Search

BackgroundNo therapies for targeting KRAS mutations in cancer have been approved. The KRAS p.G12C mutation occurs in 13% of non-small-cell lung cancers (NSCLCs) and in 1 to 3% of colorectal cancers and other cancers. Sotorasib is a small molecule that selectively and irreversibly targets KRASG12C.MethodsWe conducted a phase 1 trial of sotorasib in patients with advanced solid tumors harboring the KRAS p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.ResultsA total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma.ConclusionsSotorasib showed encouraging anticancer activity in patients with heavily pretreated advanced solid tumors harboring the KRAS p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

BackgroundEntrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS activity due to its ability to penetrate the blood-brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.MethodsAn integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0-2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients [aged ≤21 years]), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012-000148-88 (ALKA-372-001).FindingsPatients were enrolled in ALKA-372-001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77-18·76). 31 (57%; 95% CI 43·2-70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven [10%] of 68 patients in the NTRK fusion-positive safety population and in 18 [5%] of 355 patients in the overall safety-evaluable population) and anaemia (8 [12%] and 16 [5%]). The most common serious treatment-related adverse events were nervous system disorders (three [4%] of 68 patients and ten [3%] of 355 patients). No treatment-related deaths occurred.InterpretationEntrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.FundingIgnyta/F Hoffmann-La Roche.

Current cell-free DNA (cfDNA) next generation sequencing (NGS) precision oncology workflows are typically limited to targeted and/or disease-specific applications. In advanced cancer, disease burden and cfDNA tumor content are often elevated, yielding unique precision oncology opportunities. We sought to demonstrate the utility of a pan-cancer, rapid, inexpensive, whole genome NGS of cfDNA approach (PRINCe) as a precision oncology screening strategy via ultra-low coverage (~0.01x) tumor content determination through genome-wide copy number alteration (CNA) profiling. We applied PRINCe to a retrospective cohort of 124 cfDNA samples from 100 patients with advanced cancers, including 76 men with metastatic castration-resistant prostate cancer (mCRPC), enabling cfDNA tumor content approximation and actionable focal CNA detection, while facilitating concordance analyses between cfDNA and tissue-based NGS profiles and assessment of cfDNA alteration associations with mCRPC treatment outcomes. Therapeutically relevant focal CNAs were present in 42 (34%) cfDNA samples, including 36 of 93 (39%) mCRPC patient samples harboring AR amplification. PRINCe identified pre-treatment cfDNA CNA profiles facilitating disease monitoring. Combining PRINCe with routine targeted NGS of cfDNA enabled mutation and CNA assessment with coverages tuned to cfDNA tumor content. In mCRPC, genome-wide PRINCe cfDNA and matched tissue CNA profiles showed high concordance (median Pearson correlation = 0.87), and PRINCe detectable AR amplifications predicted reduced time on therapy, independent of therapy type (Kaplan-Meier log-rank test, chi-square = 24.9, p < 0.0001). Our screening approach enables robust, broadly applicable cfDNA-based precision oncology for patients with advanced cancer through scalable identification of therapeutically relevant CNAs and pre-/post-treatment genomic profiles, enabling cfDNA- or tissue-based precision oncology workflow optimization.

