Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial.

BACKGROUND: DESTINY-Lung01 is a multicentre, open-label, phase 2 study evaluating the antitumour activity and safety of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpressing or HER2 (ERBB2)-mutant unresectable or metastatic non-small-cell lung cancer (NSCLC). The results of the HER2-mutant cohort (cohort 2) have been reported elsewhere. Herein, we report the primary analysis of cohorts 1 and 1A, which aimed to evaluate the activity and safety of trastuzumab deruxtecan 5·4 mg/kg and 6·4 mg/kg in patients with HER2-overexpressing NSCLC. METHODS: Patients aged 18 years or older with unresectable or metastatic (or both unresectable and metastatic) non-squamous NSCLC who had relapsed following or were refractory to standard treatment or for whom no standard treatment was available, with an HER2 immunohistochemistry score of 3+ or 2+ (without known HER2 mutations) and an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled at 20 specialist hospitals in France, Japan, the Netherlands, Spain, and the USA. Patients were assigned to cohorts sequentially, first to cohort 1, to receive trastuzumab deruxtecan 6·4 mg/kg (cohort 1), then to cohort 1A, to receive trastuzumab deruxtecan 5·4 mg/kg, both administered intravenously once every 3 weeks. The primary endpoint was confirmed objective response rate by independent central review and was assessed in the full analysis set, which included all patients who signed an informed consent form and were enrolled in the study. Safety was assessed in all enrolled patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT03505710, and is ongoing (closed to recruitment). FINDINGS: Between Aug 27, 2018, and Jan 28, 2020, 49 patients were enrolled in cohort 1 (median age 63·0 years [IQR 58·0-68·0], 30 [61%] male, 19 [39%] female, and 31 [63%] White), and from June 16 to Dec 9, 2020, 41 patients were enrolled in cohort 1A (median age 62·0 years [IQR 56·0-66·0], 22 [54%] male, 19 [46%] female, and 31 [76%] White). As of data cutoff (Dec 3, 2021), the median treatment duration was 4·1 months (IQR 1·4-7·1) in cohort 1 and 5·5 months (1·4-8·7) in cohort 1A, and median follow-up was 12·0 months (5·4-22·4) in cohort 1 and 10·6 months (4·5-13·5) in cohort 1A. Confirmed objective response rate by independent central review was 26·5% (95% CI 15·0-41·1; 13 of 49, all partial responses) in cohort 1 and 34·1% (20·1-50·6; 14 of 41; two complete responses and 12 partial responses) in cohort 1A. The most common treatment-emergent adverse events of grade 3 or worse were neutropenia (12 [24%] of 49 in cohort 1, none in cohort 1A), pneumonia (six [12%] and two [5%], respectively), fatigue (six [12%] and three [7%], respectively), and disease progression (six [12%] and four [10%], respectively). Drug-related treatment-emergent adverse events of grade 3 or worse occurred in 26 (53%) of 41 patients in cohort 1 and nine (22%) of 49 patients in cohort 1A. Drug-related serious adverse events were reported in ten (20%) patients and three (7%) patients, respectively. Deaths due to treatment-emergent adverse events occurred in ten (20%) patients in cohort 1 (disease progression in six (12%) patients and bronchospasm, hydrocephalus, respiratory failure, and pneumonitis in one [2%] patient each), and in seven (17%) patients in cohort 1A (due to disease progression in four (10%) patients and dyspnoea, malignant neoplasm, and sepsis in one (2%) patient each). One death due to a treatment-emergent adverse event was determined to be due to study treatment by the investigator, which was in cohort 1 (pneumonitis). Independent adjudication of interstitial lung disease or pneumonitis found that drug-related interstitial lung disease or pneumonitis occurred in ten (20%) patients in cohort 1 (two [4%] grade 1, five [10%] grade 2, and three [6%] grade 5) and two (5%) patients in cohort 1A (one [2%] grade 2 and one [2%] grade 5). An additional patient in cohort 1A had grade 4 pneumonitis after the data cutoff, which was subsequently adjudicated as drug-related grade 5 interstitial lung disease or pneumonitis. INTERPRETATION: Given the low antitumour activity of existing treatment options in this patient population, trastuzumab deruxtecan might have the potential to fill a large unmet need in HER2-overexpressing NSCLC. Our findings support further investigation of trastuzumab deruxtecan in patients with HER2-overexpressing NSCLC. FUNDING: Daiichi Sankyo and AstraZeneca.

