Precision medicine has helped identify several tumor molecular aberrations to be treated with targeted therapies. These therapies showed substantial improvement in efficacy without excessive toxicity in patients with specific oncogenic drivers with advanced cancers. In metastatic lung cancers, the implementation of broad platforms for molecular tumor sequencing has helped oncology providers identify oncogenic drivers linked with better outcomes when treated upfront with targeted therapies. Mesenchymal-epithelial transition factor (MET) alterations are present in up to 60% of non-small cell lung cancer and are associated with a poor prognosis. Capmatinib and tepotinib are currently the only two approved targeted therapies by the U.S. Food and Drug Administration (FDA) for patients with MET exon 14 skipping mutation. Several agents are being developed to tackle an unmet need in patients with MET alterations. Some of these agents are being used in combination with EGFR targeted therapy to mitigate resistance to EGFR inhibitor. These agents are poised to provide new hope for these patients.

Human epidermal growth factor receptor 3 (HER3) is the only family member of the EGRF/HER family of receptor tyrosine kinases that lacks an active kinase domain (KD), which makes it an obligate binding partner with other receptors for its oncogenic role. When HER3 is activated in a ligand-dependent (NRG1/HRG) or independent manner, it can bind to other receptors (the most potent binding partner is HER2) to regulate many biological functions (growth, survival, nutrient sensing, metabolic regulation, etc.) through the PI3K-AKT-mTOR pathway. HER3 has been found to promote tumorigenesis, tumor growth, and drug resistance in different cancer types, especially breast and non-small cell lung cancer. Given its ubiquitous expression across different solid tumors and role in oncogenesis and drug resistance, there has been a long effort to target HER3. As HER3 cannot be targeted through its KD with small-molecule kinase inhibitors via the conventional method, pharmaceutical companies have used various other approaches, including blocking either the ligand-binding domain or extracellular domain for dimerization with other receptors. The development of treatment options with anti-HER3 monoclonal antibodies, bispecific antibodies, and different combination therapies showed limited clinical efficiency for various reasons. Recent reports showed that the extracellular domain of HER3 is not required for its binding with other receptors, which raises doubt about the efforts and applicability of the development of the HER3-antibodies for treatment. Whereas HER3-directed antibody-drug conjugates showed potentiality for treatment, these drugs are still under clinical trial. The currently understood model for dimerization-induced signaling remains incomplete due to the absence of the crystal structure of HER3 signaling complexes, and many lines of evidence suggest that HER family signaling involves more than the interaction of two members. This review article will significantly expand our knowledge of HER3 signaling and shed light on developing a new generation of drugs that have fewer side effects than the current treatment regimen for these patients.

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BACKGROUND: This study provides insights into the treatment use and outcomes of metastatic non-small cell lung cancer (NSCLC) patients in a real-world setting prior to and after the availability of immuno-oncology (IO) regimens in the first line (1L).
METHODS: Metastatic NSCLC patients, who initiated systemic 1L anticancer treatment from 2014 to 2020, were identified from health records. Patients were grouped into Pre-1L IO and Post-1L IO, according to the availability of pembrolizumab 1L monotherapy at the date of initiating 1L systemic anticancer treatment. Patient characteristics, treatment patterns and outcomes were assessed by the cohort. Overall survival (OS) and real-world progression-free survival (rwPFS) were calculated using the Kaplan-Meier method.
RESULTS: The most common 1L treatment was platinum-based chemotherapy regimens in both groups (≥46%), followed by single-agent chemotherapy (27.0%) in Pre-1L IO and pembrolizumab (26.0%) in Post-1L IO. Median OS was 6.2 (95% CI 5.5-7.4) in Pre- and 8.9 months (95% CI 7.5-10.6) in Post-1L IO, while rwPFS was 3.7 (95% CI 3.3-4.2) and 4.7 months (95% CI 3.9-5.7), respectively.
CONCLUSIONS: Even if a small proportion of patients received a 1L IO, the data showed an improved survival outcomes in the Post-1L IO group.

The leading cause of death due to malignancy in the USA is lung cancers. They can be divided into small cell lung cancer and non-small cell lung cancer. Of the latter, adenocarcinoma comprises the majority of lung cancers. Manifestations of lung cancer can be divided into thoracic, extra-thoracic and paraneoplastic syndromes. We describe a case of ventricular tachycardia in a patient who presented with dysphagia, ultimately found to have a non-small cell lung cancer invading the esophagus and heart.

