Recently, there has been a coordinated effort from academic institutions and the pharmaceutical industry to identify biomarkers that can predict responses to immune checkpoint blockade in cancer. ...Several biomarkers have been identified; however, none has reliably predicted response in a sufficiently rigorous manner for routine use. Here, we argue that the therapeutic response to immune checkpoint blockade is a critical state transition of a complex system. Such systems are highly sensitive to initial conditions, and critical transitions are notoriously difficult to predict far in advance. Nevertheless, warning signals can be detected closer to the tipping point. Advances in mathematics and network biology are starting to make it possible to identify such warning signals. We propose that these dynamic biomarkers could prove to be useful in distinguishing responding from non-responding patients, as well as facilitate the identification of new therapeutic targets for combination therapy.
SummaryBackgroundRationale exists for combined treatment with immune checkpoint inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors in a variety of solid tumours. This study aimed to ...investigate the safety and antitumour effects of pamiparib, an oral PARP 1/2 inhibitor, combined with tislelizumab, a humanised anti-PD-1 monoclonal antibody, in patients with advanced solid tumours and to determine the optimum doses for further evaluation. MethodsWe did a multicentre, open-label, phase 1a/b study at five academic sites or community oncology centres in Australia. We recruited adults (aged ≥18 years) with advanced solid tumours who had received one or more previous lines of therapy, with an Eastern Cooperative Oncology Group performance score of 1 or less, and a life expectancy of 12 weeks or more. Patients were enrolled into one of five dose-escalation cohorts, with dose-escalation done in a 3 + 3 design. Cohorts 1–3 received intravenous tislelizumab 2 mg/kg every 3 weeks plus 20, 40, or 60 mg oral pamiparib twice daily, respectively; cohorts 4 and 5 received 200 mg intravenous tislelizumab every 3 weeks plus 40 or 60 mg oral pamiparib twice daily, respectively. The primary endpoints of the phase 1a dose-escalation part of the study were safety and tolerability, including the occurrence of dose-limiting toxicities and determination of the maximum tolerated dose and recommended phase 2 dose. All primary endpoints were analysed in the safety analysis set, which included all patients who received at least one dose of tislelizumab or pamiparib, with the exception of the occurrence of dose-limiting toxicities, which was analysed in the dose-limiting toxicity analysis set, which included all patients who received at least 90% of the first scheduled tislelizumab dose and at least 75% of scheduled pamiparib doses, or who had a dose-limiting toxicity event during cycle 1. Reported here are results of the phase 1a dose-escalation stage of the trial. This trial is registered with ClinicalTrials.gov, number NCT02660034, and is ongoing. FindingsBetween Jan 22, 2016, and May 16, 2017, we enrolled 49 patients (median age 63 years IQR 55–67), all of whom received at least one dose of pamiparib or tiselzumab. Four patients had dose-limiting toxicities (intractable grade 2 nausea n=1 and grade 3 rash n=1 in cohort 4, and grade 2 nausea and vomiting n=1 and grade 4 immune-mediated hepatitis n=1 in cohort 5). The recommended phase 2 dose was tislelizumab 200 mg every 3 weeks plus pamiparib 40 mg twice daily (the dose given in cohort 4). The most common treatment-emergent adverse events were nausea (in 31 63% of 49 patients), fatigue (26 53%), diarrhoea (17 35%), and vomiting (15 31%). 23 (47%) of 49 patients had immune-related adverse events, of whom nine (39%) had asymptomatic grade 3–4 hepatic immune-related adverse events, which were reversible with corticosteroid treatment. The most common adverse event of grade 3 or worse severity was anaemia (in six 12% patients) and no grade 5 adverse events were reported. Hepatitis or autoimmune hepatitis was the only serious adverse event to occur in two or more patients (in four 8% patients). At a median follow-up of 8·3 months (IQR 4·8–12·8), ten (20%) of 49 patients achieved an objective response according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, including two complete responses and eight partial responses. InterpretationPamiparib with tislelizumab was generally well tolerated and associated with antitumour responses and clinical benefit in patients with advanced solid tumours supporting further investigation of the combination of pamiparib with tislelizumab. FundingBeiGene.
