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Objective: The results from basket trials utilized to gain regulatory approval of tumor-agnostic therapies can be difficult to interpret without the context of a comparator arm. We describe the role and efficacy of histology-based treatments to provide a historical comparison with larotrectinib., Methods: A systematic literature review (SLR) was conducted on the clinical outcomes of current histology-based standard of care treatments used in non-small cell lung cancer, colorectal cancer, thyroid cancer, gliomas, soft tissue sarcoma, salivary gland cancer, and infantile fibrosarcoma (7 of the 21 tumor histologies in the larotrectinib trials). The review focused on advanced stage/metastatic disease to make a historical comparison with larotrectinib., Results: Larotrectinib provides positive outcomes in both adult and pediatric patients with advanced or metastatic solid tumors known to harbor NTRK gene fusions across a wide range of tumor types. Although the numbers of patients per tumor type are limited, the results of this historical comparison demonstrated that larotrectinib is an efficacious treatment option when naïvely indirectly compared with historical treatments across all 7 reviewed tumor types, especially in comparison to later lines of therapy., Conclusions: Utilizing larotrectinib as a case example across these types of historical comparisons shows that larotrectinib provides positive efficacy outcomes in TRK fusion cancer across tumor histologies known to harbor NTRK gene fusions that may be preferable to historical treatments.

Background: Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours., Methods: Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics (PD) and preliminary efficacy of AZD1208., Results: Sixty-seven patients received treatment: 32 in the AML study over a 120-900 mg dose range, and 25 in the solid tumour study over a 120-800 mg dose range. Nearly all patients (98.5%) in both studies experienced adverse events, mostly gastrointestinal (92.5%). Dose-limiting toxicities included rash, fatigue and vomiting. AZD1208 was not tolerated at 900 mg, and the protocol-defined MTD was not confirmed. AZD1208 increased CYP3A4 activity after multiple dosing, resulting in increased drug clearance. There were no clinical responses; PD analysis showed biological activity of AZD1208., Conclusions: Despite the lack of single-agent clinical efficacy with AZD1208, PIM kinase inhibition may hold potential as an anticancer treatment, perhaps in combination with other agents.

Background: The anticancer multikinase inhibitors (MKIs) are associated with cutaneous adverse events, including hand-foot skin reaction (HFSR), a condition affecting 20%-40% of patients. Symptoms are usually mild, but can evolve into a painful condition that limits function and impacts quality of life (QoL), resulting in shortened cancer treatment duration or intensity. The goal of this study was to systematically review the literature on the prevention and palliation of MKI-associated HFSR, to identify areas for further clinical study, and to provide a foundation for evidence-based guidelines for HFSR management., Methods: Systematic searches of the National Library of Medicine's PubMed database, Cochrane Reviews, BIOSIS, CancerLit, and the American Society of Clinical Oncology website were conducted using search terms for cutaneous toxicities associated with chemotherapeutic agents. Articles were categorized (C) based on type of agent and cutaneous reaction as: C1 (MKI and HFSR); C2 (MKI and other cutaneous toxicity); C3 (other antineoplastic agents and HFSR); and C4, other., Results: Of the 2,069 abstracts screened, 350 (17%) met the criteria for C1-C4, with 56 (16%) coded as C1 with details of HFSR histology, pathogenesis, clinical outcome, QoL impact, and/or prevention and treatment approaches in MKI-treated patients. No randomized, controlled trials (RCTs) on prevention/palliation of HFSR were identified. Anecdotal evidence or expert opinion advocated protective measures, preventive and therapeutic skin care, systemic analgesics for pain, vitamin B(6), and MKI dose modification., Conclusion: No articles containing evidence from RCTs on preventive/palliative approaches to MKI-associated HFSR have been published. Systematic study of optimal treatment strategies for HFSR is needed to advance development of evidence-based treatment guidelines.

