MTAP as an emerging biomarker in thoracic malignancies.

S-methyl-5'-thioadenosine phosphorylase (MTAP) deficiency is an emerging biomarker in non-small cell lung cancer (NSCLC) and beyond. The MTAP gene is located in the chromosomal region 9p21.3, which shows one of the most common homozygous deletions across all human cancers (9p21 loss). Loss of 9p21 is found in the majority of pleural mesotheliomas, where it serves as an established diagnostic marker. Until recently, fluorescence in situ hybridization (FISH) was the gold standard for the detection of 9p21 losses, but loss of MTAP expression by immunohistochemistry (IHC) gains increasing importance as an easy to apply and cost-effective diagnostic surrogate marker. Besides, MTAP loss, which has been reported in 13% of NSCLC, is becoming an emerging predictive biomarker in two different scenarios in NSCLC and other cancer types: 1) MTAP loss seems to negatively predict the response to immune checkpoint inhibitor (ICI) treatment via silencing of the tumor microenvironment, and 2) MTAP loss serves as a predictive biomarker for novel targeted treatment strategies. MTAP deficiency leads to an impaired function of the protein arginine methyltransferase 5 (PRMT5) due to its partial inhibition by MTAP's accumulating substrate methylthioadenosine (MTA). This process leaves MTAP deficient tumor cells heavily dependent on the remaining function of PRMT5, making it a perfect target for synthetic lethality. Indeed, MTA-cooperative PRMT5-inhibitors are now tested in several clinical trials with promising early results in solid malignancies. With its emergence as a predictive biomarker, the implementation of MTAP IHC into diagnostic routine for NSCLC and other tumors is likely to take place soon. In this review article, we summarize the current literature on the role of MTAP in thoracic tumors and evaluate different testing methods, including IHC, FISH and next generation sequencing.

Potent covalent irreversible inhibitor of KRAS G12C IBI351 in patients with advanced solid tumors: First-in-human phase I study.

BACKGROUND: IBI351 is an irreversible and covalent inhibitor of KRAS G12C. Despite FDA approval of two KRAS G12C inhibitors, there are still significant unmet clinical needs in Chinese patients and ongoing concerns about the optimal dosage. Herein, we presented the phase Ia/Ib study of IBI351 monotherapy in Chinese patients with advanced solid tumors harboring KRAS G12C mutation. METHODS: In phase Ia dose escalation, IBI351 at 250/450/700/900 mg once daily and 450/600/750 mg twice daily (BID) were evaluated. Potentially efficacious doses and optimal recommended phase 2 dose (RP2D) were further evaluated in patients with advanced non-small cell lung cancer (NSCLC) in phase Ia dose expansion and phase Ib. Safety, pharmacokinetics, and investigator-assessed tumor response were evaluated. RESULTS: As of June 13, 2023, 176 patients were enrolled. IBI351 was well tolerated with no dose-limiting toxicity reported across all evaluated doses. The RP2D was determined as 600 mg BID by considering safety, efficacy and pharmacokinetics. A total of 168 patients (95.5 %) had at least one treatment-related adverse event (TRAE), and 64 patients (36.4 %) had grade 3 or higher TRAEs, most commonly gamma-glutamyl transferase increased (10.2 %) and anemia (6.8 %). For patients with NSCLC, the confirmed objective response rate (ORR) was 45.5 % across all doses. At 600 mg BID, the confirmed ORR was 46.8 % and median progression-free survival was 9.6 months with a median follow-up of 6.9 months. CONCLUSIONS: IBI351 was well tolerated in patients with advanced solid tumors and showed promising antitumor activity in advanced NSCLC patients with KRAS G12C mutation.

Nivolumab plus ipilimumab with chemotherapy for non-small cell lung cancer with untreated brain metastases: A multicenter single-arm phase 2 trial (NIke, LOGiK 2004).

