Intracranial Duration Of Response Research Articles

A pooled analysis of trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer with brain metastases

This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. The endpoints included intracranial objective response rate (ORR; complete or partial response in the brain) per blinded independent central review (BICR) by RECIST version 1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. A total of 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median intracranial DoR was 12.3 [95% confidence interval (CI) 9.1-17.9] months, and for those with untreated/active BMs, it was 17.5 months (95% CI 13.6-31.6 months). The median CNS-PFS and OS were 12.3 months (95% CI 11.1-13.8 months) and not reached (95% CI 22.1 months-not estimable) in those with treated/stable BMs, and 18.5 months (95% CI 13.6-23.3 months) and 30.2 months (95% CI 21.3 months-not estimable) in those with untreated/active BMs, respectively. Drug-related treatment-emergent adverse events grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

Lazertinib in EGFR-Variant Non–Small Cell Lung Cancer With CNS Failure to Prior EGFR Tyrosine Kinase Inhibitors

EGFR-variant non-small cell lung cancer (NSCLC) is associated with a high rate of central nervous system (CNS) metastases, even with treatment with first-generation or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). To investigate CNS activity with lazertinib, a third-generation EGFR TKI. This multicenter single-arm, phase 2 nonrandomized controlled trial was conducted in South Korea and included patients with EGFR-variant NSCLC who had asymptomatic or mildly symptomatic brain metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs. Data were collected from June 2021 to April 2022, with a data cutoff date of December 15, 2022. Lazertinib, 240 mg, once daily. The primary end point was intracranial objective response rate (iORR) in the evaluable population according to the Response Evaluation Criteria in Solid Tumours version 1.1 assessed by the investigators. Secondary end points included intracranial progression-free survival (iPFS) and iORR in patients with T790M-negative disease and isolated CNS progression as well as overall ORR, duration of response, intracranial duration of response, disease control rate, overall survival, cerebrospinal fluid penetration of lazertinib, and safety. Among 40 included patients, 25 (63%) were women, and the median (range) age was 63 (29-85) years. A total of 38 patients were evaluable for tumor response, including 12 patients with leptomeningeal metastases. At data cutoff, the median (range) follow-up was 13.6 (2.9-17.7) months. The iORR for the evaluable population was 55% (21 of 38; 95% CI, 38.3-71.4); for patients with T790M-positive disease, 80% (4 of 5; 95% CI, 28.4-99.5); for patients with T790M-negative disease, 43% (9 of 21; 95% CI, 21.8-66.0); and for patients with T790M-unknown disease, 67% (8 of 12; 95% CI, 34.9-90.1). The median iPFS was 15.8 months (95% CI, 15.2-not reached) for the evaluable population, 15.2 months (95% CI, 4.2-not reached) for the T790M-positive subgroup, 15.4 months (95% CI, 7.9-not reached) for the T790M-negative subgroup, and 18.0 months (95% CI, 3.9-not reached) for the T790M-unknown subgroup. The cerebrospinal fluid penetration rate of lazertinib was 46.2% (95% CI, 10.0-49.6), providing further support for its mechanism of intracranial response. Most adverse events were grade 1 or 2. In this study, lazertinib had substantial CNS activity, regardless of T790M status, against the progression of intracranial metastases with or without leptomeningeal metastases after unsuccessful treatment with first-generation or second-generation EGFR TKIs in patients with metastatic EGFR-variant NSCLC. These results suggest that using lazertinib instead of brain local treatment could be a potential strategy in patients with EGFR-variant NSCLC whose CNS metastases progressed after prior EGFR TKI treatment. ClinicalTrials.gov Identifier: NCT05326425.

Abstract CT289: A phase II study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in patients with HER2-positive metastatic solid tumors and metastases to brain (TUCATEMEB)