Simple Summary: Larotrectinib and entrectinib have never been directly compared in a clinical trial for the treatment of TRK fusion-positive cancer, so a comparison must use separate data from each drug's trials. This study used established statistical methods to balance the patient populations across trials and found that, compared to entrectinib, larotrectinib was associated with a higher overall survival, longer duration of response, and higher complete response rates, and numerically better progression-free survival and similar overall response and safety rates. Based on treatment guidelines, healthcare stakeholders have only one opportunity to decide which TRK inhibitor to select for patients. The results of this analysis can help physicians decide between available treatment options for TRK fusion-positive solid cancer. Information regarding the comparative efficacy of first-generation receptor tyrosine kinase inhibitors is limited. This matching-adjusted indirect comparison (MAIC) evaluated differences in efficacy and safety across larotrectinib and entrectinib trials. Data from clinical trials for larotrectinib (LOXO-TRK-14001 (NCT02122913), SCOUT (NCT02637687), and NAVIGATE (NCT02576431)) and entrectinib (ALKA-372-001 (EudraCT 2012-000148-88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267)) were used. Adults (≥18 years) across trials were matched on available baseline characteristics. Outcomes evaluated included overall response rate (ORR), complete response (CR) rate, duration of response (DoR), overall survival (OS), progression-free survival (PFS), any serious treatment-related adverse events of grade ≥ 3 (TRAEs), and TRAEs leading to treatment discontinuation. The MAIC included 74 patients from entrectinib trials and 117 and 147 patients for the larotrectinib efficacy and safety populations, respectively. Post-matching, larotrectinib was associated with a significantly longer median duration of OS than entrectinib (p < 0.05) and a numerically longer median PFS (p = 0.07). ORR was similar for both agents (p = 0.63). The CR rate was higher (p < 0.05) and the DoR was longer for larotrectinib (p < 0.05). Safety outcomes were comparable and low for both treatments. Results were consistent in sensitivity analyses. These findings suggest favorable efficacy for larotrectinib and comparable safety profiles versus entrectinib in treating tropomyosin receptor kinase fusion cancer. [ABSTRACT FROM AUTHOR]

Background. Skin toxicity (hand-foot syndrome/hand-foot skin reaction, HFS/R) related to antineoplastic therapy is a significant issue in oncology practice, with potentially large impacts on health-related quality of life (HRQL). Materials and Methods. Apatient-reported questionnaire, the hand-foot skin reaction and quality of life (HF-QoL) questionnaire was developed to measure the HFS/R symptoms associated with cancer therapeutic agents and their effect on daily activities. The validity and reliability of the HF-QoL questionnaire was tested in a randomized trial of capecitabine with sorafenib/placebo in 223 patients with locally advanced/metastatic breast cancer. Other measures completed included patient ratings of condition severity, the Functional Assessment of Cancer Therapy-Breast cancer (FACT-B), and the clinician-rated National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 3.0, hand-foot skin reaction grade. The psychometric properties of the HFQoL tested included structural validity, internal consistency, construct validity, discriminant validity, and responsiveness. Finally, the minimal clinically important difference (MCID) was estimated. Results. The HF-QoL instrument comprises a 20-item symptom scale and an 18-item daily activity scale. Each scale demonstrated excellent measurement properties and discriminated between NCI-CTCAE grade and patient-rated condition severity with large effect sizes. The daily activity scale had excellent internal consistency and correlated with the FACT-B and HF-QoL symptom scores. Both HF-QoL scale scores increased linearly with increasing patient-rated condition severity. The MCIDs were estimated as 5 units for daily activities and 8 units for symptoms mean scores. Conclusion. The HF-QoL was sensitive to symptoms and HRQL issues associated with HFS/R among participants treated with capecitabine with and without sorafenib.The HF-QoL appears suitable for assessing the HRQL impairment associated with HFS/R to cancer therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Clinical trials for new drugs to treat rare diseases are difficult to evaluate due to the limited patient population available for recruitment. Growth modulation index (GMI) is a very useful tool in these instances, as this calculation compares the patient's outcome on the current drug to the same patient's outcome on their most recent prior therapy, using the patient as their own control. GMI is the ratio of progression-free survival on the current therapy to time to progression on the last prior line of therapy and offers a method to determine if the investigational drug provides a benefit compared to the patient's last prior treatment. Using a GMI ≥ 1.33 as the threshold of meaningful clinical activity, we found that larotrectinib, a tropomyosin receptor kinase (TRK) inhibitor approved to treat patients with TRK fusion cancer, improves progression-free survival for most patients with TRK fusion cancer compared with prior therapy. 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 < 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. [ABSTRACT FROM AUTHOR]