The phosphoinositide 3-kinase (PI3K) pathway plays an integral role in many cellular processes and is frequently altered in cancer, contributing to tumor growth and survival. Small molecule ...inhibitors have been developed that target the three major nodes of this pathway: PI3K, AKT, and mammalian target of rapamycin. However, because oncogenic PI3K pathway activation is achieved in diverse, potentially redundant ways, the clinical efficacy of these inhibitors as monotherapies has, so far, been limited, despite demonstrating promising preclinical activity. Moreover, pathway activation is associated with resistance to other therapies; thus, in combination, PI3K pathway inhibitors could restore therapeutic sensitivity to these agents. To maximize therapeutic benefit, drug combinations and schedules must be explored to identify those with the highest efficacy and lowest toxicity overlap. In addition, defining appropriate patient subpopulations, for both monotherapy and drug combinations, will be important. However, identifying predictive biomarkers remains a challenge.
Summary Background In the randomised, parallel assignment, open-label, phase 3 TH3RESA study, progression-free survival was significantly longer with trastuzumab emtansine versus treatment of ...physician's choice in previously treated patients with HER2-positive advanced breast cancer. We report results from the final overall survival analysis of the TH3RESA trial. Methods Eligible patients for the TH3RESA trial were men and women (aged ≥18 years) with centrally confirmed HER2-positive advanced breast cancer previously treated with both trastuzumab and lapatinib (advanced setting) and a taxane (any setting) and with progression on two or more HER2-directed regimens in the advanced setting. Patients had to have an Eastern Cooperative Oncology Group performance status of 0–2, left ventricular ejection fraction of at least 50%, and adequate organ function. Patients were randomly assigned (2:1) by an interactive voice and web response system with permuted block randomisation in blocks of six to receive trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or treatment of physician's choice administered per local practice. Randomisation was stratified by world region, number of previous regimens for advanced breast cancer, and presence of visceral disease. On Sept 12, 2012, the study protocol was amended to allow patients with disease progression to crossover from treatment of physician's choice to trastuzumab emtansine. The coprimary endpoints for TH3RESA were investigator-assessed progression-free survival and overall survival in the intention-to-treat population. We report results from a preplanned second interim analysis of overall survival, which was planned for when approximately 67% (n=330) of 492 expected deaths had occurred. This study is registered with ClinicalTrials.gov , number NCT01419197. Findings Between Sept 14, 2011, and Nov 19, 2012, 602 patients were enrolled from 146 centres in 22 countries and randomly assigned to trastuzumab emtansine (n=404) or treatment of physician's choice (n=198). At data cutoff (Feb 13, 2015), 93 (47%) of 198 patients in the physician's choice group had crossed over to trastuzumab emtansine. Overall survival was significantly longer with trastuzumab emtansine versus treatment of physician's choice (median 22·7 months 95% CI 19·4–27·5 vs 15·8 months 13·5–18·7; hazard ratio 0·68 95% CI 0·54–0·85; p=0·0007). As the stopping boundary for overall survival was crossed, this overall survival analysis serves as the final and confirmatory analysis of overall survival and the study was terminated according to the protocol. The incidence of grade 3 or worse adverse events was 161 (40%) of 403 patients in the trastuzumab emtansine group and 87 (47%) of 184 patients in the treatment of physician's choice group. Of the most common grade 3 or worse adverse events (affecting ≥2% of patients in either group), those with a 3% or greater difference in incidence between groups that were more frequent with treatment of physician's choice than with trastuzumab emtansine were diarrhoea (three 1% of 403 patients in the trastuzumab emtansine group vs eight 4% of 184 patients in the treatment of physician's choice group), neutropenia (ten 3% vs 29 16%), and febrile neutropenia (one <1% vs seven 4%); whereas those that were more frequent with trastuzumab emtansine were thrombocytopenia (24 6% of 403 patients vs five 3% of 184 patients) and haemorrhage of any type (17 4% of 403 vs one <1% of 184). Serious adverse events were reported in 102 (25%) of 403 patients in the trastuzumab emtansine group and 41 (22%) of 184 in the physician's choice group. Deaths from adverse events were reported in three patients (2%) in the physician's choice group (of which one was judged to be treatment related) and nine (2%) in the trastuzumab emtansine group (of which three were judged to be treatment related). Interpretation In patients who had progressed on two or more HER2-directed regimens, trastuzumab emtansine treatment resulted in a significant improvement in overall survival versus treatment of physician's choice. These data further solidify the role of trastuzumab emtansine in the management of patients with previously treated HER2-positive advanced breast cancer, and validate HER2 as a therapeutic target even after multiple lines of previous therapy. Funding F Hoffman-La Roche/Genentech.