Abstract Background: HER2 overexpression or amplification is a validated prognostic and predictive biomarker for treatments in several tumor types. The development of brain metastases is an unfortunate and common complication in patients with metastatic cancer and the incidence of brain metastases continues to grow as advances in cancer treatment extend the survival. Unfortunately many of the clinical trials still exclude patients with brain metastases. Tucatinib is a selective small molecule HER2 inibitor that has shown intracranial activity and it is approved with trastuzumab and capecitabine for treatment of patients with breast cancer including with active brain metastases. Tucatinib showed significant preclinical and clinical antitumor activity in combination with other HER2-targeted therapies, including T-DM1 in breast and other cancers. We hypothesize that the combination of tucatinib and T-DM1 will be a safe and effective treatment in HER2-positive (+) metastatic solid tumors that have metastasized to the brain. To test this hypothesis, we are conducting a Phase II Study of Tucatinib and T-DM1 in Patients with HER2+ Metastatic Solid Tumors and Metastases to Brain (TUCATEMEB). Methods: Eligible adult patients with HER2-positive solid tumors and active brain metastases (with at least one untreated brain lesion ≥0.5 cm and <3.0 cm) will be enrolled in the study. HER2 positivity is defined as HER2 overexpression by immunohistochemistry 3+ or 2+ and fluorescence in situ hybridization positive and/or HER2 amplification by in situ hybridization or next-generation sequencing and/or activating ERBB2 mutation. Patients will receive the study treatment in 21-day cycles: Tucatinib 300 mg orally twice daily; T-DM1 3.6 mg/kg intravenously on Day 1. The primary objective is to determine the intracranial antitumor activity of the tucatinib and T-DM1 combination per the modified RECIST in patients with HER2+ metastatic solid tumors and brain metastases. The secondary objectives are to determine the intracranial antitumor activity per the RANO-BM criteria; to evaluate the safety and tolerability, the duration of intracranial response, the overall survival, the progression free survival, the systemic antitumor activity and clinical benefit rate in patients with HER2+ metastatic solid tumors and brain metastases. Exploratory objectives are to assess predictive and pharmacodynamic markers of response and to corelate them with clinical and molecular characteristics. The efficacy endpoint will be monitored using the Bayesian optimal phase 2 BOP2 design and safety and tolerability will be monitored based on Bayesian posterior probability. Restaging brain MRI and systemic scans will be performed every 6 weeks for the first 12 weeks, and every 9 weeks thereafter. The trial opened in May 2023 and is enrolling patients (NCT05673928). Citation Format: Ecaterina E. Dumbrava, Amber M. Kennon, Rashmi K. Murthy, Emma J. Montazari, Hussein Tawbi, Jing Li, Frederick F. Lang, Gisela Sanchez, Jianbo Wang, Isabella C. Glitza, Barbara J. O'Brien, Thomas Beckham, Todd Swanson, Martin C. Tom, Uyen M. Vu, Tanisha T. Darko, Tiantian Cai, Komal Shah, Funda Meric-Bernstam, Jordi Rodon. A phase II study of Tucatinib and Ado-trastuzumab Emtansine (T-DM1) in patients with HER2-positive metastatic solid tumors and metastases to brain (TUCATEMEB) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT289.

Stereotactic Radiotherapy (SRT) in Combination with Aumolertinib to Treat Intracranial Oligometastatic Non-Small Cell Lung Cancer (NSCLC): An Update of a Phase II, Prospective Study

Stereotactic radiotherapy (SRT) is highly effective and less toxic for limited intracranial metastases. Aumolertinib is a tolerable third-generation epidermal growth factor receptor tyrosine kinase inhibitor that has CNS efficacy in patients with EGFR-mutant NSCLC. We aim to investigate the efficacy and safety of aumolertinib followed by SRT in patients with intracranial oligometastatic NSCLC. Intracranial oligometastatic Patients with EGFR sensitive mutations (EGFR-TKIs naive) were enrolled and received aumolertinib 110mg daily until intracranial disease progression. Then SRT (32-40 Gy total, 8 Gy/f) was given to intracranial oligo-progression disease if possible. The primary endpoint was intracranial objective response rate (iORR). Secondary endpoints included intracranial progression-free survival (iPFS), intracranial duration of response (iDOR)according to RECIST 1.1, cerebral radiation necrosis rate (CRNR) and overall survival (OS). Safety was evaluated according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). This trial is registered with ClinicalTrials.gov, NCT04519983. To February 10, 2023, a total of 38 patients were enrolled and 35 patients were assessable followed for 3 months to 18 months. All patients received 110mg aumolertinib daily and received at least one independent imaging evaluation by a radiologist. After oral administration of aumolertinib, the best response of 94% patients in intracranial and extracranial lesions was partial response (PR). Two patients had stable intracranial disease. At data cut-off, one patient developed intracranial primary lesion progression at 12 months after oral administration of aumolertinib but stable in extracranial lesions. SRT treatment was given to this patient. No grade ≥3 adverse events occurred after continued oral administration of aumolertinib. The most common adverse reactions were rash and abnormal liver enzymes, 1 patient had grade 2 CK elevation. This report showed pronounced intracranial objective response benefit in patients with intracranial oligometastatic disease followed by SRT after intracranial oligo-progression and no new safety signals. Aumolertinib has promising efficacy and good tolerability in intracranial oligometastatic EGFR mutated NSCLC. [Keywords] Non-small cell lung cancer; epidermal growth factor receptor tyrosine kinase inhibitor; Aumolertinib; Stereotactic radiotherapy.

