Immunotherapy has significantly altered the treatment landscape for many cancers, including non-small cell lung cancer (NSCLC). Currently approved immuno-oncology agents for lung cancer are aimed at the reversal of immune checkpoints, programmed death protein-1 (PD-1) and programmed death ligand-1 (PD-L1). Although responses to checkpoint inhibitors are encouraging, and in some cases durable, these successes are not universal among all treated patients. In order to optimize our treatment approach utilizing immunotherapy, we must better understand the interaction between cancer and the immune system and evasion mechanisms. In this review, we will provide an overview of the immune system and cancer, and review novel therapies that promote tumor antigen release for immune system detection, activate the effector T-cell response, and reverse inhibitory antitumor signals.

Malignant pleural mesothelioma (MPM) is a heterogeneous cancer composed of distinct molecular and pathologic subtypes. Unfortunately, MPM is aggressive, and current therapies for advanced, unresectable disease remain limited to cytotoxic chemotherapy and immunotherapy. Our understanding of the genomic landscape of MPM is steadily growing, while the discovery of effective targeted therapies in MPM has advanced more slowly than in other solid tumors. Given the prevalence of alterations in tumor suppressor genes in MPM, it has been challenging to identify actionable targets. However, efforts to characterize the genetic signatures in MPM over the last decade have led to a range of novel targeted therapeutics entering early-phase clinical trials. In this review, we discuss the advancements made thus far in targeted systemic therapies in MPM and the future direction of targeted strategies in patients with advanced MPM.

Immunotherapy plays a central role in the treatment of NSCLC and biomarkers predicting response to ICIs are valuable therapeutic tools. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) is integral in therapy selection as its positive predictive nature to ICIs in the metastatic setting is well documented. Tumor mutational burden (TMB) has undergone much study and, while results are somewhat mixed, there is evidence for its positive predictive value with ICI use. Additional markers such as tumor-infiltrating lymphocytes (TILs), gene expression profiling (GEP), mismatch repair (MMR) and microsatellite instability (MSI), somatic mutations, neutrophil to leukocyte ratio (NLR), smoking history, medication history, and immune-related adverse event (irAE) development can further guide clinicians.

Lorlatinib is an oral third-generation inhibitor of anaplastic lymphoma kinase (ALK) with activity in advanced ALK-positive non-small cell lung cancer (NSCLC) in both the first and subsequent line setting. Superior systemic and intracranial efficacy of lorlatinib over crizotinib, a first-generation ALK tyrosine kinase inhibitor (TKI), in treatment-naïve patients with advanced ALK-positive NSCLC was demonstrated by the phase 3 CROWN trial. Lorlatinib retains anti-tumor effect against single and some compound ALK resistance mutations after disease progression on first- and second-generation ALK TKIs. Currently, alectinib, brigatinib, ceritinib, crizotinib and lorlatinib are approved for treatment of advanced ALK-positive NSCLC. However, no head-to-head studies have directly compared lorlatinib to second-generation ALK inhibitors. Herein, we aim to provide an overview of the efficacy and safety of lorlatinib and discuss where lorlatinib stands in the therapeutic approach to advanced ALK-positive NSCLC.

Objective

To describe a clinical approach to and outcomes of IVF in reproductive-aged cancer survivors receiving targeted cancer therapies.

Design

Case report.

Setting

Not applicable.

Patient(s)

The first case is of a female patient with metastatic lung cancer receiving long-term crizotinib, an anaplastic lymphoma kinase inhibitor. The second case is of a female patient with metastatic colon cancer receiving long-term denosumab, a RANKL antibody. Both patients presented desiring fertility.

Intervention(s)

In vitro fertilization.

Main outcome measure(s)

Live birth and embryo banking.

Result(s)

The potential impact of targeted therapy on oocytes and pregnancy was investigated via literature review and pharmaceutical company inquiries. After oncologic, fertility, and psychological counseling, both survivors underwent ovarian stimulation, IVF, and preimplantation genetic screening. One couple achieved live births of dizygotic twins via gestational surrogacy. The second couple froze one euploid blastocyst for future fertility. Both survivors are stable from their cancer standpoints.

Conclusion(s)

Successful fertility treatments are possible in the context of exposure to crizotinib and denosumab.

Background

Monitoring circulating tumor cells (CTC) has been shown to be prognostic in most solid malignancies. There is no CTC assay in clinical use for lung cancer therapy monitoring due to inconclusive clinical utility data. Limited data has been published outside of the standard CTC enumerations, regarding clinical significance of phenotypic heterogeneity of CTCs in late stage NSCLC and its ability to correlate with treatment outcomes.