Non-small cell lung cancers (NSCLC) harboring mutation-induced dysregulation of Ras signaling present some of the most difficult-to-manage cases, since directly targeting the constitutively active mutant Ras proteins has not resulted in clinically useful drugs. Therefore, modulating Ras activity for targeted treatment of cancer remains an urgent healthcare need.
In the current study, we investigated a novel class of compounds, the polyisoprenylated cysteinyl amide inhibitors (PCAIs), for their anticancer molecular mechanisms using the NSCLC cell panel with K-Ras and/or other mutant genes.
The effect of the PCAIs on intracellular K-Ras levels, cell viability, apoptosis, spheroid and colony formation were determined.
Treatment of the lung cancer cells with the PCAIs, NSL-RD-035, NSL-BA-036, NSL-BA- 040 and NSL-BA-055 resulted in concentration-dependent cell death in both K-Ras mutant (A549, NCI-H460, and NCI-H1573), N-Ras mutant (NCI-H1299) and other (NCI-H661, NCI-H1975, NCIH1563) NSCLC cells. The PCAIs at 1.0 -10 μM induced the degeneration of 3D spheroid cultures, inhibited clonogenic cell growth and induced marked apoptosis via the extrinsic pathway. The most potent of the PCAIs, NSL-BA-055, at 5 μM induced a seven-fold increase in the activity of caspase- 3/7 and a 75% selective depletion of K-Ras protein levels relative to GAPDH in A549 cells that correlated with PCAIs-induced apoptosis. NSL-BA-040 and NSL-BA-055 also induced the phosphorylation of MAP kinase (ERK 1/2).
Taken together, PCAIs may be potentially useful as targeted therapies that suppress NSCLC progression through disruption of Ras-mediated growth signaling.

A phytochemical investigation into the bark of Erythrophleum fordii yielded four new compounds, two new cassaine diterpenoids (erythrofordin T and U, 1 and 2) and two new cassaine diterpenoid amines (erythroformine A and B, 6 and 7), as well as nine known compounds. We report for the first time the isolation of erythrofordin V (3) from a natural source and that of the remaining eight known diterpenoids (4-5, 8-13) from E. fordii. All structures were elucidated using spectroscopic analysis. Cytotoxic activity of the isolated compounds (1-13) was examined in vitro against three non-small cell lung cancer cell lines (A549, NCI-H1975, and NCI-H1229) using the MTT assay. Cassaine diterpene amines (6-10, 12, 13) exhibited potent cytotoxic activity against all three cell lines with IC50 values between 0.4μM and 5.9μM. Erythroformine B (7) significantly induced apoptosis in all three cancer cells in a concentration-dependent manner.

BACKGROUND: Reference data for European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaires do not include studies from the Indian subcontinent. The objective of the current study was to establish a reference dataset for Indian patients of non-small cell lung cancer (NSCLC) presenting with brain metastases (BM).
METHODS: One hundred forty patients with NSCLC with BM treated between 2012-2015 were registered in a prospective cohort study (CTRI/2013/01/003299). The baseline quality of life was evaluated using the EORTC general quality of life questionnaire QLQ-C30 and lung cancer specific module LC13. Minimum important difference (MID) scores for individual domains of the EORTC QLQ-C30 and LC13 questionnaires were derived (MID = 0.2 x standard deviation) from the reference data for patients with recurrent/metastatic lung cancers. In addition, a systematic review was conducted to identify studies reporting baseline quality of life scores for recurrent/metastatic NSCLC.
RESULTS: Scores of several functional as well as symptom scales in the current NSCLC population differed by more than the MID from the baseline mean scores in the reference EORTC population as well as that reported from other studies. Differences in mean score from the EORTC reference data ranged from 6.2 and 9.4 points for the role functioning and cognitive functioning domains. In the symptom scales, the largest differences were observed for the financial difficulties (23.9) scores for the QLQ-C30 and peripheral neuropathy (21.7) for LC13 questionnaires.
CONCLUSIONS: The current study demonstrates that baseline reference scores need to be established for patients from the Indian subcontinent. The findings from the current study have important implications for studies employing quality of life (QOL) assessment in the Indian NSCLC patient population.

OBJECTIVE: We hypothesized that omission of clinical target volumes (CTV) in lung cancer radiotherapy would not compromise control by determining retrospectively if the addition of a CTV would encompass the site of failure.
METHODS: Stage II-III patients were treated from 2009-2012 with daily cone-beam imaging and a 5 mm planning target volume (PTV) without a CTV. PTVs were expanded 1 cm and termed CTVretro. Recurrences were scored as 1) within the PTV, 2) within CTVretro, or 3) outside the PTV. Locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated.
RESULTS: Among 110 patients, Stage IIIA 57%, IIIB 32%, IIA 4%, and IIB 7%. Eighty-six percent of Stage III patients received chemotherapy. Median dose was 70 Gy (45-74 Gy) and fraction size ranged from 1.5-2.7 Gy. Median follow-up was 12 months, median OS was 22 months (95% CI 19-30 months), and LRC at two years was 69%. Fourteen local and eight regional events were scored with two CTVretro failures equating to a two-year CTV failure-free survival of 98%.
CONCLUSIONS: Omission of a 1 cm CTV expansion appears feasible based on only two events among 110 patients and should be considered in radiation planning.

We report a case of oligometastatic non-small-cell lung cancer (NSCLC) in a 60-year-old male that was treated with both local and systemic therapies with an exceptional response to therapy. This case provides evidence that oligometastatic lung cancer, when treated with curative intent, may be an opportunity for long-term survival in select patients.