BACKGROUND: The effect of dual immunotherapy combined with platinum-based chemotherapy on untreated brain metastases derived from non-small cell lung cancer (NSCLC) has remained unclear. METHODS: This multicenter single-arm phase 2 study enrolled patients with chemotherapy-naïve advanced NSCLC and at least one brain metastasis ≥ 5 mm in size that had not been previously treated. Patients received nivolumab plus ipilimumab combined with platinum-doublet chemotherapy (two cycles), followed by nivolumab-ipilimumab alone. The primary endpoint of the study was intracranial response rate as determined by modified Response Evaluation Criteria in Solid Tumors (RECIST) for brain metastases of ≥ 5 mm as target lesions. RESULTS: A total of 30 patients from 18 institutions was enrolled in this study. The median age was 66.5 years (range, 47-83 years), and 26 patients (87 %) had a non-squamous cell carcinoma histology. The median size of all target brain lesions was 8.4 mm, with a range of 5-39 mm. The intracranial response rate assessed by modified RECIST was 50.0 % (95 % CI, 33.2-66.8 %), with the rate of complete response being 20.0 %, and the study met its primary endpoint. The systemic response rate was 53.3 % (95 % CI, 36.1-69.8 %), and responses for intracranial and extracranial lesions were generally consistent. The median intracranial progression-free survival was 8.1 months, and both the median intracranial duration of response and time to brain radiotherapy were not reached. CONCLUSION: Nivolumab plus ipilimumab combined with platinum-based chemotherapy showed promising intracranial activity in NSCLC patients with untreated brain metastases. TRIAL REGISTRATION: jRCT071210019.

A phase 2 single-arm trial of high-dose precision targeted radiotherapy added to immunotherapy for patients with metastatic non-small cell lung cancer.

HYPOTHESIS: For metastatic non-small cell lung cancer (NSCLC), the addition of radiotherapy (RT) to immune checkpoint inhibitor (ICI) therapy could have synergistic anti-cancer effects and address the most threatening tumors. We posited that the addition of high-dose RT to ICI could prolong progression-free survival (PFS). METHODS: In this single arm phase 2 trial, 45 patients with metastatic NSCLC who had received an anti-PD-1/anti-PD-L-1 ICI for 4+ weeks were enrolled from July 2017-May 2021. Patients received high-dose RT to 1-4 extracranial tumors and continued ICI until progression or unacceptable toxicity. The primary endpoint was PFS at 24 weeks, comparing to a historical control rate of 35%. RESULTS: Of 44 evaluable patients, median age was 71, 75% had adenocarcinoma, 64% had polymetastatic disease, and 85% of cancers with known PD-L1 percentage were PD-L1 positive. Median number of treated tumors was two and most common dose was 40 Gy in 10 fractions (41/81 tumors). Median follow-up was 23.3 months. The trial met the primary outcome: 24-week PFS was 60% (95% CI 44-75%), higher than the historical control rate (p<0.001). Median PFS was 6.9 months (95% CI 4.0-13.5 mo) and median OS was 27.4 months (95% CI 20.4-not reached). Several patients with pre-study disease progression on ICI treatment achieved durable responses to study treatment, up to 53 months. Local recurrence rate was low: cumulative incidence of 5% at one, two, and three years. Two dose-limiting toxicities were observed (5%), including one grade 5 pneumonitis. CONCLUSIONS: The strategy improved 24-week PFS compared to historical controls receiving ICI alone. The excellent local control supports the efficacy of high-dose RT in addressing macroscopic disease.

Relationship between Lactate Dehydrogenase and survival in patients with non-small cell lung cancer receiving immunotherapy. / Relación entre el lactato deshidrogenasa y la supervivencia en pacientes con cáncer de pulmón no microcítico que reciben tratamiento con inmunoterapia.

OBJECTIVE: The expression level of programmed death ligand 1 (PD-L1) is the only approved biomarker for predicting response to immunotherapy, yet its efficacy is not always consistent. Lactate dehydrogenase (LDH) has been associated with tumor aggressiveness and poorer prognosis across various cancer types and may serve as a useful biomarker for monitoring treatment response. The objective of this study is to analyze the relationship between LDH levels prior to the start of treatment with immune checkpoint inhibitors (ICIs) and clinical outcomes in patients with non-small cell lung cancer (NSCLC). METHOD: A retrospective study was conducted including patients diagnosed with NSCLC who were treated with at least three cycles of immunotherapy. Data on demographics, clinical and pathological characteristics, treatment received, pre-treatment LDH levels, and clinical outcomes such as treatment response and overall survival (OS) were analyzed. RESULTS: A total of 181 patients diagnosed with NSCLC were included. Elevated pre-treatment LDH levels (more than 244 U/l) were associated with significantly reduced OS. The median survival was 548 days in patients with LDH less than 244 U/l, compared to 332 days in those with LDH more than 244 U/l (p = 0.037). Among men, OS was greater in the LDH less than 244 U/l group (623 days) versus 332 days in the LDH more than 244 U/l group (p = 0.043). In patients with metastatic disease, OS was higher in those with LDH less than 244 U/l (474 days) compared to 249 days in those with LDH more than 244 U/l (p = 0.023). In patients receiving both immunotherapy and chemotherapy, OS was greater in those with LDH less than 244 U/l (623 days) compared to 281 days in the LDH more than 244 U/l group (p = 0.042). CONCLUSIONS: High levels of LDH prior to the start of treatment with ICIs are associated with lower treatment efficacy and a worse prognosis of the disease, especially in male, metastatic patients with a PD-L1 expression level less than 1%.

