Meghan Shea

Management of advanced non-small cell lung cancers with known mutations or rearrangements: latest evidence and treatment approaches

Precision oncology is now the evidence-based standard of care for the management of many advanced non-small cell lung cancers (NSCLCs). Expert consensus has defined minimum requirements for routine testing and identification of epidermal growth factor (EGFR) mutations (15% of tumors harbor EGFR exon 19 deletions or exon 21 L858R substitutions) and anaplastic lymphoma kinase (ALK) rearrangements (5% of tumors) in advanced lung adenocarcinomas (ACs). Application of palliative targeted therapies with oral tyrosine kinase inhibitors (TKIs) in advanced/metastatic lung ACs harboring abnormalities in EGFR (gefitinib, erlotinib, afatinib) and ALK/ROS1/MET (crizotinib) has consistently led to more favorable outcomes compared with traditional cytotoxic agents. In addition, mutations leading to resistance to first-line EGFR and ALK TKIs can now be successfully inhibited by soon to be approved third-generation EGFR TKIs (osimertinib, rociletinib) and second-generation ALK TKIs (ceritinib, alectinib). Notably, increasing feasibility, accessibility, and application of molecular profiling technologies has permitted dynamic growth in the identification of actionable driver oncogenes. Emerging genomic aberrations for which TKIs have shown impressive results in clinical trials and expansion of drug labels for approved agents are awaited include ROS1 rearrangements (1–2% of tumors, drug: crizotinib) and BRAF-V600E mutations (1–3% of tumors, drugs: vemurafenib, dafrafenib + trametinib). Evolving genomic events in which TKI responses have been reported in smaller series include MET exon 14 skipping mutations (2–4% of tumors, drug: crizotinib); high-level MET amplification (1–2% of tumors, drug: crizotinib); RET rearrangements (1% of tumors, drug: cabozantinib); and ERBB2 mutations (2–3% of tumors, drug: afatinib), among others. Unfortunately, the most common genomic event in NSCLC, KRAS mutations (25–30% of tumors), is not targetable with approved or in development small molecule inhibitors. Here, we review currently approved, emerging, and evolving systemic precision therapies matched with their driver oncogenes for the management of advanced NSCLC.

Correlation between Classic Driver Oncogene Mutations in EGFR, ALK, or ROS1 and 22C3–PD-L1 ≥50% Expression in Lung Adenocarcinoma

Introduction: Targeted somatic genomic analysis (EGFR, anaplastic lymphoma receptor tyrosine kinase gene [ALK], and ROS1) and programmed death ligand 1 (PD‐L1) tumor proportion score (TPS) determined by immunohistochemistry (IHC) are used for selection of first‐line therapies in advanced lung cancer; however, the frequency of overlap of these biomarkers in routine clinical practice is poorly reported. Methods: We retrospectively probed the first 71 pairs of patients with lung adenocarcinoma from our institution. They were analyzed for PD‐L1 by IHC using the clone 22C3 pharmDx kit (Agilent Technologies, Santa Clara, CA) and evaluated for co‐occurrence of genomic aberrations and clinicopathologic characteristics. Results: Surgical resection specimens, small biopsy (transbronchial or core needle) samples, and cytologic cell blocks (needle aspirates or pleural fluid) were tested. A PD‐L1 TPS of at least ≥50% was seen in 29.6% of tumors. Of 19 tumors with EGFR mutations, ALK fluorescence in situ hybridization positivity, or ROS1 fluorescence in situ hybridization positivity, 18 had a PD‐L1 TPS less than 50% versus only one tumor with a PD‐L1 TPS of at least 50% (p = 0.0073). Tumors with a PD‐L1 TPS of at least 50% were significantly associated with smoking status compared with tumors with a PD‐L1 TPS less than 50% but were not associated with patient sex, ethnicity, tumor stage, biopsy site, or biopsy type/preparation. Conclusions: PD‐L1 IHC can be performed on routine clinical lung cancer specimens. A TPS of at least 50% seldom overlaps with presence of driver oncogenes with approved targeted therapies. Three biomarker‐specified groups of advanced lung adenocarcinomas can now be defined, each paired with a specific palliative first‐line systemic therapy of proven clinical benefit: (1) EGFR/ALK/ROS1‐affected adenocarcinoma paired with a matched tyrosine kinase inhibitor (˜20% of cases), (2) PD‐L1–enriched adenocarcinoma (TPS ≥50%) paired with anti–PD‐1 pembrolizumab (˜30% of cases), and (3) biomarker‐negative (i.e., EGFR/ALK/ROS1/PD‐L1–negative) adenocarcinoma paired with platinum doublet chemotherapy with or without bevacizumab (˜50% of cases).