Methods

In 81 patients with stage IV NSCLC, multiple timepoints for CTC analysis were collected after initiation of treatment across 139 lines of therapy using single cell high definition diagnostic pathology imaging of all nucleated cells from 362 peripheral blood samples as a liquid biopsy.

Results

We analyzed the subset of 25 patients with complete time series data, totaling 117 blood samples, to determine the significance of HD-CTC kinetics during the initiation of treatment. These kinetics follow three distinct patterns: an increase in HD-CTCs with therapy (mean + 118.40 HD-CTCs/mL), unchanged HD-CTCs numbers (stable; mean 0.54 HD-CTCs/mL), and a decrease in HD-CTCs numbers (mean - 81.40 HD-CTCs/mL). Patients with an increasing CTC count during the first 3 months post initiation of new treatment had a better PFS and OS compared to the other groups. There was weak correlation between the absolute number of HD-CTCs at a single time point of therapy and patient outcomes (OS p value = 0.0754). In the whole cohort of 81 patients, HD-CTCs were detected in 51 (63%) patients at initiation of therapy with a median of 2.20 (range 0-509.20) and a mean of 26.21 HD-CTCs/mL (± 15.64).

Conclusions

CTCs are identifiable in most patients with stage IV NSCLC. While absolute HD-CTC counts do not correlate with prognosis, the changes in CTC counts were predictive of survival in patients with metastatic lung cancer receiving chemotherapy. The level and dynamics of CTCs indicate very different biological and pharmacological phenomena at different stages of disease and timepoints of treatment, highlighting the complex role of CTCs in cancer research and clinical management.

BACKGROUND:With the advent of immune-checkpoint inhibitor (ICI) therapy (anti-CTLA-4, anti-PD-1), immune-related adverse events such as thyroid function test abnormalities (TFTAs) are common, with a reported incidence range of 2%-15% depending upon the ICI used. The aim of this study is to describe the incidence of TFTAs retrospectively in patients who received ICI therapy. METHODS:A total of 285 patients were reviewed (178 male, 107 female; 16-94 years of age), of whom 218 had no baseline TFTAs, 61 had baseline TFTAs, and 6 had a history of thyroidectomy (excluded). At least one dose of ipilimumab and/or nivolumab or pembrolizumab was administered. Post-ICI therapy TFTAs were classified according to standard definitions of thyroid conditions when possible. RESULTS:A total of 35% (76/218) patients had new-onset TFTAs on ICI therapy. Of note, 70.5% (43/61) had baseline TFTAs that were exacerbated by ICI therapy. The median times to new-onset or exacerbated baseline TFTA were 46 and 33 days, respectively. Of note, 64.5% (20/31) of patients on both ipilimumab and nivolumab had new-onset TFTAs, compared with 31.3% (15/48) on ipilimumab, 31.5% (28/89) on nivolumab, and 26% (13/50) on pembrolizumab. CONCLUSION:The incidence of TFTAs with ICI therapy was higher than previously reported. Patients with baseline TFTAs and/or who were receiving ipilimumab and nivolumab combination therapy had a higher incidence of TFTAs than patients receiving single-agent ICI therapy. We recommend more frequent evaluation of thyroid function in the first 8 weeks, especially in patients with baseline TFTAs. IMPLICATIONS FOR PRACTICE:Increased use of immune-checkpoint inhibitors in cancer treatment has highlighted the importance of monitoring for and treating immune-related adverse events. This study was conducted to assess the incidence of thyroid function test abnormalities retrospectively in patients with cancer on immune-checkpoint inhibitors, which is not known exactly. This study is unique in that it included patients with a variety of histologic subtypes of cancer and also followed the clinical course of patients with baseline thyroid function test abnormalities. This study can help make oncologists aware that the incidence of thyroid function test abnormalities is higher than anticipated. Early identification and timely treatment can help ameliorate symptoms for patients and improve their overall quality of life.

Background

Small cell lung cancer (SCLC) transformation is one of the mechanisms of drug resistance to tyrosine kinase inhibitors (TKIs) in advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) and represents an increasingly recognized clinical dilemma.

Methods

We performed a retrospective review of 964 cases at the University of California, San Diego of patients with EGFR sensitizing mutations. Nine patients had a biopsy-confirmed small cell transformation. The unique gene alterations and clinicopathologic features were collected and analyzed.

