefits and acceptable tolerability in patients with HER2-positive metastatic breast cancer in phase 3 study. We compared the efficacy and safety of adding pyrotinib to trastuzumab and docetaxel vs placebo, trastuzumab and docetaxel as neoadjuvant treatment in women with HER2-positive early or locally advanced breast cancer (ABC) in this randomized, double-blind, multicenter, phase 3 study. Methods: Treatment naive patients with HER2-positive early or locally ABC (T2-3, N0-3, M0) were randomly assigned (1:1) to pyrotinib arm receiving 4 neoadjuvant cycles of pyrotinib (400 mg po qd, d1-21, q3w), trastuzumab (8 mg/kg iv, cycle 1 d1, then 6 mg/kg d1 q3w) and placebo arm with docetaxel (100 mg/m2 iv d1, q3w) or placebo, trastuzumab and docetaxel. Randomization was done via a centralized interactive web-response system and stratified by primary tumor size (&amp;gt;2 cm and ≤5cm, or &amp;gt;5cm) and hormone receptor status (ER positive and/or PR positive, or negative for both). After surgery, patients received 3 cycles of intravenous fluorouracil, epirubicin, and cyclophosphamide followed by anti-cancer treatment (anti-HER2 therapy, radiotherapy, or endocrine therapy) at physicians’ discretion in accordance with clinical practice guidelines. The primary endpoint was total pCR rate (tpCR; defined as absence of any residual invasive cancer in the breast and lymph nodes [ypT0/is, ypN0]), assessed by an independent review committee (IRC). This study is registered with ClinicalTrials.gov, number NCT03588091. The data cutoff date was April 30, 2021. Results: Between July 23, 2018 and January 8, 2021, a total of 355 patients were randomized (pyrotinib arm, n=178; and placebo arm, n=177; mean [SD] age, 48.8 [9.4] years). Baseline demographics and disease characteristics were well balanced. In the full analysis set, IRC-assessed tpCR rates were 41.0% (73 of 178) in the pyrotinib arm and 22.0% (39 of 177) in the placebo arm (difference, 19.0% [95% CI, 9.5%-28.4%]; one-sided P&amp;lt;0.0001). The local pathologist-assessed tpCR rates were 44.4% (79 of 178) and 24.3% (43 of 177) in the pyrotinib arm and the placebo arm, respectively. Incidence of grade ≥3 adverse events (AEs) was 71.3% (127 of 178) in the pyrotinib arm and 37.3% (66 of 177) in the placebo arm. Of the most-common grade ≥3 AEs (≥5% of patients in either arm), the incidences of diarrhea (79 of 178 [44.4%] vs 9 of 177 [5.1%]), decreased WBC count (29 of 178 [16.3%] vs 24 of 177 [13.6%]), vomiting (23 of 178 [12.9%] vs 2 of 177 [1.1%]), anemia (11 of 178 [6.2%] vs 2 of 177 [1.1%]), and hypokalemia (9 of 178 [5.1%] vs 0) were higher in the pyrotinib arm compared with the placebo arm. Grade 3 diarrhea occurred mainly during the first treatment cycle and decreased in the second cycle and thereafter. No grade 4 or 5 diarrheas occurred. The median duration per grade 3 episode was 2.0 days and median cumulative duration of grade 3 episodes was 4.0 days. Only 1 patient (1 of 178 [0.6%]) in the pyrotinb arm experienced diarrhea-related discontinuation. Serious AEs were reported in 14.6% of patients (26 of 178) in the pyrotinib arm and 6.8% of patients (12 of 177) in the placebo arm. Conclusions: Pyrotinib, trastuzumab, and docetaxel as neoadjuvant treatment achieved a statistically significant and clinically meaningful improvement in IRC-assessed tpCR rate for patients with HER2-positive early or locally ABC compared with placebo, trastuzumab, and docetaxel, with an acceptable and manageable safety profile. These findings support pyrotinib, trastuzumab, and docetaxel as a new neoadjuvant treatment option in this patient population. Citation Format: Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Xiaoyu Zhu, Fei Wu, Tao Zhang, Jianjun Zou. Pyrotinib in combination with trastuzumab and docetaxel as neoadjuvant treatment for HER2-positive early or locally advanced breast cancer (PHEDRA): A randomized, double-blind, multicenter, phase 3 study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-08.