Budget impact analysis of pembrolizumab versus the novel PD-1 inhibitor toripalimab in locally advanced or metastatic nonsquamous non-small cell lung cancer.

AIM: To estimate the budget impact of adding a toripalimab regimen to the existing treatment mix of pembrolizumab, both with pemetrexed and carboplatin, in patients with locally advanced or metastatic nonsquamous NSCLC within two price inputs (wholesale acquisition cost (WAC) and average sales price (ASP)). METHODS: Budget impact analysis comparing a treatment mix "without" versus "with" the toripalimab regimen in the annual US nonsquamous NSCLC population treated with a PD-1 inhibitor, a 3-year time horizon, toripalimab market share of 1% in 2024, increasing to 4% (2025) and 5% (2026), and medication use adjustments for discontinuation or progression to estimate fully-treated-patient-equivalents. Cost inputs included drugs, administration, and grade 3/4 adverse event (AE) management. The models were replicated in a 1-million-member plan to estimate costs per-member-per-month (PMPM) and per-member-per-year (PMPY). One-way (OWSA) and probabilistic sensitivity analyses (PSA) as well as two scenario analyses were performed. RESULTS: In the "without" scenario, the 3-year WAC costs for the pembrolizumab regimen total $40,750,234,637 ($39,024,548,745 for treatment and $1,725,685,894 for managing AEs). In the "with" scenario, these costs decline to $39,341,379,081. Corresponding "with" costs for toripalimab are $1,186,027,704 (treatment) and $99,454,471 (AE management) for a total of $1,285,482,175. This yields annual net savings of between $10,779,362 (at 1% market share) in 2024 and $64,858,298 (5% market share) in 2026, for 3-year savings of $123,373,381. The associated savings in a 1-million-member plan are $0.030 PMPM and $0.363 PMPY. The ASP model shows similar patterns. Savings were demonstrated in 68% of PSA simulations; OWSAs and scenario analyses reveal how parameter variability impacts results. CONCLUSION: Significant savings are likely achievable from treating between 1% (year 1) to 5% (year 3) of nonsquamous NSCLC patients with the toripalimab regimen. Projected 3-year savings range from $122 million (ASP) to $123 million (WAC); corresponding to savings of $0.030 PMPM and $0.363 PMPY.

Toripalimab is a biological agent of the PD-1 inhibitor class approved in the US for the treatment of nasopharyngeal carcinoma and approved in China, in combination with pemetrexed and platinum, for the treatment of advanced or metastatic nonsquamous non-small cell lung cancer. In this simulation analysis, we evaluated how much it would cost a US payer to cover the toripalimab plus pemetrexed and platinum regimen as a treatment alternative to a similar pembrolizumab regimen. Our model adopted a 3-year time horizon; included two US cost inputs (wholesale acquisition cost and average sales price); and assumed a market share of 1% in 2024, increasing to 4% in 2025 and 5% in 2026. Using data from published clinical trials, we adjusted for patients whose cancer progressed or who discontinued treatment to determine the number of fully-treated-patient-equivalents. We found that, by treating 1% of nonsquamous non-small cell lung cancer patients in year one and increasing to 4% in year two and 5% in year three, the 3-year savings range from $122 million (using average sales price) to $123 million (using wholesale acquisition cost) for the entire adjusted patient population.

Risk of Death From Other Diseases in Lung Cancer Patients After Sublobar Resection Versus Lobectomy.

