Search

Wildfires are a source of primary aerosols and precursors for secondary aerosols to the atmosphere. In this work, we discover that the evolution of these aerosols depends strongly on the coupled effects of dilution, photooxidation, and partitioning.

Introduction: Larotrectinib is a first-in-class, CNS-active, highly selective tropomyosin receptor kinase (TRK) inhibitor approved by the US Food and Drug Administration and European Medicines Agency for the treatment of adult and pediatric patients with tumor agnostic indication for TRK fusion-positive cancer. Larotrectinib produced an objective response rate (ORR) of 79% in 159 patients with TRK fusion-positive cancer across various tumor types (Hong DS et al. Lancet Oncol. 2020). Here we report the efficacy and safety of larotrectinib in the six patients from the NAVIGATE phase II study (NCT02576431) with TRK fusion-positive breast cancer. Methods: Data were obtained for patients with breast cancer harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and treated with larotrectinib in the NAVIGATE study. All patients received 100 mg twice daily on a continuous 28-day schedule. Responses were investigator-assessed per RECIST v1.1 (data cut-off: July 15, 2019). Results: A total of 6 patients with TRK fusion breast cancer were included: 3 with secretory carcinomas, 2 with triple-negative breast cancer (TNBC), and 1 with ER+/HER2− disease. The median age was 49 years (range 32-65). One of the patients with secretory breast cancer was male. All of the secretory cases and 1 TNBC patient harbored an ETV6-NTRK3 fusion, 1 TNBC patient had an LMNA-NTRK1 fusion, and the ER+/HER2− patient had a TPM3-NTRK1 fusion. Four patients had received ≥3 prior systemic therapies. The majority of patients had metastatic disease (n=5); 1 patient had locally advanced disease. The ORR was 83% (95% confidence interval [CI] 36-100) with 5 partial responses, while the ER+/HER2− patient had progressive disease. One of the TNBC patients had brain metastasis with complete resolution of CNS disease while on therapy. The median time to response was 1.7 months (range 0.9-1.9) and the duration of treatment ranged from 0.9 to 12+ months, with 4 patients (3 secretory and 1 TNBC) continuing on therapy at time of data cut. Median duration of response was not reached (95% CI 8.2-NE). Median progression-free survival was 9.1 months (95% CI 1.0-NE). Median overall survival was not reached at a median follow-up of 7.4 months. Four of the 6 patients had worst-grade adverse events (AEs) Grade 1-2; the most common Grade 1-2 AEs were dizziness and nausea. One patient had Grade 3 hepatocellular injury and Grade 4 hepatitis that were related to larotrectinib. There were no discontinuations due to AEs. Conclusion: Larotrectinib demonstrated an ORR in breast cancer patients similar to the ORR reported for larotrectinib across all tumor types, which supports the routine testing for NTRK gene fusions in patients with breast cancer regardless of histology. Citation Format: Ezra Y. Rosen, Antoine Italiano, Dejan Juric, John A. Reeves, Laura Dima, Nicoletta Brega, Alexander Drilon. Efficacy and safety of larotrectinib in patients with TRK fusion breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-06.

Background Tropomyosin receptor kinase (TRK) fusion proteins resulting from neurotrophic tyrosine receptor kinase (NTRK) gene fusions are rare primary oncogenic drivers in a wide array of tumors. Larotrectinib is a first-in-class, highly selective, central nervous system-active TRK inhibitor approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and over 40 countries for the treatment of TRK fusion solid tumors in adult and pediatric patients. Due to the rarity of TRK fusion cancer, larotrectinib was granted accelerated approval based on a relatively small number of patients enrolled in three early phase trials. ON-TRK aims to evaluate the safety profile of larotrectinib in a broader population and over extended time periods. Methods ON-TRK is a prospective, non-interventional, open-label, multicenter, multi-cohort, post-approval study in adult and pediatric patients with locally advanced or metastatic TRK fusion cancer treated with larotrectinib that will describe the safety and effectiveness of larotrectinib in real-world practice conditions. Adult patients will be grouped by tumor type and followed for at least 2 years. Patients Discussion The FDA Accelerated Approval Program allows for earlier approval of and patient access to drugs that treat serious conditions and fill an unmet medical need. This study is designed to fulfill post-approval requirements set by the FDA as well as post-marketing requirements set forth by local regulatory bodies and is part of the risk management plan for the EMA. Study registration This study is registered at ClinicalTrials.gov (NCT04142437). Protocol version v2.5, 25 March 2021.