Abstract P2-13-40: Treatment patterns and adverse events of pyrotinib-based therapy in HER2-positive breast cancer patients in China: Results from a multicenter, real-world study

Abstract Background: Pyrotinib, a newly-developed irreversible pan-ErbB inhibitor, has shown promising antitumor activity and acceptable tolerability in phase 1-3 studies. However, findings from randomized clinical trials may have limited generalizability to patients treated in routine clinical practice. Herein, we conducted this multicenter real-world study to examine the treatment patterns, effectiveness and safety of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients in China.Methods: This is a China-based, observational study of HER2-positive BC patients receiving pyrotinib-based therapy (NCT04158505). Both early stage and advanced disease were included. Demographics, treatment patterns, and diarrhea management were summarized. The data cutoff date was April 30, 2021, and the study is ongoing to enroll. Real-world progression-free survival (PFS) and overall survival (OS) will be analyzed. Results: Between October 2019 and April 2021, a total of 907 patients (45 in the neoadjuvant setting [median age, 51 years] and 862 in the advanced setting [median age, 54 years]) from 65 sites received at least one dose of pyrotinib. Considering the limited sample size of early stage patients so far, we focused on advanced BC patients in this report. Of 862 patients with advanced disease, 44.2% had visceral metastases, 12.5% had brain metastases, 31.1%, 35.7%, and 33.2% received pyrotinib-based therapy as first-line, second-line, and third- or later-line treatment, respectively. The majority of patients (82.5%) were trastuzumab-exposed, and 10.2% were lapatinib-treated before receiving pyrotinib. Among 744 patients with available treatment information, 75.8% started with standard dose of pyrotinib (400 mg). Pyrotinib plus capecitabine (372 [50.0%]) was the most commonly used regimen for advanced disease, followed by pyrotinib plus chemotherapy other than capecitabine (189 [25.4%]), pyrotinib plus trastuzumab and chemotherapy (100 [13.4%]), and pyrotinib alone (77 [10.3%]). At the time of data cutoff, there were 164 (19.0%) progression or death events in 862 patients with advanced disease, and the median PFS and OS was not mature for the whole population. The median PFS for patients receiving second-line pyrotinib-based therapy was 11.7 months (95% CI, 8.8-not reached). The most common adverse event was diarrhea. Any grade and grade ≥3 diarrhea occurred in 70.5% and 14.9% of 907 patients, respectively. Diarrhea in eight (0.9%) patients with advanced disease were deemed as serious adverse events. Eighty-nine (9.8%) patients received diarrhea prophylaxis, and 436 (48.1%) used antidiarrhea drugs after diarrhea occurred. Montmorillonite powder (6.0% and 33.6%) were the most commonly used drug for both diarrhea prophylaxis and treatment, followed by loperamide (3.9% and 27.9%).Conclusions: In real world, a high percentage of physicians chose to use pyrotinib-based therapy in front lines when treating HER2-positive advanced BC patients, which might maximize its antitumor activity. Diarrhea is manageable in the real-world setting. Citation Format: Yiqun Li, Zhongsheng Tong, Quchang Ouyang, Xinhong Wu, Wei Li, Li Cai, Zhiyong Yu, Zhengxiang Han, Xiaojia Wang, Man Li, Jin Yang, Li Li, Zhaofeng Niu, Haibo Wang, Qitang Wang, Yi Li, Yuee Teng, Shiguang Zhu, Binghe Xu. Treatment patterns and adverse events of pyrotinib-based therapy in HER2-positive breast cancer patients in China: Results from a multicenter, real-world study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-40.

CTNI-01. A PHASE 1-2 CLINICAL TRIAL OF EO1001 (APL-122), A NOVEL IRREVERSIBLE PAN-ERBB INHIBITOR WITH PROMISING BRAIN PENETRATION

Abstract CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive crosstalk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1-2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible. ESCALATION: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2-6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. EXPANSION: EO1001 will be administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study. Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

Real-World Analysis of the Efficacy and Safety of a Novel Irreversible HER2 Tyrosine Kinase Inhibitor Pyrotinib in Patients with HER2-Positive Metastatic Breast Cancer.