Tucatinib vs Placebo, Both in Combination With Trastuzumab and Capecitabine, for Previously Treated ERBB2 (HER2)-Positive Metastatic Breast Cancer in Patients With Brain Metastases

It is estimated that up to 50% of patients with ERBB2 (HER2)-positive metastatic breast cancer (MBC) will develop brain metastases (BMs), which is associated with poor prognosis. Previous reports of the HER2CLIMB trial have demonstrated that tucatinib in combination with trastuzumab and capecitabine provides survival and intracranial benefits for patients with ERBB2-positive MBC and BMs. To describe overall survival (OS) and intracranial outcomes from tucatinib in combination with trastuzumab and capecitabine in patients with ERBB2-positive MBC and BMs with an additional 15.6 months of follow-up. HER2CLIMB is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial evaluating tucatinib in combination with trastuzumab and capecitabine. The 612 patients, including those with active or stable BMs, had ERBB2-positive MBC previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. The study was conducted from February 23, 2016, to May 3, 2019. Data from February 23, 2016, to February 8, 2021, were analyzed. Patients were randomized 2:1 to receive tucatinib (300 mg orally twice daily) or placebo (orally twice daily), both in combination with trastuzumab (6 mg/kg intravenously or subcutaneously every 3 weeks with an initial loading dose of 8 mg/kg) and capecitabine (1000 mg/m2 orally twice daily on days 1-14 of each 3-week cycle). Evaluations in this exploratory subgroup analysis included OS and intracranial progression-free survival (CNS-PFS) in patients with BMs, confirmed intracranial objective response rate (ORR-IC) and duration of intracranial response (DOR-IC) in patients with measurable intracranial disease at baseline, and new brain lesion-free survival in all patients. Only OS was prespecified before the primary database lock. At baseline, 291 of 612 patients (47.5%) had BMs. Median age was 52 years (range, 22-75 years), and 289 (99.3%) were women. At median follow-up of 29.6 months (range, 0.1-52.9 months), median OS was 9.1 months longer in the tucatinib-combination group (21.6 months; 95% CI, 18.1-28.5) vs the placebo-combination group (12.5 months; 95% CI, 11.2-16.9). The tucatinib-combination group showed greater clinical benefit in CNS-PFS and ORR-IC compared with the placebo-combination group. The DOR-IC was 8.6 months (95% CI, 5.5-10.3 months) in the tucatinib-combination group and 3.0 months (95% CI, 3.0-10.3 months) in the placebo-combination group. Risk of developing new brain lesions as the site of first progression or death was reduced by 45.1% in the tucatinib-combination group vs the placebo-combination group (hazard ratio, 0.55 [95% CI, 0.36-0.85]). This subgroup analysis found that tucatinib in combination with trastuzumab and capecitabine improved OS while reducing the risk of developing new brain lesions, further supporting the importance of this treatment option for patients with ERBB2-positive MBC, including those with BMs. ClinicalTrials.gov Identifier: NCT02614794.

Forthcoming Phase II Study of Durvalumab (MEDI4736) Plus Chemotherapy for Small Cell Lung Cancer with Brain Metastases.

The standard of care for extensive-stage small cell lung cancer (ES-SCLC) is an immune checkpoint inhibitor (ICI) combined with platinum-etoposide (PE) chemotherapy. At initial diagnosis, about 25% of ES-SCLC patients have brain metastases, which are associated with a poor prognosis. The decision as to whether to treat brain metastases with local therapies such as surgery or radiotherapy before initiation of systemic chemoimmunotherapy is based on symptoms due to the brain lesions and the general condition of the patient. Subset analysis of the CASPIAN study showed that combination therapy with PE plus durvalumab (MEDI4736) is promising for ES-SCLC with brain metastases. However, data required in daily clinical practice, such as intracranial response rate and duration of intracranial response, are insufficient for such patients. We have designed a single-arm phase II trial of durvalumab plus PE for patients aged ≥20 years with chemotherapy-naïve ES-SCLC and at least one brain metastasis ≥5 mm in size that has not been previously treated. Patients receive durvalumab intravenously combined with four cycles of PE. Enrollment of 50 patients over 2 years at 25 oncology facilities in Japan is planned. The primary endpoint is intracranial response rate. This is the first prospective study to evaluate the effects of an ICI with PE specifically in ES-SCLC patients with brain metastases. If it demonstrates intracranial efficacy, this regimen will be a potential treatment option for such individuals, and radiation therapy or surgery for brain metastases can be avoided or postponed.

Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Primary results from phase 2 Tricotel study.

9515 Retraction The abstract by Dummer et al entitled, “Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Primary results from phase 2 Tricotel study,” ( Journal of Clinical Oncology 40, no. 16, suppl 9515) published on June 2, 2022, has been retracted due to corrected data that has led to a change in the conclusions of the abstract. The updated results have been published online by Lancet Oncology in July 2023. See Dummer R, Queirolo P, Gerard Duhard P, et al: Atezolizumab, vemurafenib, and cobimetinib in patients with melanoma with CNS metastases (TRICOTEL): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol doi: 10.1016/S1470-2045(23)00334-0. This abstract was retracted on August 7, 2023. Background: Despite recent advances in the treatment of melanoma, there remains an urgent need to improve outcomes in pts with CNS mets. To date, studies evaluating intracranial activity of immunotherapies and targeted therapies have included limited numbers of pts with symptomatic CNS mets. Cohort 2 of the phase 2 Tricotel study evaluated the safety and efficacy of A + C + V in BRAFV600-mutated melanoma with CNS mets, including symptomatic pts receiving corticosteroids. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Primary outcome was intracranial objective response rate (ORR; confirmed by assessments ≥4 wk apart per independent review committee [IRC]). Secondary end points were investigator-assessed intracranial ORR, extracranial ORR, overall ORR, duration of response (DOR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety. Prespecified subgroup analyses were performed in pts receiving corticosteroids (>2 mg/d dexamethasone) and/or with CNS-related symptoms at baseline vs asymptomatic pts. Results: This study enrolled 65 pts (median age, 55 y; 63% male). At baseline, 37% were on corticosteroids and/or were symptomatic; 49% had elevated lactate dehydrogenase. Median follow-up was 9.7 mo for all pts, 10.0 mo for pts on corticosteroids and/or symptomatic at baseline (n = 24), and 9.7 mo for asymptomatic pts (n = 41). Intracranial ORR was 42% by IRC and 51% by investigator (BOR concordance: 68%). Intracranial DOR and PFS are listed in the Table. In pts on corticosteroids and/or symptomatic at baseline, ORR was 58%, DOR was 10.2 mo, and PFS was 7.2 mo by investigator; in asymptomatic pts, ORR was 46%, DOR was 5.7 mo, and PFS was 5.5 mo. Additional secondary efficacy end points will be presented. In 60 pts who received A + C + V, grade 3/4 adverse events (AEs) occurred in 70% of pts; most commonly lipase increased (27%) and blood CPK increased (17%). Serious AEs occurred in 30% of pts. AEs led to discontinuation of any study treatment in 27% of pts. Conclusions: Addition of A to C + V provides promising intracranial activity in pts with BRAFV600-mutated melanoma with CNS mets, particularly in those receiving corticosteroids and/or in symptomatic pts. The safety profile of A + C + V is consistent with that observed in the IMspire150 study. Clinical trial information: NCT03625141. [Table: see text]

Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB).