BACKGROUND NTRK gene fusions occur in a range of tumor types, including those with CNS metastases. Larotrectinib, a highly selective FDA- and EMA- approved TRK inhibitor, demonstrated an objective response rate (ORR) of 79% across various cancers (Hong et al. Lancet Oncol. 2020). We report data on patients with TRK fusion cancer with CNS metastases treated with larotrectinib. METHODS Patients with solid tumors with CNS metastases at baseline harboring an NTRK gene fusion enrolled in two clinical trials (NCT02122913 and NCT02576431) were identified. Response was assessed by the investigator per RECIST v1.1. RESULTS As of July 15, 2019, 14 patients with CNS-metastases were enrolled: lung cancer (n=7), thyroid cancer (n=4), melanoma (n=2), and non-secretory breast cancer (n=1). Median age was 53 years (range 25–76). Including all sites of disease, the ORR was 71% (95% CI 42–92%): ten patients had a partial response (PR), two had stable disease (SD), and two had progressive disease (lung and melanoma). Of the three patients with measurable intracranial disease at baseline, the best intracranial response was 1 complete response, 1 PR, and 1 SD. Median duration of response for all patients was 14.8 months (range 1.9+ to 17.4+), median progression-free survival was 9.9 months (range 1.4 to 19.3+), and median overall survival was 27.8 months (range 1.4+ to 27.8). Treatment duration ranged from 1.4 to 25.0 months; six patients continued treatment beyond progression (lasting between 0.1+ and 8.5 months). Treatment-emergent adverse events (TEAEs) were mainly Grade 1 and 2; Grade 3 TEAEs occurred in seven patients (50%), with one (myalgia) attributed to larotrectinib (7%). There were no Grade 4 TEAEs. CONCLUSIONS Larotrectinib was highly active and well tolerated in TRK fusion cancer patients with CNS metastases. These results support testing for NTRK gene fusions across all cancers, including in patients with CNS metastases.

TPS207 Background: Hand-foot skin reaction (HFSR) is a common skin toxicity associated with regorafenib that may lead to drug withdrawal, dose reduction, or drug interruption. Predicting or recognizing early symptoms of HFSR could allow for better care. Digital solutions for ambulatory monitoring of patients provide an opportunity for monitoring and early detection of HFSR in home conditions. Methods: FACET is a phase 4, prospective, open-label, multicenter, interventional trial designed to assess the clinical utility, technical feasibility and usability of a system including a camera, FeetMe Connected insoles for gait assessment, ePRO questionnaires (HFS-14, EQ-5D-5L, FAS and VAS), and educational materials to detect and grade the severity of HFSR. During the study, enrolled patients developing an HFSR will be assigned to the HFSR group and patients without any sign of HFSR, they will be assigned to non-HFSR group. Study registration number at ANSM (French Authority): ID-RCB 2020-A03080-39. Patients will have metastatic colorectal cancer requiring initiation of regorafenib in accordance with clinical practice standard. Other key inclusion criteria are ECOG Performance Status 0-2, ability to understand the instructions and complete the ePRO questionnaires, ability to understand and communicate in French language, familiarity in using mobile communication devices and mobile application software, no previous episode of HFSR or HFS. The primary objective is to explore fit-for-purpose, and usability of the ePRO instruments and the data collecting devices. The primary endpoint is participants’ compliance with data collection measured by ePRO questionnaires completion, use of camera to take images vs expected and number of device days of insoles usage vs expected. Secondary objectives are to characterize variables exhibiting significant associations with development of HFSR. Secondary endpoints include summary statistics of ePRO questionnaires scores at the HFSR worst grade event in the HFSR group vs at 3 weeks in the non-HFSR group; Summary statistics for Feetme Connected insoles variables; Regorafenib dose modifications and treatment discontinuation; Participant’s device daily use to generate data; Participants ability to reach a hotline for technical issues or usability complaints. For HFSR related secondary endpoints, a blinded and independent Preliminary Adjudication Committee (PAC) will retrospectively assign participants to two groups (HFSR vs. no-HFSR) based on a case-by-case blinded assessment. An independent Final Adjudication Committee will compare the PAC assessment and investigators’ assessments done on site. It is planned to include a total of 38 participants from 4 centers. As of September 2021, all sites are open and ready to enroll. Study funded by Bayer.