BackgroundAs a novel irreversible pan-ErbB inhibitor recently approved in China, pyrotinib has exhibited promising anticancer efficacy and acceptable safety profile in HER2-positive metastatic breast cancer (mBC). The aim of this retrospective study was to estimate the efficacy and safety of pyrotinib treatment in Chinese mBC patients.MethodsWe retrospectively reviewed the real-world clinicopathological and treatment data of HER2-positive mBC patients receiving pyrotinib-based treatment from August 2018 to July 2019 in Qilu Hospital of Shandong University and other medical centers of Shandong Province in China.ResultsA total of 64 patients treated with pyrotinib were included for analysis, and the median follow-up duration was 260 days (interquartile range, 199.0 to 339.0 days). Fifty-nine (92.2%) patients had been previously treated with trastuzumab and/or T-DM1, while 11 (17.2%) patients had been exposed to lapatinib. The objective response rate (ORR) of all patients was 73.4%, and the disease control rate (DCR) was 98.4%, with a clinical benefit rate (CBR) of 87.5%. Patients with exposure to lapatinib responded well to pyrotinib-based treatment, although the ORR was significantly lower compared with that of patients without exposure to lapatinib (44.1% vs 77.5%, p=0.037). Previous lapatinib exposure was negatively associated with the objective response of pyrotinib treatment (odds ratio [OR]=0.248, 95% confidence interval [CI] 0.063–0.970, p=0.045). The median progression-free survival (mPFS) for patients with previous lapatinib exposure and patients with visceral metastasis was 299 days (95% CI 240.1–357.9 days) and 359 days (95% CI 258.3–459.7 days), respectively. But the mPFS of the whole cohort has not been reached until the cut-off date. Cox multivariate analysis revealed that only visceral metastasis was an independent predictor of significantly shorter PFS (p=0.041) but not previous exposure to lapatinib (p=0.092). Diarrhea (28.1%), hand-foot syndrome (17.2%), and neutropenia (9.4%) were the most common grade 3 adverse events associated with pyrotinib treatment.ConclusionPyrotinib is highly beneficial to HER2-positive metastatic breast cancer patients, even in patients with previous lapatinib exposure. Pyrotinib is a feasible replacement of lapatinib in combination with chemotherapeutic drugs or as a monotherapy. Adverse effects are tolerable and easily manageable.

Pyrotinib treatment enhances the radiosensitivity in HER2-positive brain metastatic breast cancer patients.

Brain metastasis is a common cause of death in HER2-positive breast cancer patients. Currently, it is mainly treated by whole-brain radiotherapy. Pyrotinib is an irreversible pan-ErbB inhibitor, which has demonstrated promising tumor-suppressing activity and acceptable tolerance in previous phase trials. In the present study, we evaluated the efficacy of pyrotinib on HER2-positive brain metastatic breast cancer patients treated with whole-brain radiotherapy. A total of 20 such patients were separated into pyrotinib plus capecitabine and capecitabine-only groups in a 1:1 ratio. All patients met either the primary or secondary endpoints. Oral admission of pyrotinib together with radiotherapy can significantly increase the overall response rate, progression-free survival, time to progression and duration of response of HER2+ brain metastatic breast cancer patients, without causing extra adverse events. In addition, pyrotinib can enhance the radiosensitivity of in-vitro cultured HER2+ breast cancer cell lines. The outcome of our study suggests that pyrotinib might be an effective medication to enhance the tumor radiosensitivity of HER2-positive brain metastatic breast cancer patients.

TRLS-06. A Phase 1–2 clinical trial of EO1001 (APL-122), a novel irreversible pan-ErbB inhibitor with promising brain penetration

CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive cross-talk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models.We report on a first-in-human Phase 1–2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, with adequate bone marrow, renal and liver function are eligible.Materials and methods Escalation: One subject per dose cohort is enrolled in an accelerated dose-escalation design until drug-related toxicity (≥G2) is observed in the first cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Cycle 1: Patients receive a single oral dose of EO1001 on day 1; single-dose pharmacokinetics are measured. Beginning on day 8, EO1001 is administered once daily for 21 days; multi-dose pharmacokinetics are measured. Cycles 2–6: EO1001 is administered once daily in continuous 28-day cycles for up to 20 weeks. Expansion: EO1001 is administered once daily to 20 patients at the MTD in continuous 28-day cycles for up to 6 cycles to determine a recommended Phase 2 dose (RP2D) for further study.Toxicity is assessed based on NCI CTCAEv5 and tumor response is assessed by RECIST 1.1. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

Pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2 positive gastric cancer or solid tumors: Safety and efficacy results from a phase Id trial.

e16009 Background: Pyrotinib (an irreversible pan-ErbB inhibitor) combined with SHR6390 (a novel oral small molecule CDK4/6 inhibitor) had shown anti-tumor activity in pyrotinib-resistant PDX models. A phase Id trial was conducted to evaluate the safety and efficacy of pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2 positive gastric cancer or solid tumors (NCT03480256). Methods: A standard “3+3” design was conducted in this trial. Patients (Pts) received pyrotinib (qd, d1-28; q4w) combined SHR6390(qd, d1-21; q4w) at dose of 400/100mg (cohort A), 320/100mg (cohort E) and 400/75mg (cohort F) until disease progression or intolerable toxicity. The primary endpoint was safety and maximum tolerated dose. Results: From Sep. 2019 to Dec. 2020, 19 pts (14 gastric cancer, 3 colorectal cancer, 2 other solid tumors) were enrolled (A: n = 6; E: n = 6; F: n = 7). 15 pts received and progressed on Herceptin before enrollment. In cohort A, one DLT was observed (Grade 4 neutropenia), and another 3 pts suffered G3 neutropenia, anemia or thrombocytopenia. Considered of safety, the dose levels were decreased and designed as cohort E and F. In cohort E, one DLT was observed (G4 neutropenia). No DLT was observed in cohort F. The most common hematologic toxicities were neutropenia (95%), anemia (74%) and thrombocytopenia (74%). The most common non-hematologic toxicities were diarrhea (53%), mucositis (26%) and nausea (21%). The most common G3/4 AEs were leukopenia (37%) and anemia (16%). No G3/4 non-hematologic toxicity was observed. 18 pts were included in efficacy analysis. The overall response rate was 38.9%, with 7 PR (A: n = 3; E: n = 2; F: n = 2) and 7 SD. The median PFS was 3.83 months, with 2 pts received treatment over 12 months (A: n = 1; F: n = 1). Conclusions: Pyrotinib combined with SHR6390 had shown acceptable safety profile and encouraging efficacy in refractory advanced HER2 positive solid tumors. Further study would be carried out at the dose in cohort A. Clinical trial information: NCT03480256.

CTNI-08. A PHASE 1–2 CLINICAL TRIAL OF EO1001, A NOVEL IRREVERSIBLE PAN-ErbB INHIBITOR WITH PROMISING BRAIN PENETRATION

Abstract Mutations causing errant ErbB activation are implicated in many cancers, including tumors correlated with high incidence of CNS metastasis. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs, particularly in advanced disease. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. EO1001 is being advanced into first-in-man studies under the Australia Clinical Trials Notification (CTN) scheme (ANZCTR Reg.#ACTRN12320000589343p). METHODS: Adult patients with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. Toxicity is assessed by NCI CCTCAEv5 and tumor response is assessed by RECISTv1.1. CNS exposure is evaluated in in select patients with confirmed CNS disease involvement via CSF collection. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (≥ G2) is observed, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). DOSE ESCALATION: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2–6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD EXPANSION: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). An update on the progress of this trial will be presented.

294P Pyrotinib and capecitabine for HER2–positive metastatic breast cancer patients with previously untreated brain metastases: A single-group multicenter phase II study

The aim of this study was to investigate the effect of pyrotinib, an irreversible pan-ErbB inhibitor, and capecitabine in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with untreated brain metastases.