Summary Background Patients with progressive disease after two or more HER2-directed regimens for recurrent or metastatic breast cancer have few effective therapeutic options. We aimed to compare ...trastuzumab emtansine, an antibody–drug conjugate comprising the cytotoxic agent DM1 linked to trastuzumab, with treatment of physician's choice in this population of patients. Methods This randomised, open-label, phase 3 trial took place in medical centres in 22 countries across Europe, North America, South America, and Asia-Pacific. Eligible patients (≥18 years, left ventricular ejection fraction ≥50%, Eastern Cooperative Oncology Group performance status 0–2) with progressive HER2-positive advanced breast cancer who had received two or more HER2-directed regimens in the advanced setting, including trastuzumab and lapatinib, and previous taxane therapy in any setting, were randomly assigned (in a 2:1 ratio) to trastuzumab emtansine (3·6 mg/kg intravenously every 21 days) or physician's choice using a permuted block randomisation scheme by an interactive voice and web response system. Patients were stratified according to world region (USA vs western Europe vs other), number of previous regimens (excluding single-agent hormonal therapy) for the treatment of advanced disease (two to three vs more than three), and presence of visceral disease (any vs none). Coprimary endpoints were investigator-assessed progression-free survival (PFS) and overall survival in the intention-to-treat population. We report the final PFS analysis and the first interim overall survival analysis. This study is registered with ClinicalTrials.gov , number NCT01419197. Findings From Sept 14, 2011, to Nov 19, 2012, 602 patients were randomly assigned (404 to trastuzumab emtansine and 198 to physician's choice). At data cutoff (Feb 11, 2013), 44 patients assigned to physician's choice had crossed over to trastuzumab emtansine. After a median follow-up of 7·2 months (IQR 5·0–10·1 months) in the trastuzumab emtansine group and 6·5 months (IQR 4·1–9·7) in the physician's choice group, 219 (54%) patients in the trastuzumab emtansine group and 129 (65%) of patients in the physician's choice group had PFS events. PFS was significantly improved with trastuzumab emtansine compared with physician's choice (median 6·2 months 95% CI 5·59–6·87 vs 3·3 months 2·89–4·14; stratified hazard ratio HR 0·528 0·422–0·661; p<0·0001). Interim overall survival analysis showed a trend favouring trastuzumab emtansine (stratified HR 0·552 95% CI 0·369–0·826; p=0·0034), but the stopping boundary was not crossed. A lower incidence of grade 3 or worse adverse events was reported with trastuzumab emtansine than with physician's choice (130 events 32% in 403 patients vs 80 events 43% in 184 patients). Neutropenia (ten 2% vs 29 16%), diarrhoea (three <1% vs eight 4%), and febrile neutropenia (one <1% vs seven 4%) were grade 3 or worse adverse events that were more common in the physician's choice group than in the trastuzumab emtansine group. Thrombocytopenia (19 5% vs three 2%) was the grade 3 or worse adverse event that was more common in the trastuzumab emtansine group. 74 (18%) patients in the trastuzumab emtansine group and 38 (21%) in the physician's choice group reported a serious adverse event. Interpretation Trastuzumab emtansine should be considered as a new standard for patients with HER2-positive advanced breast cancer who have previously received trastuzumab and lapatinib. Funding Genentech.
Trastuzumab emtansine (T-DM1) is a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate, composed of trastuzumab, a stable thioether linker, and the potent cytotoxic agent ...DM1 (derivative of maytansine), in phase III development for HER2-positive cancer. Extensive analysis of T-DM1 in preclinical studies has shown that T-DM1 combines the distinct mechanisms of action of both DM1 and trastuzumab, and has antitumor activity in trastuzumab- and lapatinib-refractory experimental models. Clinically, T-DM1 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1, with no evidence of DM1 accumulation following repeated T-DM1 doses. Although a few covariates were shown to affect interindividual variability in T-DM1 exposure and clearance in population-pharmacokinetics analyses, the magnitude of their effect on T-DM1 exposure was not clinically relevant. Phase I and phase II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel, and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are recruiting patients: EMILIA (NCT00829166) is evaluating T-DM1 compared with lapatinib plus capecitabine, and MARIANNE (NCT01120184) is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Additional combinations of T-DM1 (for example, with GDC-0941) and additional disease settings (early-stage HER2-positive breast cancer) are also under investigation. Data from the phase III trials and other studies of T-DM1-containing agents are eagerly awaited.
