Summary Background Anaplastic lymphoma kinase ( ALK ) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with ...potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK -rearranged NSCLC. Methods In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK -rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30–300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK -rearranged NSCLC (cohort 1), crizotinib-treated ALK -rearranged NSCLC (cohort 2), EGFRT790M -positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK -rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov , number NCT01449461. Findings Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 58% with ALK -rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% 95% CI 40–100) of four patients in cohort 1 had an objective response, 31 (74% 58–86) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% 4–41) of 18 did in cohort 4, and five (83% 36–100) of six did in cohort 5. 51 (72% 60–82) of 71 patients with ALK -rearranged NSCLC with previous crizotinib treatment had an objective response (44 62% (50–73) had a confirmed objective response). All eight crizotinib-naive patients with ALK -rearranged NSCLC had a confirmed objective response (100% 63–100). Three (50% 95% CI 12–88) of six patients in cohort 5 had an intracranial response. The most common grade 3–4 treatment-emergent adverse events across all doses were increased lipase concentration (12 9% of 137), dyspnoea (eight 6%), and hypertension (seven 5%). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten 7%), pneumonia (nine 7%), and hypoxia (seven 5%). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. Interpretation Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK -rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK -rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK -rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). Funding ARIAD Pharmaceuticals.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
IMPORTANCE: There is empirical evidence that social determinants of health (SDOH) impact health outcomes in Black and Hispanic and Latinx individuals in the US. Recently, SDOH have risen to the top ...as essential intervention targets that could help alleviate racial and ethnic disparities. Neuromyelitis optica spectrum disorder (NMOSD) disproportionately affects Black individuals, and multiple sclerosis (MS) has seen a recent shift in select racial groups. It is unclear to what degree SDOH have been investigated and contribute to racial and ethnic health disparities and inequities. OBSERVATIONS: This narrative review provides a contemporary synthesis of SDOH associated with racial and ethnic health disparities and inequities in MS, NMOSD, and other autoimmune disorders, such as myelin oligodendrocyte glycoprotein antibody (MOG-Ab)–associated disease. These immune-mediated neurological diseases were chosen for their capacity to be a high burden to society and because of complementary SDOH-associated challenges among minority populations. A paucity of research addressing inequities and the role of SDOH in MS and NMOSD was noted despite findings that Black individuals have a higher risk of developing MS or NMOSD and associated mortality compared with White individuals. Greater health disparities were also found for those with lower income and education, lower health literacy, and negative illness perceptions in MS. No studies in MOG-Ab disorders were found. CONCLUSIONS AND RELEVANCE: Increased efforts are needed to better understand the role of SDOH in racial and ethnic health disparities and inequities in MS, NMOSD, and emerging autoimmune disorders. This includes developing research frameworks aimed at understanding the magnitude and interrelationships of SDOH to better develop system-based multilevel interventions across the spectrum of care for these neurological conditions.
Less than 10% of the plastics generated globally are recycled, while the rest are incinerated, accumulated in landfills, or leak into the environment. New technologies are emerging to chemically ...recycle waste plastics that are receiving tremendous interest from academia and industry. Chemists and chemical engineers need to understand the fundamentals of these technologies to design improved systems for chemical recycling and upcycling of waste plastics. In this paper, we review the entire life cycle of plastics and options for the management of plastic waste to address barriers to industrial chemical recycling and further provide perceptions on possible opportunities with such materials. Knowledge and insights to enhance plastic recycling beyond its current scale are provided. Outstanding research problems and where researchers in the field should focus their efforts in the future are also discussed.
This paper reviewed the entire life cycle of plastics and options for the management of plastic waste to address barriers to industrial chemical recycling and further provide perceptions on possible opportunities with such materials.