Abstract CT154: An ascending single and multiple dose study of the safety, tolerability, pharmacokinetics and antitumor activity of once-daily oral treatment with EO1001, a novel irreversible pan-ErbB inhibitor with promising brain penetration, in patients with advanced cancer

Abstract Background: ErbB receptor tyrosine kinases: EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4) are part of a complex network activating signaling pathways involved in cell growth and survival. Mutations causing errant ErbB activation is an oncodriver in many cancers. Inhibitors targeting ErbB mutations have transformed patient outcomes; however, treatment resistance develops rapidly and crosstalk between ErbB family members is associated with acquired resistance. The development of next-generation agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor with superior CNS penetration targeting ErbB1, ErbB2 and ErbB4. Preclinical data suggests a favorable pharmacokinetic and toxicity profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Methods: This study examines the safety and tolerability of EO1001 to define a recommended dose for advanced human clinical trials and to assess efficacy. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS disease involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (%gt=G2) is observed in the first dosing cycle, after which the dose escalation scheme will revert to a 3+3 design in a modified-Fibonacci dose-escalation scheme to determine the maximum tolerated dose (MTD). Dose Escalation: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2-6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD Expansion: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). Toxicity will be assessed based on NCI CCTCAEv5 and tumor response will be assessed by RECIST 1.1 or RANO for CNS disease. CNS exposure will be evaluated in patients via CSF collection with confirmed CNS disease involvement. Citation Format: Jeffrey A. Bacha, Dennis Brown, Sarath Kanekal, Ian Nisbet, Neil Sankar, Wang Shen, Helen Wheeler, Kathy Skoff, Zhen Zhong Wang. An ascending single and multiple dose study of the safety, tolerability, pharmacokinetics and antitumor activity of once-daily oral treatment with EO1001, a novel irreversible pan-ErbB inhibitor with promising brain penetration, in patients with advanced cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT154.

70. A PHASE 1–2 CLINICAL TRIAL OF EO1001, A NOVEL IRREVERSIBLE pan-ErbB INHIBITOR WITH PROMISING BRAIN PENETRATION

CNS metastasis has become a prominent driver of morbidity and mortality in recent years as new targeted therapies have improved systemic outcomes. Mutations in the ErbB family of kinases are known oncodrivers in many of these cancers. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor with superior CNS penetration targeting ErbB1, ErbB2 and ErbB4. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (≥G2) is observed in the first dosing cycle, after which dose escalation will revert to a 3 + 3 design to determine the maximum tolerated dose (MTD). Dose Escalation: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2–6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD Expansion: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). Toxicity is assessed based on NCI CCTCAEv5 and tumor response will be assessed by RECIST 1.1 or RANO for CNS disease. CNS exposure is evaluated in patients via CSF collection with confirmed CNS disease involvement.

Effectiveness and Safety of Pyrotinib, and Association of Biomarker With Progression-Free Survival in Patients With HER2-Positive Metastatic Breast Cancer: A Real-World, Multicentre Analysis.

Background: Pyrotinib, an irreversible pan-ERBB inhibitor, has shown promising antitumour activity, and acceptable tolerability. This research was conducted to evaluate the actual use and effectiveness of pyrotinib in China, therefore, contributed to solve the problem of real-world data scarcity.Methods: In this retrospective study, 168 patients who received pyrotinib treatment for HER2-positive metastatic breast cancer (MBC) in Hunan Province from June 2018 to August 2019 were included. Progression-free survival (PFS), tumor mutation burden (TMB), and drug-related adverse events (AEs) after pyrotinib administration were analyzed.Results: The median PFS (mPFS) time in the 168 participants was 8.07 months. The mPFS times in patients with pyrotinib in second-line therapy (n = 65) and third-or-higher-line therapy (n = 94) were 8.10 months and 7.60 months, respectively. Patients with brain metastases achieved 8.80 months mPFS time. In patients with pyrotinib in third-or-higher-line therapy, patients who had previously used lapatinib still got efficacy but showed a shorter mPFS time (6.43 months) than patients who had not (8.37 months). TMB was measured in 28 patients, K-M curve (P = 0.0024) and Multivariate Cox analysis (P = 0.0176) showed a significant negative association between TMB and PFS. Diarrhea occurred in 98.2% of participants (in any grade) and 19.6% in grade 3–4 AEs.Conclusion: Pyrotinib is highly beneficial to second-or-higher-line patients or HER2-positive MBC patients with brain metastases. Pyrotinib seems to be a feasible strategy both in combination of chemotherapeutic drugs or as a replacement of lapatinib if diseases progressed. TMB could be a potential predictor for evaluating pyrotinib's effectiveness in HER2-positive MBC.