Randomized controlled basket trials investigating drugs targeting a rare molecular alteration are challenging. Using patients as their own control overcomes some of these challenges. Growth modulation index (GMI) is the ratio of progression-free survival (PFS) on the current therapy to time to progression (TTP) on the last prior line of therapy, GMI ≥ 1.33 is considered a threshold of meaningful clinical activity. In a retrospective, exploratory analysis among patients with advanced tropomyosin receptor kinase (TRK) fusion cancer treated with the selective TRK inhibitor larotrectinib who received ≥1 prior line of therapy for locally advanced/metastatic disease, we determined the proportion of patients with GMI ≥ 1.33, patients who had not progressed by data cut-off were censored for PFS. Among 72 eligible patients, median GMI was 2.68 (range 0.01–48.75). Forty-seven patients (65%) had GMI ≥ 1.33, 13/25 patients (52%) with GMI &lt, 1.33 had not yet progressed on larotrectinib. Kaplan–Meier estimates showed a median GMI of 6.46. The probability of attaining GMI ≥ 1.33 was 0.75 (95% confidence interval (CI), 0.65–0.85). Median TTP on previous treatment was 3.0 months (95% CI, 2.6–4.4). Median PFS on larotrectinib was not estimable ((NE), 95% CI, NE, hazard ratio, 0.220 (95% CI, 0.146–0.332)). This analysis suggests larotrectinib improves PFS for patients with TRK fusion cancer compared with prior therapy.

David in the Muslim Tradition: The Bathsheba Affair. By Khaleel Mohammed. Lanham, MD: Lexington Books, 2015. Pp. ix + 225. $85, £51.95.

