Intravenous immunoglobulin is safe and effective in controlling pre-existing paraneoplastic neuromuscular diseases in cancer patients treated with immune checkpoint inhibitors: two case reports and literature review.

Immune checkpoint inhibitors cause rare but potentially fatal neuromuscular complications, leading to a concern to use these agents in cancer patients with pre-existing autoimmune or inflammatory neuromuscular diseases. We report two such patients with paraneoplastic dermatomyositis and "seronegative" paraneoplastic demyelinating neuropathy, respectively, who have been successfully treated with immune checkpoint inhibitor monotherapy as well as maintenance intravenous immunoglobulin. While controlling the paraneoplastic or autoimmune neuromuscular diseases, the use of intravenous immunoglobulin did not compromise the anti-cancer effect of immune checkpoint inhibitor.

Hospitalized cancer patients with comorbidities and low lymphocyte counts had poor clinical outcomes to immune checkpoint inhibitors.

Background: Immune checkpoint inhibitor (ICI) therapy has improved survivals with a favorable toxicity profile in a variety of cancer patients. We hypothesized that hospitalized cancer patients who have acute or chronic comorbidities may have suppressed immune systems and poor clinical outcomes to ICIs. The objective of this study was to explore clinical outcomes and predictive factors of hospitalized cancer patients who received ICI therapy at an NCI-designated Comprehensive Cancer Center. Methods: A retrospective review of electronic medical records was conducted for adult cancer patients who received an FDA-approved ICI during admission from 08/2016 to 01/2022. For each patient we extracted demographics, cancer histology, comorbidities, reasons for hospitalization, ICI administered, time from treatment to discharge, time from treatment to progression or death, and complete blood counts. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. The 95% confidence interval for survival was calculated using the exact binomial distribution. Statistical significance was defined as 2-sided p<0.05. Results: Of 37 patients identified, 2 were excluded due to lack of complete blood counts on admission. Average hospital stay was 24.2 (95% CI 16.5, 31.9) days. Ten (27.0%) patients died during the same hospitalization as treatment. Of those who followed up, 22 (59.5%) died within 90 days of inpatient therapy. The median PFS was 0.86 (95% CI 0.43, 1.74) months and median OS was 1.55 (95% CI 0.76, 3.72) months. Patients with ≥3 comorbidities had poorer PFS (2.4 vs. 0.4 months; p=0.0029) and OS (5.5 vs. 0.6 months; p=0.0006). Pre-treatment absolute lymphocyte counts (ALC) <600 cells/µL were associated with poor PFS (0.33 vs. 1.35 months; p=0.0053) and poor OS (0.33 vs. 2.34 months; p=0.0236). Pre-treatment derived neutrophil to lymphocyte ratio (dNLR) <4 was associated with good median PFS (1.6 vs. 0.4 months; p=0.0157) and OS (2.8 vs. 0.9 months; p=0.0375). Conclusions: Administration of ICI therapy was associated with poor clinical outcomes and high rates of both inpatient mortality and 90-day mortality after inpatient ICI therapy. The presence of ≥3 comorbidities, ALC <600/µL, or dNLR >4 in hospitalized patients was associated with poor survival outcomes.

Targeting HER2 genomic alterations in non-small cell lung cancer.

Oncogenic mutations and amplifications in the erythroblastic oncogene B (ERBB2), or human epidermal growth factor receptor 2 (HER2), have emerged as distinct oncogenic drivers and drug targets in non-small cell lung cancer (NSCLC). Each genomic alteration occurs in 2-4% of NSCLC by next generation sequencing and is associated with constitutive HER2 activation. The most common HER2 mutations in NSCLC are exon 20 mutation A775_G776insYVMA mutation in the kinase domain and S310F mutation in the extracellular domain. Unlike in breast and gastric cancer, HER2 protein overexpression in NSCLC is not validated to be a biomarker predictive of clinical response to HER2-targeted agents. High HER2 protein overexpression by immunohistochemistry (3+) only occurs in 2-4% of NSCLC. Until now HER2-targeted agents (such as afatinib and ado-trastuzumab emtansine) only demonstrate modest clinical activity in patients with HER2-mutant NSCLC. Retrospective studies show concern for inferior clinical benefit of immune checkpoint inhibitors in HER2-mutated NSCLC. Therefore, platinum-based chemotherapy with or without an anti-angiogenesis inhibitor remains the first line standard treatment for this patient population. In May 2020 trastuzumab deruxtecan (T-DXd) received the U.S. Food and Drug Administration breakthrough therapy designation for HER2-mutant metastatic NSCLC, and was added as an option for HER2-mutant NSCLC to the NCCN guidelines V1.2021. A global phase III study of pyrotinib compared to docetaxel as a second line therapy for advanced NSCLC harboring HER2 exon 20 mutations was just opened for enrollment in September 2020. In this review, we highlight the current knowledge and perspectives on targeting-HER2 genomic alterations in NSCLC.