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, providing remarkable clinical responses in some patients. However, the majority of patients do not respond. It is therefore ...crucial both to identify predictive biomarkers of response and to increase the response rates to immune checkpoint therapy. In this review we explore the current literature about the predictive characteristics of the tumor microenvironment and discuss therapeutic approaches that aim to change this toward a milieu that is conducive to response. We propose a personalized biomarker-based adaptive approach to immunotherapy, whereby a sensitizing therapy is tailored to the patient's specific tumor microenvironment, followed by on-treatment verification of a change in the targeted biomarker, followed by immune checkpoint therapy. By incorporating detailed knowledge of the immunological tumor microenvironment, we may be able to sensitize currently non-responsive tumors to respond to immune checkpoint therapy.
Summary Background Dabrafenib, an inhibitor of mutated BRAF, has clinical activity with a manageable safety profile in studies of phase 1 and 2 in patients with BRAFV600 -mutated metastatic melanoma. ...We studied the efficacy of dabrafenib in patients with BRAFV600E -mutated metastatic melanoma. Methods We enrolled patients in this open-label phase 3 trial between Dec 23, 2010, and Sept 1, 2011. This report is based on a data cutoff date of Dec 19, 2011. Patients aged 18 years or older with previously untreated, stage IV or unresectable stage III BRAFV600E mutation-positive melanoma were randomly assigned (3:1) to receive dabrafenib (150 mg twice daily, orally) or dacarbazine (1000 mg/m2 intravenously every 3 weeks). Patients were stratified according to American Joint Committee on Cancer stage (unresectable III+IVM1a+IVM1b vs IVM1c). The primary endpoint was investigator-assessed progression-free survival and was analysed by intention to treat; safety was assessed per protocol. This study is registered with ClinicalTrials.gov , number NCT01227889. Findings Of the 733 patients screened, 250 were randomly assigned to receive either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free survival was 5·1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard ratio (HR) of 0·30 (95% CI 0·18–0·51; p<0·0001). At data cutoff, 107 (57%) patients in the dabrafenib group and 14 (22%) in the dacarbazine group remained on randomised treatment. Treatment-related adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and headache. The most common adverse events with dacarbazine were nausea, vomiting, neutropenia, fatigue, and asthenia. Grade 3–4 adverse events were uncommon in both groups. Interpretation Dabrafenib significantly improved progression-free survival compared with dacarbazine. Funding GlaxoSmithKline.
Summary Background Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients ...with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases. Methods We undertook a phase 1 trial between May 27, 2009, and March 20, 2012, at eight study centres in Australia and the USA. Eligible patients had incurable solid tumours, were 18 years or older, and had adequate organ function. BRAF mutations were mandatory for inclusion later in the study because of an absence of activity in patients with wild-type BRAF. We used an accelerated dose titration method, with the first dose cohort receiving 12 mg dabrafenib daily in a 21-day cycle. Once doses had been established, we expanded the cohorts to include up to 20 patients. On the basis of initial data, we chose a recommended phase 2 dose. Efficacy at the recommended phase 2 dose was studied in patients with BRAF-mutant tumours, including those with non-Val600Glu mutations, in three cohorts: metastatic melanoma, melanoma with untreated brain metastases, and non-melanoma solid tumours. This study is registered with ClinicalTrials.gov , number NCT00880321. Findings We enrolled 184 patients, of whom 156 had metastatic melanoma. The most common treatment-related adverse events of grade 2 or worse were cutaneous squamous-cell carcinoma (20 patients, 11%), fatigue (14, 8%), and pyrexia (11, 6%). Dose reductions were necessary in 13 (7%) patients. No deaths or discontinuations resulted from adverse events, and 140 (76%) patients had no treatment-related adverse events worse than grade 2. Doses were increased to 300 mg twice daily, with no maximum tolerated dose recorded. On the basis of safety, pharmacokinetic, and response data, we selected a recommended phase 2 dose of 150 mg twice daily. At the recommended phase 2 dose in 36 patients with Val600 BRAF-mutant melanoma, responses were reported in 25 (69%, 95% CI 51·9–83·7) and confirmed responses in 18 (50%, 32·9–67·1). 