Results

Nine cases (9/964, 0.9%) were identified, all with stage IV adenocarcinoma (ADC) at diagnosis, 7 were poorly differentiated, and 7 had an EGFR exon 19 deletion. All nine patients had tumor protein p53 (TP53) mutation. Among seven cases that had next-generation sequencing (NGS), 5 harbored retinoblastoma 1 (RB1) loss. WNK lysine deficient protein kinase 1 (WNK1) mutation was found in two patients that had longer survival. The median time from the initial diagnosis to transformation was 22.7 months (IQR: 15.1-25.1). After small cell transformation on EGFR inhibition, all patients were treated with etoposide/platinum, conferring a median progression-free survival (PFS) of 3.2 months (IQR, 2.2-6.5 months) and post-chemotherapy survival of 8.6 months (IQR, 4.0-19.0 months). Six patients, as they retained the initial EGFR mutations, resumed (did so after terminating chemotherapy)/continued (did so concomitantly with chemotherapy) TKIs with a median duration of 13.8 months (IQR, 3.8-27.7 months). Two patients received immunotherapy but had no benefit.

Conclusions

In our series, most patients with small cell transformation had poorly differentiated adenocarcinomas at baseline. RB1 loss was not universal in transformed patients in this series, though TP53 mutation was present in all tumor samples. WNK1 mutation may be a new resistance mechanism to TKIs that may be associated with improved survival.

Purpose

Fusions that involve neurotrophic-tropomyosin receptor kinase (NTRK) genes are known drivers of oncogenesis. Therapies that target these ultra-rare, constitutionally active NTRK fusions have been remarkably effective. Herein, we analyze the prevalence of the full array of NTRK alterations-fusions, mutations, copy number alterations, and increased transcript expression-in diverse adult and pediatric tumor types to understand the landscape of NTRK aberrations in cancer.

Methods

We assessed 13,467 samples available from The Cancer Genome Atlas (adult tumors) and the St Jude PeCan database (pediatric tumors) for the prevalence of NTRK fusions, as well as associated genomic and transcriptomic co-aberrations in different tumor types.

Results

NTRK fusions were observed in 0.31% of adult tumors and in 0.34% of pediatric tumors. The most common gene partners were NTRK3 (0.16% of adult tumors) followed by NTRK1 (0.14% of pediatric tumors). NTRK fusions were found more commonly in pediatric melanoma (11.1% of samples), pediatric glioma (3.97%), and adult thyroid cancers (2.34%). Additional genomic and transcriptomic NTRK alterations- mutation, amplification, and mRNA overexpression-occurred in 14.2% of samples, whereas the frequency of alterations that implicated NTRK ligands and the NTRK co-receptor (p75NTR) ranged from 3.8% to 5.4%. Among 31 adult samples carrying NTRK fusions, co-alterations occurred often and usually involved the downstream phosphoinositide-3-kinase signaling pathway, cell-cycle machinery, other tyrosine-kinase receptors, and mitogen-activated protein kinase signals.

Conclusion

Whereas NTRK fusions are exceedingly rare, other NTRK abnormalities affect 14% of patients with cancer. Affecting these alterations has not yet been achievable in cancer. Genomic co-alterations occur frequently with NTRK fusions, but it is not known if co-targeting them can attenuate primary or secondary resistance to NTRK inhibitors.

PURPOSE: Clinical trial adverse event (AE) data are increasingly complex and high-dimensional, especially for trials evaluating novel targeted agents and immunotherapies. Standard approaches to summarize and analyze AEs remain generally tabular, failing to describe the nature of AEs. Novel dynamic and data visualization methods are needed to enable a more comprehensive assessment of the overall toxicity profile of treatments. METHODS: We developed methods for visualizing the numerous categorizations and types of AEs along with a dynamic approach to better reflect its highly dimensional nature without sacrificing the reporting of rare events. Circular plots displaying the proportion of maximal-grade AEs by system organ classes (SOCs) and butterfly plots displaying the proportion of AEs by severity for each AE term were developed to enable comparisons of AE patterns by treatment arm. These approaches were applied to a randomized phase III trial (S1400I; ClinicalTrials.gov identifier: NCT02785952) comparing nivolumab with nivolumab plus ipilimumab in patients with stage IV squamous non-small-cell lung cancer. RESULTS: Our visualizations revealed that patients randomly assigned to nivolumab and ipilimumab had higher rates of grade 3 or higher AEs compared with nivolumab alone for several SOCs, including musculoskeletal (5.6% v 0.8%), skin (5.6% v 0.8%), vascular (5.6% v 1.6%), and cardiac (4% v 1.6%) toxicities. They also suggested a pattern of higher prevalence of moderate GI and endocrine toxicities and showed that although the rates of cardiac and neurologic toxicities were similar, the types of events were discordant. CONCLUSION: The graphical approaches we proposed enable a more comprehensive and intuitive evaluation of toxicity types by treatment groups, which is not apparent in tabular and descriptive reporting methods.