Introduction: Neurotrophic tyrosine receptor kinase (NTRK) gene fusions are oncogenic drivers in various tumor types. Larotrectinib is a first-in-class, highly selective, central nervous system (CNS)-active TRK inhibitor approved in over 40 countries, including the US, for the treatment of adult and pediatric patients with TRK fusion cancer. Larotrectinib was approved by the FDA in 2018 based on efficacy and safety outcomes in a primary analysis cohort of 55 patients with TRK fusion cancer from 3 clinical trials (Drilon A et al. NEJM. 2018). Here, we report long-term efficacy follow-up for larotrectinib and molecular data on co-occurring mutations in this primary analysis cohort. Methods: Patients with non-primary CNS TRK fusion cancer treated with larotrectinib were identified from 3 clinical trials (NCT02122913, NCT02576431, NCT02637687). NTRK gene status was determined by local molecular testing. Adult and pediatric patients received larotrectinib 100 mg and 100 mg/m2 twice daily, respectively. The primary endpoint was investigator-assessed objective response rate (ORR) (per RECIST v1.1). Next-generation sequencing was performed on pre-treatment tumor samples from a subset of patients with evaluable tumor material (n=31) using the FoundationOne® CDx assay. The data cut-off was July 15, 2019. Results: A total of 55 patients with 17 different tumor types were included in the primary analysis cohort. Median age was 45 years (range 0.3-76 years). Patients had gene fusions involving NTRK1 (45%), NTRK2 (2%), or NTRK3 (53%). For 31 patients the detailed genomic profile, including co-occurring mutations, will be presented. Forty-four (80%) patients had received prior systemic therapy, with a median of 2 prior therapies (range 0-10). ORR with larotrectinib was 80% (95% confidence interval [CI] 67-90%); 13 (24%) patients had a complete response (CR), 31 (56%) patients had a partial response (PR), 5 (9%) patients had stable disease, and 6 (11%) patients had progressive disease. With longer follow-up, best response for 4 patients improved from PR to CR. Median duration of response and progression-free survival were 35.2 months (95% CI 19.8-not estimable [NE]) and 25.8 months (95% CI 9.9-NE), respectively. Median overall survival (OS) was not reached (95% CI 44.4-NE) over a median follow-up of 32.5 months. The 36-month OS rate was 76% (95% CI 63-89%). In an expanded safety population (n=279), larotrectinib-related adverse events were mainly Grade 1-2. Conclusions: Larotrectinib demonstrated a robust response rate with long durability and extended survival benefits in adult and pediatric patients with TRK fusion cancer. These data highlight the importance of identifying NTRK gene fusions in patients with cancer. Citation Format: Alexander Drilon, Shivaani Kummar, Catherine M. Albert, Ramamoorthy Nagasubramanian, Jaclyn F. Hechtman, John A. Reeves, Georg Beckmann, Marion Rudolph, Justyna A. Wierzbińska, Laura Dima, Nicoletta Brega, Theodore W. Laetsch, David S. Hong. Long-term outcomes of patients with TRK fusion cancer treated with larotrectinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT020.

Background: NTRK gene fusions are oncogenic drivers in various tumor types. Overall survival (OS) of patients (pts) with tumors harboring NTRK fusions compared to pts without is unknown, and data on co-occurrence of NTRK fusions with other oncogenic drivers are limited.1 Methods: This retrospective study used genomic data generated by the 100,000 Genomes Project with linked clinical data from UK cancer databases. Pts with cancer who had undergone tumor whole genome sequencing between Mar 2016 and Jul 2019 were included. OS of pts with and without NTRK fusions, matched by exact and distance matching with a 1:4 NTRK+:NTRK− ratio, was analyzed by Kaplan-Meier method and Cox regression. Key alterations in ALK, BRAF, EGFR, HER2, KRAS and ROS1, and tumor mutation burden (TMB) and microsatellite instability (MSI), were evaluated along with NTRK gene fusions. Results: Of 15,223 pts analyzed, 38 (0.2%) had NTRK fusions, identified in 11 cancers (Genomics England classification), the most common being breast cancer (n=9), colorectal cancer (CRC; n=9), and sarcoma (n=7). While there was no significant OS difference in pts with and without NTRK fusions, the HR was 1.47 (95% CI 0.39-5.57; Table). Of the tested oncogenic drivers, only KRAS mutation was identified in 2 (5%) pts with an NTRK fusion (both hepatobiliary cancer), while oncogenic driver frequency in pts without NTRK fusions ranged from 0.1-11.6%. High TMB was more common in pts with NTRK fusions than in those without (21% vs 6%), as was high MSI (18% vs 6%); all pts with NTRK fusions and high TMB and/or MSI had CRC. Conclusions: While no statistical difference in OS was observed, there was a trend to higher risk of death in pts with NTRK fusions compared to those without, consistent with a recent US study.1 Co-occurrence of NTRK fusions and other biomarkers was rare, except for high TMB and high MSI in CRC. These results highlight NTRK fusions as actionable biomarkers and emphasize the need for NTRK gene fusion testing. NTRK− (n=72†)NTRK+ (n=18†)Median follow-up (IQR), years2.28 (1.57-2.98)2.01 (1.40-2.97)Median OS (IQR), yearsNE (NE-NE)NE (NE-NE)Landmark OS, % (95% CI)1 year96 (91-100)94 (84-100)2 years94 (89-100)87 (71-100)3 years88 (78-99)87 (71-100)HR (95% CI)1.47 (0.39-5.57)†Only patients with linked clinical data and who were matched were included in the OS analysis.1CI, confidence interval; HR, hazard ratio; IQR, interquartile range; NE, not estimable; NTRK; neurotrophic tyrosine receptor kinase; OS, overall survival.1. Bazhenova L, et al. Clin Cancer Res. 2020;26(12 Suppl 1):09-09. Citation Format: John Bridgewater, Xiaolong Jiao, Mounika Parimi, Clare Flach, Jeran Stratford, Atanas Kamburov, Arndt Schmitz, Jihong Zong, John A. Reeves, Karen Keating, Amanda Bruno, Marc Fellous, Lyudmila Bazhenova. Prognosis and molecular characteristics of patients with TRK fusion cancer in the 100,000 Genomes Project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 394.

