HER2 in Non-Small Cell Lung Cancer: A Review of Emerging Therapies.

Human epidermal growth factor receptor 2 (HER2), a member of the ERBB family of tyrosine kinase receptors, has emerged as a therapeutic target of interest for non-small cell lung cancer (NSCLC) in recent years. Activating HER2 alterations in NSCLC include gene mutations, gene amplifications, and protein overexpression. In particular, the HER2 exon 20 mutation is now a well clinically validated biomarker. Currently, there are limited targeted therapies approved for NSCLC patients with HER2 alterations. This remains an unmet clinical need, as HER2 alterations are present in 7-27% of de novo NSCLC and may serve as a resistance mechanism in up to 10% of EGFR mutated NSCLC. There has been an influx of research on antibody-drug conjugates (ADCs), monoclonal antibodies, and tyrosine kinase inhibitors (TKIs) with mixed results. The most promising therapies are ADCs (trastuzumab-deruxtecan) and novel TKIs targeting exon 20 mutations (poziotinib, mobocertinib and pyrotinib); both have resulted in meaningful anti-tumor efficacy in HER2 mutated NSCLC. Future studies on HER2 targeted therapy will need to define the specific HER2 alteration to better select patients who will benefit, particularly for HER2 amplification and overexpression. Given the variety of HER2 targeted drugs, sequencing of these agents and optimizing combination therapies will depend on more mature efficacy data from clinical trials and toxicity profiles. This review highlights the challenges of diagnosing HER2 alterations, summarizes recent progress in novel HER2-targeted agents, and projects next steps in advancing treatment for the thousands of patients with HER2 altered NSCLC.

Systemic Treatment Patterns and Outcomes in Patients With EGFR Mutated Non-small Cell Lung Cancer and Leptomeningeal Disease.

INTRODUCTION: Leptomeningeal (LM) disease occurs in 9% to 10% of EGFR mutated non-small cell lung cancer (NSCLC) cases. The natural history and optimal systemic treatment strategies for this disease are not well-characterized, particularly in the era of osimertinib. MATERIALS AND METHODS: We identified 54 patients with EGFR mutated NSCLC and LM disease diagnosed between January 3, 2000 to March 31, 2020 and treated at an academic oncology practice in Seattle, Washington. We abstracted demographic, tumor, treatment, and outcome data from the electronic medical record. Univariate Cox models were run to evaluate the association between post-LM disease systemic therapy and overall survival. Differences in LM disease natural history and healthcare utilization between groups were assessed using Student's t test or a chi-squared test. RESULTS: Patients that received osimertinib prior to LM disease had a longer median time to LM disease diagnosis and trended toward better performance status than those that did not. Patients that received any post-LM disease systemic therapy had a lower risk of death relative to those that did not (HR 0.17, P < .001), with a suggestion that osimertinib-containing regimens result in longer median overall survival. Emergency department, hospital and hospice utilization were not associated with receipt of post-LM disease systemic therapy. CONCLUSION: Prior exposure to osimertinib appears to favorably influence the natural history of LM disease. Any systemic therapy after LM disease diagnosis is associated with longer survival and does not increase healthcare utilization. Additional research is needed to assess whether an osimertinib-containing regimen confers a survival benefit after LM disease diagnosis among patients who received prior osimertinib.

Durable Response of Leptomeningeal Disease With Osimertinib and Pemetrexed in EGFR-Mutated Metastatic NSCLC: A Case Report.

Optimal management of EGFR-mutated NSCLC with leptomeningeal (LM) disease progression through EGFR tyrosine kinase inhibitor remains unclear. We present a 39-year-old man with EGFR-mutated NSCLC and LM disease progression through osimertinib 80 mg daily, with subsequent durable radiographic and symptomatic response to systemic pemetrexed in combination with osimertinib. This builds on the limited data evaluating LM disease response to systemic pemetrexed and lends further support to consideration of this treatment strategy.

Impact of Clinical Trial Participation on Survival of Patients with Metastatic Non-Small Cell Lung Cancer.

INTRODUCTION: The impact of clinical trial participation on overall survival is unclear. We hypothesized that enrollment in a therapeutic drug clinical trial is associated with longer overall survival in patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We linked electronic medical record and Washington State cancer registry data to identify patients with metastatic NSCLC diagnosed between January 1, 2007, and December 31, 2015 who received treatment at a National Cancer Institute-designated cancer center. The exposure was trial enrollment. The primary outcome was overall survival, defined as the date of second-line treatment initiation to date of death or last follow-up. We used a conditional landmark analysis starting at the date of second-line treatment initiation and propensity scores with inverse probability of treatment weighting to estimate the association between trial enrollment and survival. RESULTS: Of 215 patients, 40 (19%) participated in a second-line trial. Trial participants were more likely to be never smokers (45% vs 27%), have a good performance status (88% vs 77%) and have EGFR (48% vs 14%) and ALK mutations (8% vs 5%) than nonparticipants. Trial participants had similar overall survival to nonparticipants (HR 1.05; 95% CI, 0.72, 1.53; p = 0.81) after adjusting for sociodemographic and disease characteristics. CONCLUSION: Accounting for the immortal time bias and selection bias, trial participation does not appear detrimental to survival. This finding may be reassuring to patients and supports programs and policies to improve clinical trial access.