Purpose: Identify risk factors for biliary toxicity in patients with colorectal liver metastases who received floxuridine (FUDR) via a surgically implanted hepatic artery infusion pump (HAIP). Describe the incidence of biliary toxicity and evaluate relevant patterns in the biliary toxicity cohort. Methods: A single center, retrospective, case-control study included adult colorectal cancer patients with liver metastases who received at least one cycle of FUDR via a surgically implanted HAIP from 1 January 2017, to 1 October 2021. Patients were excluded if they had incomplete records, cholangiocarcinoma diagnosis, or received concurrent mitomycin and FUDR. Biliary toxicity criteria derived from existing HAIP literature were utilized to determine whether patients experienced biliary toxicity. Multiple variables were compared by univariate statistical analysis between the biliary toxicity and non-biliary toxicity cohorts to identify potential risk factors for development of FUDR-induced biliary toxicity. Results: Out of 50 patients who had a HAIP implanted, 39 met the inclusion criteria. Five of the 39 patients (12.7%) included in the analysis met the pre-specified biliary toxicity criteria. No risk factors for biliary toxicity were identified. All five patients who developed biliary toxicity demonstrated elevations in alkaline phosphatase (ALP) prior to meeting the toxicity criteria. Conclusion: Biliary toxicity remains a significant and therapy-limiting consequence of FUDR administration. Rising ALP may be an early indicator of subsequent biliary toxicity. Future studies with more patients may identify risk factors that can facilitate risk mitigation strategies. [ABSTRACT FROM AUTHOR]

Using pharmacogenetics (PGx) to inform clinical decision making can benefit patients but clinical use of PGx testing has been limited. Existing genetics data obtained in the course of research could be used to identify patients who are suspected, but have not yet been confirmed, to carry clinically actionable genotypes, in whom confirmatory genetic testing could be conducted for highly efficient PGx implementation. Herein, we demonstrate that it is regulatorily and technically feasible to implement PGx by identifying suspected carriers of actionable genotypes within an institutional genetics data repository and conduct confirmatory PGx testing immediately prior to that patient receiving the PGx‐relevant drug, using a case study of DPYD testing prior to fluoropyrimidine chemotherapy. In 2 years since launching this program, ~ 3,000 suspected DPYD carriers have been passively monitored and one confirmed DPYD carrier was prevented from receiving unacceptably toxic fluoropyrimidine treatment, for minimal cost and effort. Now that we have demonstrated the feasibility of this strategy, we plan to transition to PGx panel testing and expand implementation to other genes and drugs for which the evidence of clinical benefit of PGx‐informed treatment is high but PGx testing is not generally conducted. This highly efficient implementation process will maximize the clinical benefits of testing and could be explored at other institutions that have research‐only genetic data repositories to expand the number of patients who benefit from PGx‐informed treatment while we continue to work toward wide‐scale adoption of PGx testing and implementation. [ABSTRACT FROM AUTHOR]

The immune system may discriminate normal cells from abnormal cells, yet some tumors escape immune recognition and destruction mechanisms. Tumor cells may hide from the immune system by not expressing identifying surface proteins, secreting immunosuppressive agents, or expressing proteins the system identifies as normal. The immune system may control virus-related tumors by killing infected cells. Immunotherapy may enhance identification of tumor cells, heighten immune recognition of normal cells, or deliver antibodies that bind to tumors or deliver toxic agents to tumor cells., Malignant tumors express antigens that may stimulate and serve as targets for antitumor immunity. Virally induced tumors usually contain integrated proviral genomes in their cellular genomes and often express viral genome-encoded proteins that may stimulate specific host immune responses. Antigens unique to individual tumors that stimulate specific rejection of transplanted tumors have been demonstrated only in experimental animals. Other tumor antigens that potentially can stimulate immune responses are shared by different tumors. These include products of mutated or rearranged oncogenes or tumor-suppressor genes. Tumors may also overexpress tissue differentiation antigens or embryonic antigens, which also have the potential to be recognized by the immune system. The recent identification of tumor antigens recognized by cytotoxic T cells opens up new possibilities for constructing chemically defined antigens for specific immunotherapy. Treatment of malignant tumors in humans by immunologic approaches, although theoretically attractive, has not yet succeeded on a large scale. Important progress in immunotherapy of cancer is emerging with several different treatment modalities. JAMA. 1997;278:1972-1981

Renal proximal tubule cells were isolated from adult rabbit and grown in cell culture. Cells were characterizing using two approaches, namely recombinant retrovirus and histological processing. Two conclusions were made: first, that adult renal proximal tubule cells have a high capacity to differentiate morphogenically into kidney tubules; second, that these cells have a high capacity for self-renewal following severe ischemic or toxic injury.