BACKGROUND AND OBJECTIVES: A recent Japanese phase three clinical trial for lung cancer suggested a possible advantage of segmentectomy over lobectomy in terms of death from other diseases. This study aimed to compare the risk of death from other diseases based on surgical procedures in lung cancer patients without recurrence. METHODS: We retrospectively reviewed 2121 patients without disease recurrence after curative resection for lung cancer at our institution. Patient characteristics and overall survival were compared between sublobar resection and lobectomy. RESULTS: The sublobar group (n = 595) had a significantly higher proportion of women, non-smokers, patients without comorbidities, patients with a history of other cancers, and patients with earlier-staged disease when compared with the lobectomy group (n = 1526). The overall survival was significantly longer in the sublobar group than in the lobectomy group (p = 0.0034). After adjusting for background characteristics in an analysis of 488 patients, the overall survival had a trend to be longer in the sublobar group than in the lobectomy group (p = 0.071). CONCLUSIONS: Our results suggested that the risk of death from other diseases was potentially higher after lobectomy than after sublobar resection. Although several clinical factors could influence the results, these results may support the benefit of sublobar resection, assuming that the curability of both procedures is similar.

The clinical value of combined detection of seven lung cancer-related autoantibodies in assisting the diagnosis of non-small-cell lung cancer.

Aim: Evaluate the clinical value of lung-cancer-related autoantibodies (CAGE, GAGE7, GBU4-5, MAGEA1, P53, PGP9.5, SOX2) in auxiliary diagnosis of non-small-cell lung cancer (NSCLC).Methods: We detected the concentrations of above 7 antibodies and lung cancer markers (CEA, NSE, CYFRE21-1) and drew area under the receiver characteristic curve of 316 patients.Results: The concentrations of CAGE, GBU4-5, MAGEA1, P53, PGP9.5 and SOX2 of significantly higher than other groups (p < 0.01). The sensitivity of different stages and pathological types of NSCLC consistent. Among them, the sensitivity of combined-detection in diagnosing adenocarcinoma and squamous cell carcinoma significantly better than CEA, NSE and CYFRA21-1.Conclusion: The combined detection has better efficacy in assisting the diagnosis of NSCLC and has certain clinical promotion and application value.

[Box: see text].

An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer.

The discovery of KRAS mutations, particularly the KRASG12C variant, has been a milestone in understanding the molecular underpinnings of non-small cell lung cancer (NSCLC). These mutations are associated with aggressive tumor behavior and resistance to conventional therapies, highlighting the urgent need for targeted interventions. In this comprehensive review, we analyze the advancements in KRAS G12C inhibitors for the treatment of non-small cell lung cancer. Literature search is made from PubMed, Medline ASCO and ESMO Annual Meetings abstracts by using the following search keywords: "sotorasib", "adagrasib", "divarasib" and "KRAS G12C inhibitors." The last search was on 5 June 2024. This review highlights the importance of pharmacokinetics, pharmacodynamics and potential adverse effects for treating individual patients and ensuring the best outcomes. Additionally, the review discusses research identifying biomarkers that can predict therapy responses and mentions the combination strategies to overcome resistance. Results of the studies and ongoing clinical trials are also briefly summarized in this review. KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.

[Box: see text].

Patient, tumour, and dosimetric factors influencing survival in non-small cell lung cancer patients treated with stereotactic ablative body radiotherapy.

Objectives: We aimed to analyse clinical outcomes of peripheral, early-stage non-small cell lung cancer (NSCLC) patients treated with stereotactic ablative body radiotherapy (SABR), and evaluate potential patient, tumour, and dosimetric variables influencing survival. Methods: Data were collected retrospectively from patients treated between September 2012 and December 2016 and followed up until January 2021. Patient demographics, tumour characteristics, SABR dosimetric parameters, and survival data were collected from electronic patient medical records. Descriptive statistics were performed, and SPSS software was used for survival analysis. Results: Eighty-nine patients were included of whom 49.5% were male and 50.5% female. Median age was 74 years. 98.8% of patients had T1-2 tumours and 89.9% underwent 55 Gy in 5 fractions. Median overall survival time was 58.7 months. On uni- and multi-variate analysis, neither patient nor tumour variables showed association with overall survival. However, planning target volume (PTV) and minimum dose to PTV correlated with overall survival. There was a signal for association between mean lung dose and overall survival on multivariate analysis. Conclusions: Our long-term results show SABR is an effective treatment for peripheral, early-stage NSCLC with excellent overall survival, comparable to other series. Our study found only the PTV and minimum dose to PTV had an impact on overall survival, which demonstrates the importance of generating optimal SABR plans. Advances in knowledge: Our work identified lung SABR dosimetric parameters that correlate with survival, which illustrates the importance of producing optimal lung SABR plans.