The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion oncogene represents a molecular target in a small subset of non-small cell lung cancers (NSCLCs). ...This fusion leads to constitutive ALK activation with potent transforming activity. In a pivotal phase 1 clinical trial, the ALK tyrosine kinase inhibitor (TKI) crizotinib (PF-02341066) demonstrated impressive antitumor activity in the majority of patients with NSCLC harboring ALK fusions. However, despite these remarkable initial responses, cancers eventually develop resistance to crizotinib, usually within 1 y, thereby limiting the potential clinical benefit. To determine how cancers acquire resistance to ALK inhibitors, we established a model of acquired resistance to crizotinib by exposing a highly sensitive EML4-ALK-positive NSCLC cell line to increasing doses of crizotinib until resistance emerged. We found that cells resistant to intermediate doses of crizotinib developed amplification of the EML4-ALK gene. Cells resistant to higher doses (1 μm) also developed a gatekeeper mutation, L1196M, within the kinase domain, rendering EML4-ALK insensitive to crizotinib. This gatekeeper mutation was readily detected using a unique and highly sensitive allele-specific PCR assay. Although crizotinib was ineffectual against EML4-ALK harboring the gatekeeper mutation, we observed that two structurally different ALK inhibitors, NVPTAE684 and AP26113, were highly active against the resistant cancer cells in vitro and in vivo. Furthermore, these resistant cells remained highly sensitive to the Hsp90 inhibitor 17-AAG. Thus, we have developed a model of acquired resistance to ALK inhibitors and have shown that second-generation ALK TKIs or Hsp90 inhibitors are effective in treating crizotinib-resistant tumors harboring secondary gatekeeper mutations.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Ponatinib was developed to overcome resistance to the tyrosine kinase inhibitors used to treat leukemias that are positive for the Philadelphia chromosome. In a phase 1 study, ponatinib was ...associated with dramatic antitumor effects, with pancreatitis as a dose-limiting toxicity.
The fusion protein product of the Philadelphia chromosome (Ph), BCR-ABL, is a constitutively active tyrosine kinase that gives rise to chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (Ph-positive ALL).
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Three tyrosine kinase inhibitors targeting the BCR-ABL protein (imatinib, nilotinib, and dasatinib) have been approved for the treatment of patients with newly diagnosed chronic-phase CML.
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Resistance to tyrosine kinase inhibitors is the major reason for the failure of therapy in patients with Ph-positive disease. Primary or secondary resistance to imatinib occurs in approximately 20 to 30% of patients with newly diagnosed chronic-phase CML.
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In the treatment of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC), secondary mutations within the ALK kinase ...domain have emerged as a major resistance mechanism to both first- and second-generation ALK inhibitors. This report describes the design and synthesis of a series of 2,4-diarylaminopyrimidine-based potent and selective ALK inhibitors culminating in identification of the investigational clinical candidate brigatinib. A unique structural feature of brigatinib is a phosphine oxide, an overlooked but novel hydrogen-bond acceptor that drives potency and selectivity in addition to favorable ADME properties. Brigatinib displayed low nanomolar IC50s against native ALK and all tested clinically relevant ALK mutants in both enzyme-based biochemical and cell-based viability assays and demonstrated efficacy in multiple ALK+ xenografts in mice, including Karpas-299 (anaplastic large-cell lymphomas ALCL) and H3122 (NSCLC). Brigatinib represents the most clinically advanced phosphine oxide-containing drug candidate to date and is currently being evaluated in a global phase 2 registration trial.
KIT is the major oncogenic driver of gastrointestinal stromal tumors (GIST). Imatinib, sunitinib, and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of ...polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here, we explore the KIT-inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in patients with GIST.
The cellular and in vivo activities of ponatinib, imatinib, sunitinib, and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib-KIT costructure was also determined. The clinical activity of ponatinib was examined in three patients with GIST previously treated with all three FDA-approved agents.
In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nmol/L ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nmol/L. This inhibitory profile could be rationalized on the basis of structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three patients with GIST.
Ponatinib possesses potent activity against most major clinically relevant KIT mutants and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in patients with GIST.
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ...ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
•Ponatinib continued to provide deep, durable responses in heavily pretreated patients with CP-CML.•Tolerability was acceptable in this heavily pretreated population with 5 years of follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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