ChatGPT-A promising generative AI tool and its implications for cancer care.

PLAIN LANGUAGE SUMMARY: Since its launch, ChatGPT has taken the internet by storm and has the potential to be used broadly in the health care system, particularly in a setting such as medical oncology. ChatGPT is well suited to review and extract key content from records of patients with cancer, interpret next-generation sequencing reports, and offer a list of potential clinical trial options.

Current understanding and future implications of sepsis-induced thrombocytopenia.

Sepsis is a global health burden that needs intensive medical care. Thrombocytopenia in sepsis is well known to increase morbidity as well as mortality. Several studies have been performed both in animal models and in humans to understand the mechanism by which sepsis causes thrombocytopenia. Recent studies have shown that inhibiting thrombocytopenia improves outcomes in sepsis patients. Understanding these mechanisms to identify targets in use of newer treatment modalities besides using resuscitation measures, antibiotics and removal of thrombocytopenia inducing agent could potentially help us improve outcomes in sepsis.

Pulmonary Neuroendocrine Tumors: Adjuvant and Systemic Treatments.

OPINION STATEMENT: Bronchial carcinoids are uncommon tumors accounting for 20 to 30% of all neuroendocrine tumors and about 1-2% of all cancers of pulmonary origin. Bronchial carcinoids are well-differentiated neuroendocrine tumors and have a favorable survival outcome when compared with other subtypes of lung cancers. Treatment of bronchial carcinoids is not simple owing to intricacy of symptom presentation and heterogeneity of disease biology. Successful treatment of patients requires a multimodality approach. Resection is curative in the majority of patients with localized tumors and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced disease. To date, very few randomized clinical trials have been done, partly owing to the relative rarity of this malignancy. Somatostatin analogs (SSAs) are reasonable first-line choice for patients with tumors expressing somatostatin receptors. Everolimus is an appropriate first-line choice for somatostatin receptor negative tumors and for any patients with progressive disease. PRRT can also be considered for progressive tumors expressing somatostatin receptors. Based on retrospective series, cytotoxic chemotherapy can be selected in patients with progressive tumors, primarily when cytoreduction is needed. Herein, we will discuss evidence supporting the role of adjuvant and systemic treatment therapies for those with bronchial carcinoid tumors by focusing on various studies.

A US Registry-Based Assessment of Use and Impact of Chemotherapy in Stage I HER2-Positive Breast Cancer.

Background: Despite the paucity of evidence supporting chemotherapy in the treatment of node-negative, HER2-positive breast cancer measuring <2 cm, use of trastuzumab-based chemotherapy has increased over the past decade. Therefore, we used the National Cancer Database to evaluate the use and impact of chemotherapy on survival in this population. Methods: We identified female patients aged 18 to 70 years with node-negative, HER2-positive breast cancer measuring <2 cm. A propensity-matched cohort model was used to control for risk factors known to influence survival. Primary end points assessed were receipt of chemotherapy and overall survival (OS). Results: In our propensity-matched cohort model (n=8,222), adjuvant chemotherapy (ACT) was associated with a lower 5-year OS rate in T1mi breast cancer (n=626; 89.1% [95% CI, 81.8%-93.5%] vs 99.1% [96.6%-99.8%]), no significant effect in T1a disease (n=2,901; 95.4% [93.2%-96.9%] vs 96.9% [94.1%-98.3%]), and improved 5-year OS in T1b (n=2,340; 97.1% [95.1%-98.4%] vs 92.3% [88.5%-94.9%]) and T1c tumors (n=2,355; 95.9% [93.5%-97.5%] vs 91.5% [88.4%-93.9%]). In the entire cohort of 21,148 patients who met the inclusion criteria, ACT was associated with lower 5-year OS in T1mi (89.6% [83.7%-93.4%] vs 98.1% [96.6%-98.9%]) and T1a tumors (94.9% [92.9%-96.3%] vs 96.5% [94.6%-97.7%]), and improved 5-year OS in T1b (96.8% [95.6%-97.7%] vs 92.3% [88.7%-94.8%]) and T1c tumors (95.8% [94.9%-96.5%] vs 91.6% [88.5%-93.9%]). Increased use of ACT was observed over the study period. From 2010 to 2013, annual treatment rates were 71.5%, 72.4%, 73.3%, and 74.4%, respectively (trend test, P<.0001). Conclusions: Our data support the use of ACT for HER2-positive, node-negative T1b and T1c breast cancer, whereas no benefit was observed for ACT in T1mi and T1a HER2-positive, node-negative breast cancer. Although use of ACT is increasing in node-negative, HER2-positive breast cancer <2 cm, our findings caution against its use in the smallest of these tumors (T1mi and T1a) due to lack of survival benefit.