1005 Background: Tucatinib (TUC) is an investigational, highly selective HER2 kinase inhibitor. HER2CLIMB (NCT02614794) showed clinically meaningful and statistically significant improvements in overall survival (OS) and progression free survival (PFS) in all pts, prolongation of PFS in pts with brain metastases (BM), and objective response rate (ORR) when TUC was added to trastuzumab (T) and capecitabine (C). Primary methods and outcomes have been reported previously (Murthy NEJM 2019). We report the results of exploratory efficacy analyses in pts with BM. Methods: All pts with HER2+ metastatic breast cancer (MBC) enrolled in HER2CLIMB had a baseline brain MRI. Pts with BM were eligible and classified as untreated, treated stable, or treated and progressing. Pts were randomized 2:1 to receive TUC or placebo, in combination with T and C. Efficacy analyses in pts with BM at baseline were performed by applying RECIST 1.1 to the brain based on investigator evaluation. CNS-PFS (progression in the brain or death) and OS were evaluated in BM pts overall. Intracranial (IC) confirmed ORR (ORR-IC) and IC duration of response (DOR-IC) were evaluated in BM pts with measurable IC disease. After isolated brain progression, pts could continue study therapy after local treatment until second progression, and time from randomization to second progression or death was evaluated. Results: Overall, 291 pts (48%) had BM at baseline: 198 (48%) in the TUC arm and 93 (46%) in the control arm. There was a 68% reduction in risk of CNS-PFS in the TUC arm (HR: 0.32; 95% CI: 0.22, 0.48; P < 0.0001). Median CNS-PFS was 9.9 mo in the TUC arm vs 4.2 mo in the control arm. Risk of death overall was reduced by 42% in the TUC arm (OS HR: 0.58; 95% CI: 0.40, 0.85; P = 0.005). Median OS was 18.1 mo vs 12.0 mo. ORR-IC was higher in the TUC arm (47.3%; 95% CI: 33.7, 61.2) vs the control arm (20.0%; 95% CI: 5.7, 43.7). Median DOR-IC was 6.8 mo (95% CI: 5.5, 16.4) vs 3.0 mo (95% CI: 3.0, 10.3). In pts with isolated brain progression who continued study therapy after local treatment (n = 30), risk of second progression or death was reduced by 67% (HR: 0.33; 95% CI: 0.11, 1.02), and median PFS from randomization was 15.9 mo vs 9.7 mo, favoring the TUC arm. Conclusions: In pts with heavily previously treated HER2+ MBC with BM, TUC in combination with T and C doubled the ORR-IC, reduced risk of IC progression or death by two thirds and reduced risk of death by nearly half. If approved, TUC in combination with T and C has the potential to become a new standard of care in pts with HER2+ MBC with and without BM. Clinical trial information: NCT02614794 .

A phase II study of lorlatinib in patients (pts) with ALK-positive (ALK+) lung cancer with brain-only progression.

9595 Background: Lorlatinib is a 3rd-generation ALK tyrosine kinase inhibitor (TKI) developed to penetrate the central nervous system (CNS) and overcome resistance to 2nd-generation (2nd-gen) ALK TKIs. In a phase II study, lorlatinib demonstrated significant intracranial (IC) activity after failure of 2nd-gen TKIs. As treatment discontinuation for extracranial (EC) progression can confound assessment of durability of IC response, we performed a phase II study (NCT02927340) to selectively evaluate lorlatinib activity in ALK+ pts with CNS-only disease. Methods: Between 11/2016 and 1/2019, 22 pts with IC progression on an ALK TKI with no other sites of measurable disease were enrolled at 2 institutions. Pts received lorlatinib at a starting dose of 100 mg QD. The primary endpoint was the IC disease control rate (DCR) at 12 weeks per modified RECIST v1.1. Secondary endpoints were IC objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Results: Of the 22 pts enrolled, 21 (95%) had progressed on a 2nd-gen ALK TKI and 14 (64%) had previously received CNS radiation (median 21.1 months between radiation and lorlatinib). Median number of prior ALK TKIs was 2 (range 1-4). As of the data cutoff of 12/15/19, median follow-up was 14 months. At 12 weeks, the IC-DCR was 95%, including 8 pts with stable disease. Best IC ORR was 59% with 6 complete and 7 partial responses. Nine (41%) pts relapsed on study, including 3 IC-only, 5 EC-only, and 1 combined relapse. Four pts continued treatment beyond EC-only progression. Although median IC DOR and PFS were not estimable due to few progression events, the IC progression-free rate at 12 months was 81% (95% CI: 53%-94%). Twelve pts have discontinued study treatment due to progression (n = 6), edema (n = 1), pulmonary hypertension (n = 1), or transition to commercial lorlatinib (n = 4). Conclusions: Lorlatinib induces durable intracranial responses in pts with CNS-only progression on 2nd-gen ALK TKIs, suggesting that CNS-specific relapses are primarily driven by ALK-dependent mechanisms. Further studies are needed to characterize the molecular basis of sensitivity to lorlatinib in this unique subgroup of pts with ALK+ lung cancer. Clinical trial information: NCT02927340 .

Phase 2 study of brigatinib in patients (pts) with anaplastic lymphoma kinase (ALK)−positive, advanced non–small cell lung cancer (NSCLC) that progressed on alectinib or ceritinib.