First-line selpercatinib for a patient with RET fusion-positive pulmonary large cell neuroendocrine carcinoma.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is an uncommon variant of non-small cell lung cancer (NSCLC), known for its aggressive behavior. This includes rapid progression, widespread metastases, and resistance to conventional chemotherapy, all of which contribute to a dismal prognosis. Consequently, managing pulmonary LCNEC remains a significant challenge. In this case report, we describe the successful use of selpercatinib, RET (rearranged during transfection) kinase inhibitor, as a first-line treatment in a patient with advanced pulmonary LCNEC harboring a RET fusion gene. Although RET fusion genes are exceedingly rare in pulmonary LCNEC, this case underscores the importance of early genetic testing in patients with pulmonary LCNEC to tailor targeted therapies effectively.

Your preoperative rehabilitation assistant: A study protocol for the impact of a telemedicine-supported preoperative home rehabilitation program on the prognosis of patients undergoing thoracoscopic surgery.

Background: Reduced cardiorespiratory fitness levels are associated with increased short-term complications after surgery, and potentially exert long-lasting effects on the postoperative lives, work and educational pursuits of patients. Currently, research suggests that lifestyle interventions, such as preoperative physical exercise undertaken by patients themselves, may improve patients' cardiopulmonary fitness and reduce post-operative complications. This study aims to investigate the effectiveness and feasibility of a remote medical supervision model for prehabilitation exercise in patients undergoing thoracoscopic lung tumour resection surgery. Methods/Design: All enrolled patients will participate in a 4-week pre-operative exercise intervention to improve their cardiorespiratory fitness. During this period, patients will wear wearable devices and exercise at home based on exercise prescriptions. The exercise prescription comprises aerobic exercise (three times a week or more), muscle strengthening exercise (twice a week or more), and respiratory muscle exercise (once a day). The primary aim is to investigate whether baseline VO2max could be improved following a 4-week preoperative exercise program. Secondary objectives include changes in forced expiratory volume in 1 s and forced vital capacity, degree of acceptance of the technology, quality of life, handgrip strength, postoperative complication rate and length of hospital stay. Discussion: This study aims to evaluate the influence of preoperative prehabilitation exercises in a telemedicine active supervision mode in patients undergoing thoracoscopic lung tumour resection. As such, results of this trial might have some impact on future implementations of group- and home-based prehabilitation exercises in lung cancers. Trial registration: This study was approved by the Medical Ethics Committee of Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology (approval number: TJ-IRB20220564) with registration at ClinicalTrials.gov (identifier: NCT05608759).

Targeting MGST1 Makes Non-Small Cell Lung Cancer Cells Sensitive to Radiotherapy by Epigenetically Enhancing ALOX15-Mediated Ferroptosis.

BACKGROUND: Ferroptosis is closely related to radiotherapy resistance in multiple can-cers. Herein, the role of microsomal glutathione S-transferase 1 (MGST1) in regulating ferropto-sis and radiotherapy resistance in non-small cell lung cancer (NSCLC) was investigated. METHODS: Radiation-resistant NSCLC cells (NCI-1299-IR and HCC827-IR cells) were estab-lished. After exposure to X-ray, cell proliferation and survival were assessed by colony formation assay and CCK-8 assay, and lipid ROS level was examined by the fluorophore BODIPY™ 581/591 C11. MDA, GSH, and Fe2+ levels were measured by ELISA kits. The molecular interac-tion was analyzed using ChIP and MSP assays. RESULTS: Our results showed that RSL3 treatment greatly enhanced the radiotherapy sensitivity of NCI-1299-IR and HCC827-IR cells. It was subsequently revealed that MGST1 was highly ex-pressed in NCI-1299-IR and HCC827-IR cells than its parent cells, and silencing of MGST1 re-duced radioresistance of NCI-1299-IR and HCC827-IR cells by facilitating ferroptosis. Mechanis-tically, MGST1 knockdown greatly reduced HO-1 and DNMT1/3A protein levels, leading to re-duced DNA methylation on the ALOX15 promoter region, thereby epigenetically upregulating ALOX15 expression. As expected, the promoting effects of MGST1 silencing on radiosensitivity and ferroptosis in radiation-resistant NSCLC cells were strikingly eliminated by ALOX15 knock-down. CONCLUSION: MGST1 knockdown epigenetically enhanced radiotherapy sensitivity of NCSLC cells by promoting ALOX15-mediated ferroptosis through regulating the HO-1/DNMT1 pathway.

