Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of ...patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.
The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish ...cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the 'cancer immunity cycle' by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing. The PD-L1-PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.
Abstract Purpose To assess preliminary safety and efficacy results of the anti-programmed cell death ligand-1 (anti-PD-L1) durvalumab in combination with radiotherapy (RT) in an expansion cohort of ...patients included in a phase 1/2 trial at our institution. Patients and methods Data from patients who received concurrent palliative RT with durvalumab (10 mg/kg every 2 weeks via intravenous infusion) were analysed in terms of safety (CTCAE v4.0) and efficacy (RECIST v1.1 and tumour growth rate TGR). Results Between 02/2014 and 04/2016, 10 patients received palliative local irradiation of 15 isolated lesions. Most patients (90%) had received one or more prior lines of systemic therapy for advanced disease. The median duration of exposure to durvalumab was 5.2 months with a median delivery of 11 cycles (range, 4–38 cycles). RT (conformal 3D RT, 79% and intracranial stereotactic RT, 21%) was delivered at a median biologically-effective dose of 28 Gy (range, 6–92), in a median number of five fractions (range, 1–10) and over a median duration of 6 d (range, 1–14). Five patients (50%) reported an irradiation-related adverse event (AE) grade (G) 1 or 2 and one patient had two G2 AEs. The most frequently reported AE (3/6) was G2 mucositis. There was no G3 or more RT-related AEs. All AEs were transient, lasted less than one week, and were manageable by standard guidelines. There was no unexpected AE. On 10/15 in-field (IF) evaluable lesions, the objective response (OR) rate was 60% (complete response, 2/10 and partial response, 4/10) and 4/10 stable disease (SD). All evaluated IF lesions had a TGR decrease resulting in a significant decrease in the TGR between the two periods (before versus after RT; p < 0.01). Outfields disease evaluation retrieved 10/14 SD and 4/14 progressive disease (PD). There was no out-field OR, no abscopal effect and no out-field difference between the two periods according to TGR (p = 0.09). Conclusion In this small data set of patients, concurrent palliative RT with the anti-PD-L1 durvalumab was well tolerated. ClinicalTrials.gov number: NCT01693562 ; EudraCT number: 2012-002206-52.
Purpose Treating solid tumors with cancer immunotherapy (CIT) can result in unconventional responses and overall survival (OS) benefits that are not adequately captured by Response Evaluation ...Criteria In Solid Tumors (RECIST) v1.1. We describe immune-modified RECIST (imRECIST) criteria, designed to better capture CIT responses. Patients and Methods Atezolizumab data from clinical trials in non-small-cell lung cancer, metastatic urothelial carcinoma, renal cell carcinoma, and melanoma were evaluated. Modifications to imRECIST versus RECIST v1.1 included allowance for best overall response after progressive disease (PD) and changes in PD definitions per new lesions (NLs) and nontarget lesions. imRECIST progression-free survival (PFS) did not count initial PD as an event if the subsequent scan showed disease control. OS was evaluated using conditional landmarks in patients whose PFS differed by imRECIST versus RECIST v1.1. Results The best overall response was 1% to 2% greater, the disease control rate was 8% to 13% greater, and the median PFS was 0.5 to 1.5 months longer per imRECIST versus RECIST v1.1. Extension of imRECIST PFS versus RECIST v1.1 PFS was associated with longer or similar OS. Patterns of progression analysis revealed that patients who developed NLs without target lesion (TL) progression had a similar or shorter OS compared with patients with RECIST v1.1 TL progression. Patients infrequently experienced a spike pattern (TLs increase, then decrease) but had longer OS than patients without TL reversion. Conclusion Evaluation of PFS and patterns of response and progression revealed that allowance for TL reversion from PD per imRECIST may better identify patients with OS benefit. Progression defined by the isolated appearance of NLs, however, is not associated with longer OS. These results may inform additional modifications to radiographic criteria (including imRECIST) to better reflect efficacy with CIT agents.