TPS9115 Background: Second-generation ALK tyrosine kinase inhibitors (TKIs) alectinib and ceritinib have demonstrated efficacy and acceptable safety in ALK TKI-pretreated and TKI-naive NSCLC. However, as with crizotinib, resistance to alectinib and ceritinib eventually develops, with secondary resistance mutations detected in approximately 50% of pts. Brigatinib is a next-generation ALK TKI designed to have potent and broad activity against ALK mutants. Post-crizotinib, brigatinib demonstrated high systemic and CNS objective response rates (ORR) and the longest reported median progression-free survival (PFS) of any ALK inhibitor in this setting (16.3–16.7 mo) (Huber. J Clin Oncol 2018;36; Bazhenova. Ann Oncol 2017;28); efficacy was demonstrated regardless of mutations. Based on nonclinical and clinical data, brigatinib may show efficacy in ALK+ NSCLC that has developed resistance or failed to respond to alectinib/ceritinib. This trial was designed to assess efficacy and safety of brigatinib in pts with ALK+ NSCLC that has progressed on alectinib or ceritinib. Methods: This is a phase 2, open-label, single-arm, multicenter, international trial (NCT03535740) in pts (≥18 y) with locally advanced/metastatic NSCLC and disease progression on alectinib or ceritinib (± prior crizotinib; ≤3 different systemic regimens for locally advanced/metastatic disease). Pts receive oral brigatinib 180 mg QD with 7-day lead-in at 90 mg QD. Treatment beyond progression or escalation to brigatinib 240 mg QD is permitted. Primary endpoint: independent review committee (IRC)−assessed confirmed ORR (cORR) per RECIST v1.1. Secondary endpoints: investigator (INV)-assessed cORR, duration of response (INV- and IRC-assessed), PFS, disease control rate, and time to response; in pts with baseline brain metastases: IRC-assessed intracranial cORR, duration of intracranial response, and intracranial PFS; OS; safety/tolerability; and HRQoL. Exploratory endpoints include biomarker analyses. The study was initiated in Dec 2018 at 78 sites (North America, Europe, Asia), with a planned sample size of 103 pts. Accrual is ongoing. Clinical trial information: NCT03535740.

Brigatinib, a new treatment option in ALK-rearranged advanced non-small cell lung carcinoma