The risk of second primary malignancy in patients with stage Ia non-small cell lung cancer: a U.S. population-based study.

BACKGROUND: Lung cancer is one of the most common cancers worldwide. Patients with early stage lung cancer have improved long-term survival. With the introduction of low-dose CT scan, more patients are going to be diagnosed at an early stage. However, there is limited data on the risk of second primary malignancies (SPMs) in these subsets of patients in the United States. METHODS: We utilized SEER-13 (Surveillance, Epidemiology and End Results) registry to obtain Multiple Primary- Standardized Incidence Ratio and an Absolute Excess Risk between January 2004 and December 2010 for patients with Stage Ia non-small cell lung cancer. RESULTS: The database comprised of 12,246 patients. A total of 1431 (11.68%) patients developed 1563 SPMs with an observed to expected (O/E) ratio of 2.07 (95% CI = 1.92-2.23, p < .001) in patients with adenocarcinoma and 2.05 (95% CI = 1.92-2.19, p < .001) in squamous cell carcinoma group. CONCLUSIONS: This study showed an excess risk of SPMs in patients with early stage non-small cell lung cancer. We recommend a close follow-up, paying attention to concerning symptoms or examination findings and judicious use of age-appropriate cancer screening.

Maintenance of Certification (MOC)-Benefit vs Burden.

This Viewpoint examines the demands of maintenance of certification (MOC) requirements from the ABIM on balance with the projected benefits to quality of patient care.

Idelalisib- a PI3Kδ targeting agent for B-cell malignancies.

Idelalisib, the first in-class phosphotidlyinositol 3-kinase delta (PI3Kδ) inhibitor, was approved by the US Food and Drug Administration in July 2014. It simultaneously received breakthrough therapy designation in combination with rituximab for the treatment of relapsed chronic lymphocytic leukemia (CLL) as well as accelerated approval as monotherapy for the treatment of relapsed follicular lymphoma and relapsed small lymphocytic lymphoma. In a pivotal phase III study of 220 patients with relapsed CLL, the overall response rate of patients who received rituximab plus idelalisib was 81%. The median progression-free survival (PFS) was 5 months with rituximab plus placebo group, but was not reached in the idelalisib arm. At 24 weeks, the PFS in patients receiving idelalisib was 93%. In a phase II trial of 125 patients with relapsed or refractory indolent non-Hodgkin lymphoma who received idelalisib 150 mg twice daily, the response rate was 57%. Complete response was seen in 6% of patients. The median duration of response was 12.5 months, and median PFS was 11 months. Idelalisib is a promising new therapy for relapsed indolent B-cell malignancies.

Ketamine infusion for sickle cell pain crisis refractory to opioids: a case report and review of literature.

This article reports a rare case of the use of low-dose ketamine infusion as an adjuvant to opioids to treat pain in sickle cell disease. A 31-year-old African-American male with history of sickle cell disease presented to the emergency department with complaints of chest tightness, multiple joint pain, and headache for 1 week. His vital signs and physical examination were unremarkable. His admission lab included hemoglobin of 8.4 g/dl, reticulocyte count of 16.3%, bilirubin of 1.7 mg/dl, and LDH of 1,267 U/l. Chest X-ray showed middle and lower lobe opacity and interstitial thickening. He was treated for acute pain crisis and community-acquired pneumonia with intravenous fluids, supplemental oxygen, and intravenous levofloxacin. He was placed on fentanyl patient-controlled analgesia (PCA), oxycodone, ketorolac, and methadone with co-analgesic gabapentin and venlafaxine. Over the course of his hospitalization, his chest pain resolved, but the joint pains continued. He was then transferred to the ICU and was discharged a day later after 7 days of ketamine infusion. Ketamine is a noncompetitive antagonist at the N-methyl-D-aspartate (NMDA) receptor. This property has been shown to modulate opioid tolerance and opioid-induced hyperalgesia. There have been a very few published reports on the use of low-dose ketamine in sickle cell pain management. A PubMed search revealed four published articles (Table 1). Fourteen out of the 17 cases (82.35%) who received ketamine infusion showed improvement in self-reported pain intensity and significant reduction in opioid dosage. Only one patient (5.9%) developed serious side effect leading to discontinuation of the drug. A low-dose ketamine can be an option for pain control in sickle cell disease. Randomized trial is required to establish this benefit of ketamine over currently available therapies.