Background
LMB‐100 is an antibody‐toxin conjugate with an antimesothelin Fab linked to a 24‐kilodalton portion of Pseudomonas exotoxin A with mutations that decrease immunogenicity. The objective of ...the current first‐in‐human phase 1 study was to determine the maximum tolerated dose (MTD) and safety in patients with advanced solid tumors expressing mesothelin.
Methods
Cohorts of 1 to 7 patients received intravenous LMB‐100 at 7 dose levels from 40 µg/kg to 250 µg/kg intravenously on days 1, 3, and 5 of a 21‐day cycle.
Results
Of the 25 patients accrued, 17 had mesothelioma, 3 each had ovarian or pancreatic cancer, and 2 patients had gastric cancer. Dose‐limiting toxicities occurred in 2 of 4 patients treated at a dose of 250 µg/kg (capillary leak syndrome) and in 3 of 7 patients treated at a dose of 170 µg/kg (creatinine increase). The MTD of LMB‐100 was 140 µg/kg. Of the 10 patients with mesothelioma who were treated at doses of 170 µg/kg or 140 µg/kg, 8 had stable disease and 2 developed progressive disease. Peak LMB‐100 plasma concentrations were dose‐dependent during cycle 1. The development of antidrug antibodies decreased LMB‐100 blood levels in 8 of 21 patients (38%) who received cycle 2 and 9 of 11 patients (81.8%) who received cycle 3.
Conclusions
The MTD for single‐agent LMB‐100 was found to be 140 µg/kg given on a schedule of every other day for 3 doses every 3 weeks. Although less immunogenic than the first‐generation antimesothelin immunotoxin SS1P, the majority of patients developed antidrug antibodies after 2 cycles, indicating that LMB‐100 has limited antitumor efficacy as a single agent. Phase 2 studies of LMB‐100 plus pembrolizumab currently are ongoing for patients with mesothelioma and lung cancer.
Lay Summary
Mesothelin, a cell surface antigen, is an attractive target for cancer therapy given its limited expression in normal human tissues and high expression in many human cancers. LMB‐100 is a recombinant antimesothelin immunotoxin consisting of a humanized antimesothelin antibody fragment fused to a truncated Pseudomonas exotoxin A.
In the current study, the authors determined the safety, maximum tolerated dose, and pharmacokinetics of LMB‐100, as well as the generation of antidrug antibodies.
Ongoing phase 2 clinical trials are evaluating the combination of LMB‐100 plus pembrolizumab in patients with treatment‐refractory mesothelioma and non–small cell lung cancer.
The mesothelin‐targeting immunotoxin LMB‐100 is well tolerated with manageable adverse effects. Based on the antitumor efficacy observed in preclinical studies, the combination of LMB‐100 plus pembrolizumab currently is being evaluated in the clinic.
Tumor lymphocytic infiltration (TLI) has differing prognostic value among various cancers. The objective of this study was to assess the effect of TLI in lung cancer.
A discovery set (one trial, n = ...824) and a validation set (three trials, n = 984) that evaluated the benefit of platinum-based adjuvant chemotherapy in non-small-cell lung cancer were used as part of the LACE-Bio (Lung Adjuvant Cisplatin Evaluation Biomarker) study. TLI was defined as intense versus nonintense. The main end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs associated with TLI were estimated through a multivariable Cox model in both sets. TLI-histology and TLI-treatment interactions were explored in the combined set.
Discovery and validation sets with complete data included 783 (409 deaths) and 763 (344 deaths) patients, respectively. Median follow-up was 4.8 and 6 years, respectively. TLI was intense in 11% of patients in the discovery set compared with 6% in the validation set (P < .001). The prognostic value of TLI in the discovery set (OS: HR, 0.56; 95% CI, 0.38 to 0.81; P = .002; DFS: HR, 0.59; 95% CI, 0.42 to 0.83; P = .002; SDFS: HR, 0.56; 95% CI, 0.38 to 0.82; P = .003) was confirmed in the validation set (OS: HR, 0.45; 95% CI, 0.23 to 0.85; P = .01; DFS: HR, 0.44; 95% CI, 0.24 to 0.78; P = .005; SDFS: HR, 0.42; 95% CI, 0.22 to 0.80; P = .008) with no heterogeneity across trials (P ≥ .38 for all end points). No significant predictive effect was observed for TLI (P ≥ .78 for all end points).