Anaplastic lymphoma kinase (ALK) rearrangement is a rare feature in advanced non-small cell lung cancer (NSCLC), occurring in around 5% of the patients (1). This oncogenic addiction is more frequent in no/light-smokers, in thyroid transcription factor-1 (TTF1)-positive adenocarcinoma, with cribriform architecture and ring cells (2). ALK rearrangement—most of the time a translocation with a partner gene—induces the formation of a fusion protein with oncogenic properties. The first targeted therapy developed for ALK -rearranged NSCLC was crizotinib, an ALK tyrosine kinase inhibitor (TKI). Crizotinib was proved to be superior to chemotherapy in first-line setting in ALK -rearranged NSCLC, with an overall response rate (ORR) of 74% and a progression-free survival (PFS) of 10.9 months (3). Crizotinib in first-line treatment is now widely used. Other ALK TKIs have been developed, as brigatinib. Results of the phase I-II trial published in 2016 showed in 79 advanced NSCLC patients treated with brigatinib an ORR at 75% [72% in previously crizotinib treated patients (n=71)] and a PFS (median) of 13.2 months (4). Safety profile showed specific lung toxicity, occurring at the beginning of the treatment (median 2 days) in 8% of the patients, with incidence increasing with the dose of brigatinib. The ALTA trial, published in May 2017 in Journal of Clinical Oncology by Kim et al . was a phase II trial that randomized patients with advanced ALK -rearranged NSCLC between 2 doses of brigatinib (90 mg daily and 90 mg daily for 7 days then 180 mg daily) (5). The primary endpoint was ORR, and no comparison between the 2 arms was pre-planned. Assuming an ORR ≥35% with a power of 90% and a bilateral alpha risk at 0.025, the study had to include 109 patients per arm. Patients should have an advanced ALK -rearranged NSCLC with progression with crizotinib and a performance status (PS) between 0 and 2. Brain metastases were allowed only if asymptomatic and with stable doses of steroid treatment. Two-hundred and twenty-two patients were randomized [112 patients arm A (90 mg) and 110 patients arm B (90 mg then 180 mg)]. Both arms were well-balanced, with a median age at 54 years, 57% of women, 31% of Asian, 60% of non-smokers, 97% of adenocarcinoma, 69% of brain metastases. ORR (investigator-assessed) was 45% in arm A and 54% in arm B, and disease-control rate was 82% (arm A) and 86% (arm B). Median time to response was 1.8 months (arm A) and 1.9 months (arm B), and duration of response was 13.8 months (arm A) and 11.8 months (arm B). Median PFS was 9.2 months (arm A) and 12.9 months (arm B). Post-hoc comparison between the 2 arms for PFS showed a clear benefit for arm B, with a hazard ratio (HR) at 0.55 [95% confidence interval (CI), 0.36–0.86]. One-year overall survival (OS) probability was 71% (arm A) and 80% (arm B). As shown in the phase I-II trial, brigatinib had intracranial efficacy. ORR for measurable brain metastases was 42% (arm A, n=26) and 67% (arm B, n=18). For active brain metastases (i.e., metastases without previous brain radiotherapy, or progression after brain radiotherapy), intracranial ORR was 42% (arm A, n=19) and 73% (arm B, n=15). Intracranial PFS (median) was 15.6 months (arm A) and 12.8 months (arm B), with a duration of intracranial response (median) not reached in both arms. In term of safety, no new signal was detected. In both arms, main toxicities (≥10% patients) were nausea (33%/40%), diarrhea (19%/38%), vomiting (24%/23%), headache (28%/27%), decrease appetite (22%/15%) and hypertension (11%/21%). Grade 3–4 toxicities were rare: hypertension (6%/6%), increased creatine phosphokinase (3%/9%) and rash (1%/3%), mainly. Pulmonary early toxicity occurred in 6% of patients (n=14), during the first 2 days of treatment (always at 90mg daily of brigatinib). Grade 3–5 pulmonary toxicities concerned 3% of patients (n=7). Half of the patients (n=7) had successfully continued brigatinib after suspension, whereas 7 patients stopped brigatinib definitely. One patient died from acute respiratory failure (<1%). Multivariate analysis showed that advanced age [odds ratio (OR) =2.10; 95% CI, 1.21–3.65] and time from last crizotinib dose to first brigatinib dose less than 7 days (OR =3.88; 95% CI, 1.10–13.68) were associated with early pulmonary toxicity. Seven percent (arm A) and 20% (arm B) patients had dose reduction, due to increase of creatine phosphokinase, pneumonitis and rash.

Abstract CT151: CNS activity of ensartinib in ALK-positive non-small cell lung cancer patients

Abstract Background: Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. In animal studies, brain concentration of ensartinib in mice given at the therapeutic dose was 4 times higher than the IC50 for growth inhibition of ALK positive cells in vitro. Ensartinib was significantly more effective than crizotinib at inhibiting the intracranial growth of the SH-SY5Y neuroblastoma model harboring the F1174L mutation. We subsequently evaluated the CNS activity of ensartinib in patients with ALK positive non-small cell lung cancer (NSCLC). Methods: In this multicenter phase I/II study, patients (pts) with advanced solid tumors were enrolled and given ensartinib orally on a continuous 28-day schedule (NCT01625234). Doses from 25 mg up to 250 mg once daily were evaluated and 225 mg was selected for further evaluation in the phase II expansion. We report on patients enrolled with CNS metastases (with or without systemic disease) who were ALK TKI naïve or had received prior crizotinib or a second generation ALK TKI. Patients with untreated asymptomatic CNS metastases were allowed to enroll. All pts were assessed for adverse events using CTCAE version 4.03, and response to therapy was assessed using RECIST 1.1. Patients with only CNS disease had to have at least one measurable target lesion ≥ 3 mm in diameter. Results: As of the December 13, 2016 data cutoff, 26 pts with ALK+ NSCLC and baseline CNS metastases have been treated at ≥ 200 mg. Of the 26 pts, 13 pts had baseline target lesions (8 of which also had non-target lesions) and 13 pts had baseline non-target lesions only. Median age is 52 (21-72) years and the majority of patients had ECOG performance status of 1 (69%). CNS responses have been observed in both ALK TKI naïve pts and pts that received prior crizotinib. In the 13 pts with baseline target CNS lesions, intracranial response was achieved in 9 pts (69%), including 1 CR, and 4 pts (31%) had SD, a 100% disease control rate. In the 13 pts with non-target baseline lesions only, 1 CR was achieved and 8 pts had SD. All 3 (100%) ALK TKI naïve pts with baseline target lesions achieved CR or PR, and 5/8 pts (62%) that received prior crizotinib only and had baseline target lesions responded. The median duration of intracranial response in the 10 pts who responded (9 with target lesions, 1 with non-target lesions only) is 5.8+ months, with the longest duration being 24 months. Conclusions: Our clinical findings support the preclinical results that the use of ensartinib at doses generally well-tolerated in the clinic may result in favorable therapeutic outcomes in pts with ALK+ NSCLC with baseline CNS metastases. The ongoing phase III eXalt3 study will assess CNS response rate and time to CNS progression in pts receiving first-line ensartinib vs crizotinib (NCT02767804 and NCT01625234). Citation Format: Leora Horn, Karen L. Reckamp, Sandip Patel, George Blumenschein, Joel W. Neal, Barbara Gitlitz, Saiama Waqar, Geoffrey Oxnard, Christina Brzezniak, Gary Dukart, Fenlai Tan, Kimberly Harrow, Chris Liang, James Gibbons, Heather A. Wakelee. CNS activity of ensartinib in ALK-positive non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT151. doi:10.1158/1538-7445.AM2017-CT151