3114 Background: Larotrectinib is a highly selective, CNS-active tropomyosin receptor kinase (TRK) inhibitor that demonstrated rapid and durable responses in three phase I/II single-arm studies of patients (pts) with TRK fusion cancer. In single-arm studies the growth modulation index (GMI) can be used to provide a comparative analysis. GMI is an intra-patient comparison that uses pts as their own control by comparing progression-free survival (PFS) on current therapy to time to progression or treatment failure (TTP) on the most recent prior therapy; namely the ratio of PFS/TTP (EMA Guidelines. Guideline on the Evaluation of Anticancer Medicinal Products in Man, EMA/CHMP/205/95 Rev.5). A GMI ratio ≥1.33 has been used as a threshold of meaningful clinical activity. In a previous analysis of 122 pts with TRK fusion cancer treated with larotrectinib, 84 pts (69%) had a GMI ≥1.33. Conversely, 38 pts (31%) had a GMI < 1.33, but of these, 9 pts were ongoing treatment and censored for PFS as of July 2019 (Italiano et al, ESMO 2020). Here, we report the GMI of this initial group with a longer follow-up as well as an expanded dataset to more accurately assess the treatment effect of larotrectinib in pts with TRK fusion cancer previously treated with ≥1 line of therapy. Methods: Pts with TRK fusion cancer from three clinical trials on larotrectinib treatment with ≥1 prior line of systemic therapy were eligible for retrospective GMI analysis. TTP on the prior line of therapy was investigator-assessed. PFS on larotrectinib was determined by independent review committee per RECIST v1.1. Pts who had not progressed were censored as of date of last visit. Kaplan–Meier (KM) analyses were used to estimate median GMI, in addition to median PFS and TTP. The data cut-off was July 2020. Results: With an extended follow up of the original 122 pts, 90 (74%) pts had a GMI ≥1.33, including 6 of the 9 pts who were previously censored with a GMI < 1.33 and ongoing treatment; 6 pts (5%) had a GMI ≥1 to < 1.33 and 26 (21%) had a GMI < 1. The KM estimated median GMI increased from 7.6 (95% CI 5.7–88.0) to 9.5 (95% CI 5.7–17.4). In the expanded dataset of 140 pts, 103 pts (74%) had GMI ≥1.33, 7 (5%) had a GMI ≥1 to < 1.33 and 30 (21%) had a GMI < 1. Six of the 37 pts with a GMI < 1.33 were censored and still ongoing treatment. The KM estimated median GMI was 8.9 (95% CI 6.2–17.4). Among pts who had received 1, 2, or ≥3 prior lines of therapy, 74%, 65%, and 80%, respectively, had GMI of ≥1.33. Median TTP on the prior therapy was 3.0 months (95% CI 2.1–3.5) and median PFS on larotrectinib was 33.0 months (95% CI 16.6–34.9). Conclusions: With a longer follow-up, nearly three-quarters of pts with TRK fusion cancer treated with larotrectinib had a prolonged PFS compared to their most recent prior therapy. These results further validate the use of larotrectinib in treating patients with TRK fusion cancer. Clinical trial information: NCT02576431, NCT02122913, NCT02637687.