For many years, oncology phase I trials have been referred to as 'toxicity trials' and have been believed to have low clinical utility other than that of establishing the adverse event profile of ...novel therapeutic agents. The traditional distinction of clinical trials into three phases has been challenged in the past few years by the introduction of targeted therapies and immunotherapies into the routine management of patients with cancer. This transformation has especially affected early phase trials, leading to the current situation in which response rates are increasingly reported from phase I trials. In this Perspectives, we highlight key elements of phase I trials and discuss how each one of them contributes to a new paradigm whereby preliminary measurements of the clinical benefit from a novel treatment can be obtained in current phase I trials, which can therefore be considered to have a therapeutic intent.
Targeted therapy directed against oncogenic BRAF mutations and immune checkpoint inhibitors have transformed melanoma therapy over the past decade and prominently improved patient outcomes. However, ...not all patients will respond to targeted therapy or immunotherapy and many relapse after initially responding to treatment. This unmet need presents two major challenges. First, can we elucidate novel oncogenic drivers to provide new therapeutic targets? Second, can we identify patients who are most likely to respond to current therapeutic strategies in order to both more accurately select populations and avoid undue drug exposure in patients unlikely to respond? In an effort to evaluate the current state of the field with respect to these questions, we provide an overview of some common oncogenic mutations in patients with metastatic melanoma and ongoing efforts to therapeutically target these populations, as well as a discussion of biomarkers for response to immune checkpoint inhibitors—including tumor programmed death ligand 1 expression and the future use of neoantigens as a means of truly personalized therapy. This information is becoming important in treatment decision making and provides the framework for a treatment algorithm based on the current landscape in metastatic melanoma.
A wide variety of human malignancies exhibit sustained c-Met stimulation, overexpression, or mutation, including carcinomas
of the breast, liver, lung, ovary, kidney, and thyroid. Notably, activating ...mutations in c-Met have been positively identified
in patients with a particular hereditary form of papillary renal cancer, directly implicating c-Met in human tumorigenesis.
Aberrant signaling of the c-Met signaling pathway due to dysregulation of the c-Met receptor or overexpression of its ligand,
hepatocyte growth factor (HGF), has been associated with an aggressive phenotype. Extensive evidence that c-Met signaling
is involved in the progression and spread of several cancers and an enhanced understanding of its role in disease have generated
considerable interest in c-Met and HGF as major targets in cancer drug development. This has led to the development of a variety
of c-Met pathway antagonists with potential clinical applications. The three main approaches of pathway-selective anticancer
drug development have included antagonism of ligand/receptor interaction, inhibition of the tyrosine kinase catalytic activity,
and blockade of the receptor/effector interaction. Several c-Met antagonists are now under clinical investigation. Preliminary
clinical results of several of these agents, including both monoclonal antibodies and small-molecule tyrosine kinase inhibitors,
have been encouraging. Several multitargeted therapies have also been under investigation in the clinic and have demonstrated
promise, particularly with regard to tyrosine kinase inhibition.
Overall survival among patients with advanced-stage
KRAS
G12C
non–small-cell lung cancer (NSCLC) or colorectal cancer is approximately 1 to 2 years; this startling statistic has fueled nearly four ...decades of research dedicated to the search for a
KRAS
-targeted drug.
1,2
Because RAS has picomolar affinity for guanosine triphosphate (GTP) and intracellular GTP concentrations are exceedingly high, early strategies to find compounds that preferentially bind to the RAS–GTP pocket failed. Other strategies have attempted to interfere with RAS activation by preventing its membrane localization or by inhibiting downstream kinase signaling, but these also failed because of resistance stemming from compensatory signaling. Renewed interest . . .
Pre-analytical factors can significantly affect circulating cell-free DNA (cfDNA) analysis. However, there are few robust methods to rapidly assess sample quality and the impact of pre-analytical ...processing. To address this gap and to evaluate effects of DNA extraction methods and blood collection tubes on cfDNA yield and fragment size, we developed a multiplexed droplet digital PCR (ddPCR) assay with 5 short and 4 long amplicons targeting single copy genomic loci. Using this assay, we compared 7 cfDNA extraction kits and found cfDNA yield and fragment size vary significantly. We also compared 3 blood collection protocols using plasma samples from 23 healthy volunteers (EDTA tubes processed within 1 hour and Cell-free DNA Blood Collection Tubes processed within 24 and 72 hours) and found no significant differences in cfDNA yield, fragment size and background noise between these protocols. In 219 clinical samples, cfDNA fragments were shorter in plasma samples processed immediately after venipuncture compared to archived samples, suggesting contribution of background DNA by lysed peripheral blood cells. In summary, we have described a multiplexed ddPCR assay to assess quality of cfDNA samples prior to downstream molecular analyses and we have evaluated potential sources of pre-analytical variation in cfDNA studies.
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