Lazarus-Type Response to Crizotinib in a Patient with Poor Performance Status and Advanced MET Exon 14 Skipping Mutation–Positive Lung Adenocarcinoma

http://dx.doi.org/10.1016/j.jtho.2016.01.017 Introduction The Cancer Genome Atlas project determined that 4.3% of lung adenocarcinomas harbor MET protooncogene, receptor tyrosine kinase (MET) mutations leading to exon 14 skipping. Preclinical systems support the use of MET tyrosine kinase inhibitors (TKIs), including crizotinib, in tumors with MET exon 14 skipping mutation, and case series of patients with responses to crizotinib have been reported. However, rapid responses leading to improvement in performance status (PS) have not been previously reported, and patients with an Eastern Cooperative Oncology Group (ECOG) PS of 3 or 4 are excluded from registration in MET TKI trials.

PD-L1 testing using the clone 22C3 pharmDx kit for selection of patients with non–small cell lung cancer to receive immune checkpoint inhibitor therapy: are cytology cell blocks a viable option?

Introduction Programmed death ligand 1 (PD-L1) testing of non-small cell lung cancer (NSCLC) specimens helps select patients most likely to respond to immune checkpoint inhibitors. PD-L1 immunohistochemical testing is approved for formalin-fixed, paraffin-embedded (FFPE) surgical pathology specimens; however, the testing performance on FFPE cytology cell block specimens is unknown. Materials and Methods The study is a retrospective cohort analysis of advanced stage NSCLC patients treated at our institution where tumor PD-L1 expression using the clone 22C3 pharmDx kit on the Dako Automated Link 48 platform was performed on either cytology cell block or surgical pathology specimens. Concomitant tumor mutation biomarkers were also collected, as well as tumor clinicopathologic characteristics and clinical outcome data following pembrolizumab treatment. Results 232 patient tumor specimens were tested for PD-L1 expression (94 on cytology cell block and 138 on surgical pathology specimens). No significant differences in PD-L1 tumor proportion score (TPS) were observed between cytology and surgical pathology groups, with both patient cohorts containing ~35% of tumors showing TPS ≥50%. Although few in number, patients with PD-L1 TPS ≥50% based on cytology vs. surgical pathology who received treatment with pembrolizumab demonstrated similar response and disease control rates. Conclusions In this cohort of advanced NSCLC patients with standard of care PD-L1 testing performed on either FFPE cytology cell blocks or FFPE surgical pathology specimens, similar patterns were observed in population tumor PD-L1 expression patterns, concomitant driver mutations, and clinical response to palliative pembrolizumab in selected patients with TPS ≥50%.

Safety and Efficacy of PD-1 Inhibitors Among HIV-Positive Patients With Non–Small Cell Lung Cancer

Introduction: Despite widespread administration of programmed death receptor 1 (PD‐1) pathway inhibitors among individuals with NSCLC, little is known about the safety and activity of these agents among human immunodeficiency virus (HIV) – infected patients since this population has largely been excluded from immunotherapy clinical trials. Methods: Here, we describe seven patients with metastatic NSCLC and HIV infection who were treated with PD‐1 inhibitors nivolumab (two cases) or pembrolizumab (five cases with three in the first‐line setting). Results: Partial responses to immune checkpoint inhibitors were observed in three of seven cases. Among four patients with a programmed death ligand‐1 tumor proportion score ≥50%, three partial responses were observed. All patients received antiretroviral therapy while on anti–PD‐1 treatment. None of the patients experienced grade 3 or 4 immune‐related adverse events or immune reconstitution inflammatory syndrome, and none required PD‐1 inhibitor dose interruption or discontinuation due to toxicity. Conclusions: Nivolumab and pembrolizumab can be safe and effective among patients with NSCLC and HIV. Larger studies will be needed to determine the overall safety and efficacy of immune checkpoint inhibitors among cancer patients with HIV.

Polymyositis as a presentation of advanced carcinoma of Mullerian origin: A case report and discussion

Highlights • Ovarian cancer of Mullerian origin may have paraneoplastic features as a first presenting symptom.• Presentations of polymyositis may be associated with underlying carcinomas of Mullerian origin.• Our patient demonstrated clinical improvement in symptoms after initiation of steroids, IVIG and chemotherapy.

Radiologic and autopsy findings in a case of fatal immune checkpoint inhibitor-associated pneumonitis

Oncologists are increasingly managing drug-induced pneumonitis in lung cancer patients treated with PD-1/PD-L1 immune checkpoint inhibitors. To date only few studies on the topic have described both radiologic and pathologic findings in these patients. Here, we report a fatal case of immune checkpoint inhibitor-associated pneumonitis initially presenting with an organizing pneumonia, but who rapidly developed acute respiratory distress syndrome (confirmed histologically at the time of autopsy). As such, this case illustrates the need for clinicians to maintain a high index of suspicion for immune checkpoint inhibitor associated pneumonitis and have a low threshold to perform CT imaging in any symptomatic patient receiving checkpoint inhibition therapy. CLINICAL PRACTICE POINTS.