Impact of Cachexia and First-Line Systemic Therapy for Previously Untreated Advanced Non-Small Cell Lung Cancer: NEJ050A.

BACKGROUND: Cancer cachexia complicates advanced non-small cell lung cancer (NSCLC); however, it remains unclear how often cachexia occurs and how it affects the course of chemotherapy in patients receiving first-line systemic therapy. METHODS: We conducted a multicentre, prospective observational study and enrolled previously untreated NSCLC patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2 and cachexia between September 2020 and September 2021. The primary outcome measure was the trends in the Functional Assessment of Anorexia/Cachexia Treatment and Anorexia/Cachexia Subscale [FAACT (A/CS)] scores by cohort. Secondary outcome measures included the incidence of cachexia before the initiation of first-line systemic therapy, quality of life (QOL) measures, body weight (BW) changes, and efficacy and safety of first-line systemic therapy. RESULTS: A total of 887 consecutive patients with previously untreated advanced NSCLC and ECOG PS of 0-2 who were initiated on first-line systemic therapy were evaluated. A total of 281 patients (31.7%) experienced BW loss consistent with the criteria of cachexia, and 186 were evaluated for QOL, BW and outcome measurements. Overall, 180/186 patients received first-line systemic therapy. Cohort 1 (targeted therapy), cohort 2 [cytotoxic chemotherapy (CTx) ± immune checkpoint inhibitors (ICIs)] and cohort 3 (ICIs) included 42, 98 and 40 patients, respectively. There were significant variations in QOL trends by cohort, with chemotherapy-associated emesis affecting early appetite-related QOL. The change in the FAACT (A/CS) score at 1 week from baseline was worse in cohort 2 (the least square mean change ± standard error: -3.0 ± 0.9) than in cohorts 1 (1.6 ± 1.2, p = 0.003) and 3 (1.8 ± 1.0, p = 0.002); meanwhile, the change at 6 weeks was worse in cohort 1 (-1.5 ± 1.2) than in cohorts 2 (3.6 ± 0.9, p = 0.001) and 3 (3.5 ± 1.1, p = 0.004). BW reduction was observed in all cohorts within 6 weeks of therapy initiation. The targeted therapy cohort demonstrated superior progression-free survival (PFS) and overall survival (OS) to CTx ± ICIs cohort or ICIs cohort (median PFS was 9.7 months, 6.3 months, 3.1 months, in cohort 1, 2, 3, respectively (cohort 1 vs. cohort 2: HR, 0.58, p = 0.018; cohort 1 vs. cohort 3: HR, 0.41, p = 0.001); median OS was not reached, 15.8 months, 9.9 months, respectively (cohort 1 vs. cohort 2: HR, 0.52, p = 0.033; cohort 1 vs. cohort 3: HR, 0.37, p = 0.003). CONCLUSIONS: Approximately 1/3 patients with previously untreated advanced NSCLC have cachexia. Appetite-related QOL trends vary based on the type of first-line systemic therapy in cachectic NSCLC patients, and the PFS and OS of these patients seemed to be shorter.

Cost-effectiveness analysis of selpercatinib versus chemotherapy and pembrolizumab in the first-line treatment of rearranged during transfection fusion-positive non-small cell lung cancer in the United States.