First-Line Dual Immunotherapy, a Treatment Option in First-Line Metastatic Non-Small-Cell Lung Cancer: Are We Ready to Use It?

This article provides valuable insights into the use of dual immunotherapy for patients with metastatic NSCLC.

Racial and socioeconomic disparities in survival among patients with metastatic Non-Small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICI) have profoundly impacted survival among patients with metastatic non-small cell lung cancer (NSCLC). However, population-based studies evaluating this impact on survival by race and socioeconomic factors are lacking. METHODS: We utilized the SEER-Medicare database to identify patients with metastatic NSCLC diagnosed between 2015 and 2019. The primary study outcomes were the receipt of an ICI and overall survival (OS). Chi-square tests and logistic regression were utilized to identify demographic factors associated with receipt of ICI. The Kaplan-Meier method was used to calculate 2-year OS rates, and log-rank tests were used to compared survival by race/ethnicity. RESULTS: Out of 17,134 patients, approximately 39% received an ICI. Those diagnosed with cancer recently (in 2019), who are relatively younger (<85 years old), non-Hispanic white, non-Hispanic Asian, or Hispanic, living in high socioeconomic status or metropolitan areas, not Medicaid eligible, and with adenocarcinoma histology were more likely to receive ICI. The 2-year OS rate from diagnosis was 21% for the overall population. The 2-year OS rate from ICI initiation was 30%, among those who received at least one cycle and 11% among those who did not receive ICI. The 2-year OS rates were higher among non-Hispanic whites (22%) and non-Hispanic Asians (23%) compared to non-Hispanic Blacks (15%) and Hispanics (17%). There was no significant racial differences in survival for those who received ICI. CONCLUSION: ICI utilization rates and the resulting outcomes were inferior for certain vulnerable groups, mandating the need for strategies to improve access to care.

Perioperative Therapy for Resectable Non-Small-Cell Lung Cancer: Weighing Options for the Present and Future.

Anatomic surgical resection followed by cisplatin-based platinum-doublet adjuvant chemotherapy has been a long-standing standard of care for patients with early-stage, resectable non-small-cell lung cancer (NSCLC). More recently, incorporating of immunotherapy and targeted therapy in the perioperative setting has demonstrated improved disease-free or event-free survival in biomarker-defined subsets of patients. This article summarizes the results of major trials that led to approvals beyond chemotherapy in the perioperative setting. Alongside adjuvant osimertinib as a favored strategy for patients with EGFR mutation-positive NSCLC, there are competing potential standards of care for integrating immunotherapy in the neoadjuvant versus adjuvant setting, with advantages and disadvantages for each strategy. Emerging data in the coming years will provide further insight that may potentially lead to a combination of neoadjuvant and adjuvant treatment for many patients. Future trials should focus on clarifying the benefit of each component of treatment, defining an optimal treatment duration, and incorporating minimal residual disease to optimize treatment decisions.

MET alterations in NSCLC-Current Perspectives and Future Challenges.

Targeted therapies have revolutionized the treatment and improved the outcome for oncogene-driven NSCLC and an increasing number of oncogenic driver therapies have become available. For MET-dysregulated NSCLC (especially MET exon 14 skipping mutations and MET-amplifications, which is one of the most common bypass mechanisms of resistance in oncogene-addicted NSCLC), several anti-MET-targeted therapies have been approved recently (MET exon 14 skipping mutation) and multiple others are in development. In this narrative review, we summarize the role of MET as an oncogenic driver in NSCLC, discuss the different testing methods for exon 14 skipping mutations, gene amplification, and protein overexpression, and review the existing data and ongoing clinical trials regarding targeted therapies in MET-altered NSCLC. As immunotherapy with or without chemotherapy has become the standard of care for advanced NSCLC, immunotherapy data for MET-dysregulated NSCLC are put into perspective. Finally, we discuss future challenges in this rapidly evolving landscape.