Abstract P3-12-04: A phase 2, multi-center, open label study evaluating the efficacy and safety of GRN1005 alone or in combination with trastuzumab in patients with brain metastases from breast cancer

Abstract Rationale: Treatment of brain metastasis (BM) remains an unmet medical need due to the inability of most anti-cancer agents to effectively cross the blood-brain barrier (BBB). GRN1005 is a peptide-drug conjugate (PDC) consisting of 3 molecules of paclitaxel conjugated to a 19-amino acid peptide, Angiopep-2. GRN1005 effectively penetrates the BBB by targeting the low-density lipoprotein receptor-related protein 1 (LRP1), which is expressed on the surface of the BBB and on certain neoplastic cells. In a phase 1 study, GRN1005 demonstrated encouraging anti-tumor activity in breast cancer (BC) patients with BM. Methods: Up to 157 patients (pts) with measurable BM from BC, with or without extra-cranial disease, are currently being enrolled in an ongoing open label study. Prior cranial irradiation is allowed but lesions previously treated with stereotactic radiosurgery (SRS) are excluded from the efficacy analysis. All currently enrolled pts received GRN1005 at a starting dose of either 650 or 550 mg/m2 IV every three weeks, until intra-cranial disease progression (iPD), unacceptable toxicity, or initiation of non-protocol systemic therapy. HER2 positive pts received concomitant trastuzumab. The primary endpoint is intra-cranial objective response rate (iORR), as assessed by independent review using CNS RECIST 1.1. Additional endpoints include safety, duration of intra-cranial response, 3-month intra-cranial progression free survival (iPFS3), extra-cranial ORR, and neurocognitive function. Results: As of 4 June 2012, 24 pts (13 at 650 mg/m2 and 11 at 550 mg/m2) have been treated with a median of 2 cycles of GRN1005 (range 1–5). Median age was 51.5 years (34–68) and 14 (58%) pts have HER2-positive disease. Pts received a median of 6 (3–14) prior systemic regimens; 19 had received prior whole brain radiation therapy (WBRT) ± SRS and 2 had received prior SRS only (data pending on 3 pts). Six (25%) pts have discontinued treatment with GRN1005, including 2 due to iPD and 2 due to adverse events (AE). One additional pt had clinical progression and discontinued GRN1005. The AEs observed at 650 mg/m2 are qualitatively consistent with conventional paclitaxel but are more frequent and more severe than observed with q3 week paclitaxel which led to a protocol amendment and dose reduction to 550 mg/m2 for all subsequent pts. Among all treated pts, the most frequent AEs were neutropenia (75%), fatigue (50%), mucositis (33%), neuropathy (29%), and diarrhea (25%). Notable Grade 3–4 AEs were neutropenia in 12 pts (including 1 case of febrile), and arthralgia, fatigue, and rash in 3 pts each. Preliminary anti-tumor activity has been observed in both intra-cranial and extra-cranial lesions. Conclusions: GRN1005 is a promising treatment for BM associated with breast cancer and demonstrates a safety profile qualitatively similar to paclitaxel dosed every 3 weeks. Due to tolerability concerns at the 650 mg/m2 dose, the 550 mg/m2 dose is currently being evaluated in these heavily pretreated BC pts. Updated efficacy and safety data will be presented at the meeting. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-04.