21 (78%, 57·7–91·4) of 27 patients with Val600Glu BRAF-mutant melanoma responded and 15 (56%, 35·3–74·5) had a confirmed response. In Val600 BRAF-mutant melanoma, responses were durable, with 17 patients (47%) on treatment for more than 6 months. Responses were recorded in patients with non-Val600Glu BRAF mutations. In patients with melanoma and untreated brain metastases, nine of ten patients had reductions in size of brain lesions. In 28 patients with BRAF-mutant non-melanoma solid tumours, apparent antitumour activity was noted in a gastrointestinal stromal tumour, papillary thyroid cancers, non-small-cell lung cancer, ovarian cancer, and colorectal cancer. Interpretation Dabrafenib is safe in patients with solid tumours, and an active inhibitor of Val600-mutant BRAF with responses noted in patients with melanoma, brain metastases, and other solid tumours. Funding GlaxoSmithKline.
Abstract
The biological determinants of the response to immune checkpoint blockade (ICB) in cancer remain incompletely understood. Little is known about dynamic biological events that underpin ...therapeutic efficacy due to the inability to frequently sample tumours in patients. Here, we map the transcriptional profiles of 144 responding and non-responding tumours within two mouse models at four time points during ICB. We find that responding tumours display on/fast-off kinetics of type-I-interferon (IFN) signaling. Phenocopying of this kinetics using time-dependent sequential dosing of recombinant IFNs and neutralizing antibodies markedly improves ICB efficacy, but only when IFNβ is targeted, not IFNα. We identify Ly6C
+
/CD11b
+
inflammatory monocytes as the primary source of IFNβ and find that active type-I-IFN signaling in tumour-infiltrating inflammatory monocytes is associated with T cell expansion in patients treated with ICB. Together, our results suggest that on/fast-off modulation of IFNβ signaling is critical to the therapeutic response to ICB, which can be exploited to drive clinical outcomes towards response.
Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in
- and
-mutated cell lines including
-mutant melanoma ...resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (
= 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (
= 15), nausea (
= 12), dermatitis acneiform (
= 10), decreased appetite (
= 7), and maculopapular rash (
= 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.
Advances in cancer immunology have increased the use of immune checkpoint inhibitors in clinical practice, however not all patients respond, and treatment can have severe side-effects. Blood-based ...immunological biomarkers are an attractive method for predicting which patients will respond to therapy, however, reliable biomarkers for immune checkpoint blockade are lacking. This study aimed to identify patients before or early in treatment who would best respond to PD-1 inhibitors. We hypothesised that higher baseline PD-L1 and/or PD-1 on peripheral blood T cells could predict radiological response to PD-1 inhibitors. This pilot prospective cohort study assessed 26 patients with melanoma or non-small cell lung cancer, treated with pembrolizumab, nivolumab, or nivolumab/ipilimumab combined. Response was assessed by RECIST 1.1. Peripheral blood lymphocytes collected at baseline, after one cycle, 10 weeks and at discontinuation of therapy were analysed by flow cytometry. Patients with a higher proportion of PD-L1
T cells at baseline had improved objective response to PD-1 inhibitor therapy, and patients with a lower proportion of regulatory T cells at baseline experienced more immune-related adverse events. These findings may prove useful to assist in clinical decision making. Further studies with larger cohorts are required to validate these findings.
PDF