Intense lymphocytic infiltration, found in a minority of tumors, was validated as a favorable prognostic marker for survival in resected non-small-cell lung cancer.
Tumor mutation load (TML) has been proposed as a biomarker of patient response to immunotherapy in several studies. TML is usually determined by tumor biopsy DNA (tDNA) whole exome sequencing (WES), ...therefore TML evaluation is limited by informative biopsy availability. Circulating cell free DNA (cfDNA) provided by liquid biopsy is a surrogate specimen to biopsy for molecular profiling. Nevertheless performing WES on DNA from plasma is technically challenging and the ability to determine tumor mutation load from liquid biopsies remains to be demonstrated. In the current study, WES was performed on cfDNA from 32 metastatic patients of various cancer types included into MOSCATO 01 (NCT01566019) and/or MATCHR (NCT02517892) molecular triage trials. Results from targeted gene sequencing (TGS) and WES performed on cfDNA were compared to results from tumor tissue biopsy. In cfDNA samples, WES mutation detection sensitivity was 92% compared to targeted sequencing (TGS). When comparing cfDNA-WES to tDNA-WES, mutation detection sensitivity was 53%, consistent with previously published prospective study comparing cfDNA-TGS to tDNA-TGS. For samples in which presence of tumor DNA was confirmed in cfDNA, tumor mutation load from liquid biopsy was correlated with tumor biopsy. Taken together, this study demonstrated that liquid biopsy may be applied to determine tumor mutation load. Qualification of liquid biopsy for interpretation is a crucial point to use cfDNA for mutational load estimation.
Therapies targeting immune checkpoints have recently shown encouraging activity in patients with heavily pretreated advanced non-small cell lung cancer (NSCLC), independently of NSCLC histology or ...mutational status, with low toxicity profiles when used as monotherapy. Objective response rates of approximately 20% have been reported in patients with advanced NSCLC treated with antagonist antibodies targeting the immune checkpoint, programmed death 1 (PD-1) on activated T cells, or its primary ligand, programmed death ligand 1 (PD-L1) expressed within the tumor microenvironment. Response rates appear to be higher in patients with tumor PD-L1 expression documented by immunohistochemistry, although responses have been appreciated in patients with reportedly PD-L1-negative tumor specimens. Antibodies directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), another immunosuppressive T-cell signaling molecule, are also being evaluated in clinical trials, with one randomized phase II trial demonstrating improved immune-related progression-free survival in lung cancer patients when added to standard chemotherapy. Additional clinical trials are combining anti-CTLA-4 antibodies with either anti-PD-1 or anti-PD-L1 antibodies. Combinations of other immune checkpoint antagonists or agonist antibodies with anti-PD-1 or anti-PD-L1 antibodies are also being pursued.
Summary Background The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase ( ALK )-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and ...safety of ceritinib versus platinum-based chemotherapy in these patients. Methods This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK -rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy (cisplatin 75 mg/m2 or carboplatin AUC 5–6 plus pemetrexed 500 mg/m2 every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1–2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov , number NCT01828099. Findings Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6–27·2) in the ceritinib group and 8·1 months (5·8–11·1) in the chemotherapy group (hazard ratio 0·55 95% CI 0·42–0·73; p<0·00001). The most common adverse events were diarrhoea (in 160 85% of 189 patients), nausea (130 69%), vomiting (125 66%), and an increase in alanine aminotransferase (114 60%) in the ceritinib group and nausea (in 97 55% of 175 patients), vomiting (63 36%), and anaemia (62 35%) in the chemotherapy group. Interpretation First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK -rearranged NSCLC. Funding Novartis Pharmaceuticals Corporation.
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