BACKGROUND: Although selpercatinib has shown clinical benefits for rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC), its cost-effectiveness requires further evaluation. AIM: This study aimed to evaluate the cost-effectiveness of selpercatinib versus chemotherapy and pembrolizumab in the first-line treatment of RET fusion-positive NSCLC from the perspective of the United States (US) payer. METHOD: A partitioned survival model was developed based on data from the LIBRETTO-431 trial. Cost and utility values for the health state were obtained from database data or published literature. The measured outcomes included quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER). One-way sensitivity analysis and probabilistic sensitivity analyses (PSA) were conducted to assess the uncertainty of the model. RESULTS: Selpercatinib increased QALYs in patients with RET fusion-positive NSCLC by 0.90 compared to chemotherapy plus pembrolizumab, with an additional cost of $542,517.45, resulting in an ICER of $603,286.49/QALY, which exceeded the willingness-to-pay (WTP) threshold ($150,000) in the US. One-way sensitivity analysis suggested that the utility of progressed disease, the utility of progression-free survival, the price of selpercatinib, the discount, the price of pemetrexed, and the price of pembrolizumab had the greatest influence on the cost- effectiveness analysis process. In the PSA, 99.9% of the scatter points were distributed above the US WTP threshold of $150,000. CONCLUSION: From the perspective of the US payer, selpercatinib is not cost-effective compared to chemotherapy and pembrolizumab for first-line treatment in patients with RET fusion-positive NSCLC.

Exploring the anti-NSCLC mechanism of phillyrin targeting inhibition of the HSP90-AKT pathway.

Phillyrin (PHN), derived from the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a kind of Chinese herbal medicine with the effect of clearing heat, and has been used in China for thousands of years in treating various tumors. However, the mechanism of its main components on non-small cell lung cancer (NSCLC) remains unclear. PHN is a distinct component extracted from Forsythia suspensa with promising anti-cancer activity against various tumor types. This study sought to elucidate the promising effects of PHN on NSCLC. Based on network pharmacology results, we identified potential PHN targets and pathways for NSCLC treatment. CCK-8 assay, wound healing assay, apoptosis assay, western blot, and in vivo experiments verified the inhibitory effect of PHN on NSCLC. Network pharmacology identified 160 potential PHN targets, 955 NSCLC-related targets, and 54 common targets, along with 132 pathways and 2 core genes. Biological experiments demonstrated that PHN significantly inhibited the growth and migration of A549 and LLC cells while promoting their apoptosis. Western blot analysis revealed down-regulation of AKT, HSP90AA1, and CDC37 expression, suggesting that PHN inhibits A549 and LLC cell proliferation by down-regulating the HSP90-AKT pathway. In vivo experiments confirmed that PHN significantly inhibited NSCLC growth with low toxicity. This study, using network pharmacology and biological experiments, verified the effectiveness of PHN against NSCLC through the HSP90-AKT pathway. These findings provide a foundation for further research and analysis.

A case of neoadjuvant targeted therapy with pralsetinib for locally advanced lung adenocarcinoma with RET fusion mutation.

This case report details the successful treatment of a 68-year-old male patient with locally advanced RET-rearranged lung adenocarcinoma using neoadjuvant pralsetinib. The patient initially presented with a suspicious right upper lobe nodule, which was later diagnosed as lung adenocarcinoma following genetic testing that revealed a RET exon 12 fusion. After 2 months of neoadjuvant treatment with pralsetinib, a significant radiological response was observed, with a reduction in tumor size and metabolic activity. Subsequently, the patient underwent video-assisted thoracoscopic right upper lobectomy and mediastinal lymph node dissection. Postoperative pathological analysis revealed a major pathological response, with only 5% residual tumor cells in the primary lesion and no viable tumor cells in the lymph nodes. Postoperative pathological staging of TNM was ypT1aN0M0, stage IA1(AJCC, 8th edition). The patient recovered well after surgery, demonstrating the potential efficacy of neoadjuvant pralsetinib in locally advanced RET-rearranged lung adenocarcinoma. However, further clinical validation is required to establish the role of neoadjuvant targeted therapy and postoperative adjuvant therapy in this patient population.

Apatinib monotherapy for early non-small cell lung cancer: a case report.

Stage I non-small cell lung cancer (NSCLC) accounts for about 15% of incident cancer cases. Prognosis is poor, with a metastasis and recurrence rate of 38% within 2 years of surgery and an overall 5-year survival rate of 54-60%. Here, we report successful apatinib monotherapy of early NSCLC in a patient who had declined surgery, radiofrequency ablation, and immunotherapy. The patient received apatinib for 64 months without clinical, laboratory, or radiographic evidence of disease progression. The curative effect was judged to be stable and safe.The role of apatinib as monotherapy for patients with early stage NSCLC who are not candidates for surgery or radiotherapy, or as an adjunct to standard therapy, deserves further study.

Combined inhibition of MET and VEGF enhances therapeutic efficacy of EGFR TKIs in EGFR-mutant non-small cell lung cancer with concomitant aberrant MET activation.

BACKGROUND: Aberrant activation of mesenchymal epithelial transition (MET) has been considered to mediate primary and acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, mechanisms underlying this process are not wholly clear and the effective therapeutic strategy remains to be determined. METHODS: The gefitinib-resistant NSCLC cell lines were induced by concentration increase method in vitro. Western blot and qPCR were used to investigate the relationship between MET and vascular endothelial growth factor (VEGF)/VEGF receptor 2 (VEGFR2) signaling pathway. Double luciferase reporter gene and co-immunoprecipitation were used to further reveal the regulation mechanism between MET and VEGF/VEGFR2. The effect of combined inhibition of MET and VEGF/VEGFR2 signaling pathway on the therapeutic sensitivity of EGFR-TKI in gefitinib resistant cell lines with MET aberration was verified ex vivo and in vivo. RESULTS: We successfully obtained two gefitinib-resistant NSCLC cell lines with EGFR mutation and abnormal activation of MET. We observed that MET formed a positive feedback loop with the VEGF/VEGFR2 signaling, leading to persistent downstream signaling activation. Specifically, MET up-regulated VEGFR2 expression in a MAPK/ERK/ETS1-dependent manner, while VEGF promoted physical interaction between VEGFR2 and MET, thereby facilitating MET phosphorylation. A MET inhibitor, crizotinib, combined with an anti-VEGF antibody, bevacizumab, enhanced the sensitivity of NSCLC cells to gefitinib and synergistically inhibited the activation of downstream signaling in vitro. Dual inhibition of MET and VEGF combined with EGFR TKIs markedly restrained tumor growth in both human NSCLC xenograft models and in an EGFR/MET co-altered case. CONCLUSIONS: Our work reveals a positive feedback loop between MET and VEGF/VEGFR2, resulting in continuous downstream signal activation. Combined inhibition of MET and VEGF/VEGFR2 signaling pathway may be beneficial for reversing EGFR TKIs resistance.

Plain language summary: 5-year results from the CROWN study of lorlatinib vs crizotinib in non-small-cell lung cancer.

WHAT IS THIS STUDY ABOUT?: This is a summary of the results of an ongoing study called CROWN. In the CROWN study, researchers looked at the effects of two medicines called lorlatinib (Lorbrena) and crizotinib (Xalkori) for people with advanced non-small cell lung cancer (NSCLC) who had not been treated yet. Everyone in the study had changes in a gene called anaplastic lymphoma kinase, or ALK, in their cancer cells. The changes in the ALK gene can make cancer grow. This analysis looked at how well lorlatinib and crizotinib worked and their side effects in people with advanced ALK-positive NSCLC after 5 years. WHAT DID THIS STUDY FIND?: After observing people for an average of 5 years, researchers found that more people who took lorlatinib were still alive without their cancer getting worse than the people who took crizotinib. At 5 years, the probability of being alive without their cancer getting worse was 60% in people who took lorlatinib compared with 8% in people who took crizotinib. Fewer people who took lorlatinib had their cancer spread within or to the brain than the people who took crizotinib. In more than half of the people who took lorlatinib, tumors that had spread to the brain did not get worse, and no new tumors spread to the brain after 5 years. In contrast, in about half of the people who took crizotinib, tumors that had spread to the brain got worse or new tumors spread to the brain after 16.4 months. More people who took lorlatinib (115 out of 149, or 77%) had severe or life-threatening side effects than people who took crizotinib (81 out of 142, or 57%). These side effects were like the ones reported in the earlier 3-year analysis. WHAT DO THE FINDINGS OF THE STUDY MEAN?: The 5-year results from the CROWN study showed that more people who took lorlatinib continued to benefit from their treatment than those who took crizotinib. The 5-year benefit of lorlatinib in people with ALK-positive NSCLC has never been seen before.Clinical Trial Registration: NCT03052608 (Phase 3 CROWN study) (ClinicalTrials.gov).