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Lung Cancer (Auckland, N.Z.) 2024Selpercatinib, a potent and highly selective RET kinase inhibitor with significant CNS activity, has recently gained US approval for the treatment of NSCLC harboring...
LIBRETTO-431: Confirming the Superiority of Selpercatinib to Chemotherapy and the Lack of Efficacy of Immune Checkpoint Inhibitors in Advanced Fusion-Positive (+) NSCLC, Another Unique Never-Smoker Predominant Molecular Subtype of NSCLC.
Selpercatinib, a potent and highly selective RET kinase inhibitor with significant CNS activity, has recently gained US approval for the treatment of NSCLC harboring fusions (+) based on a large-scale single-arm study. The LIBRETTO-431 trial was the global pivotal registration phase 3 trial comparing selpercatinib to platinum-based chemotherapy with or without pembrolizumab as the first-line treatment of patients with advanced + NSCLC. Never-smokers constituted 67.4% of the + NSCLC patients enrolled. made up the vast majority (77%) of the + fusion variant with known fusion partner. The results of this study demonstrated significant improvement in progression-free survival (PFS) benefit as well as impressive intracranial disease response in participants treated with selpercatinib as compared to those treated with chemotherapy, with a HR [hazard ratio] of 0.46 (95% CI 0.33-0.70; < 0.001) for the intention-to-treat (ITT)-pembrolizumab group and HR of 0.46 (95% CI 0.31-0.70, < 0.001) for the overall ITT-group of patients. The addition of pembrolizumab to platinum/pemetrexed chemotherapy resulted in numerically identical PFS (11.2 months). These results point to selpercatinib's superiority to traditional chemotherapy regimens in the treatment of NSCLC harboring fusions and add to literature on the salience of targeted precision oncology and lack of efficacy of immune checkpoint inhibitor in NSCLC patients with never-smoker predominant actionable driver mutations. + NSCLC should be added to the list of molecular subtypes (+, +, +) of NSCLC to be excluded in chemoimmunotherapy trial.
PubMed: 38807655
DOI: 10.2147/LCTT.S460147 -
Clinical Case Reports Jun 2024One Kirsten Ras () G12C mutated non-small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first-line...
KEY CLINICAL MESSAGE
One Kirsten Ras () G12C mutated non-small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first-line KRAS-targeted treatment of sotorasib. After disease progression, partial response was achieved with chemotherapy plus immunotherapy. G12C mutated immunoenvironment in NSCLC may favor the immunotherapy.
ABSTRACT
is one of the most commonly mutated genes, which used to be untargetable. The phase II CodeBreak 100 trial revealed 6.8-month median progress-free survival (PFS) and 12.5-month overall survival (OS) in previously treated G12C-mutant NSCLC patients treated with KRAS inhibitor, sotorasib. The specimens of the brain, lymph node (LN), and blood from the patient were analyzed by next-generation sequencing. Hematoxylin and eosin staining and immunohistochemistry were performed for pathological characterization. Computed tomography (CT) and magnetic resonance imaging (MRI) scan were used for treatment response evaluation. The patient was diagnosed in a bad Eastern Cooperative Oncology Group performance status (ECOG-PS) with metastatic G12C-mutated lung adenocarcinoma who had achieved mixed response to sotorasib as the first-line treatment. Although 5-month PFS of the treatment with sotorasib was not surprising, the patient achieved significantly improved ECOG-PS score from 4 to 1. Subsequently, partial response (PR) was achieved with the treatment of pemetrexed plus pembrolizumab. This case highlights superior efficacy of first-line treatment with sotorasib for the advance untreated G12C-mutant patients. The high efficacy of the treatment with chemotherapy plus immunotherapy revealed that immunoenvironment of G12C-mutated patient may favor the immunotherapy.
PubMed: 38799516
DOI: 10.1002/ccr3.8866 -
International Journal of Molecular... May 2024Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and...
Malignant pleural mesothelioma (MPM) remains an incurable disease. This is partly due to the lack of experimental models that fully recapitulate the complexity and heterogeneity of MPM, a major challenge for therapeutic management of the disease. In addition, the contribution of the MPM microenvironment is relevant for the adaptive response to therapy. We established mesothelioma patient-derived organoid (mPDO) cultures from MPM pleural effusions and tested their response to pemetrexed and cisplatin. We aimed to evaluate the contribution of mesothelioma-associated fibroblasts (MAFs) to the response to pemetrexed and cisplatin (P+C). Organoid cultures were obtained from eight MPM patients using specific growth media and conditions to expand pleural effusion-derived cells. Flow cytometry was used to verify the similarity of the organoid cultures to the original samples. MAFs were isolated and co-cultured with mPDOs, and the addition of MAFs reduced the sensitivity of mPDOs to P+C. Organoid formation and expression of cancer stem cell markers such as ABCG2, NANOG, and CD44 were altered by conditioned media from treated MAFs. We identified IL-6 as the major contributor to the attenuated response to chemotherapy. IL-6 secretion by MAFs is correlated with increased resistance of mPDOs to pemetrexed and cisplatin.
Topics: Humans; Organoids; Interleukin-6; Cisplatin; Pemetrexed; Mesothelioma, Malignant; Cancer-Associated Fibroblasts; Mesothelioma; Tumor Microenvironment; Male; Female; Fibroblasts; Middle Aged; Aged; Antineoplastic Agents; Neoplastic Stem Cells; Lung Neoplasms
PubMed: 38791392
DOI: 10.3390/ijms25105355 -
Cureus Apr 2024Lung cancer is one of the top causes of cancer deaths globally, including in Saudi Arabia. Although several prognostic markers have been established, the clinical...
BACKGROUND
Lung cancer is one of the top causes of cancer deaths globally, including in Saudi Arabia. Although several prognostic markers have been established, the clinical features and outcomes of lung cancer in Saudi Arabia are not well understood. This study aimed to describe the clinical and therapeutic characteristics of advanced lung cancer in Najran, Saudi Arabia.
METHOD
A retrospective chart review of 44 patients diagnosed with advanced lung cancer between June 2018 and September 2021 and treated at the Oncology Center of King Khalid Hospital in Najran City, Saudi Arabia. The clinicopathological features, treatment used, response, and survival outcomes were collected and analyzed.
RESULT
The mean age was 69.3 ± 10.7 years, most of them (n = 35, 79.5%) were male and older than 70 years (n = 24, 54.5%). Adenocarcinoma was the most observed cancer (n = 35, 79.5%), followed by squamous cell carcinoma in six (13.6%). Most cases (n = 42, 95.5%) were in stage IV. Epidermal growth factor receptor (EGFR) mutations were positive in two (4.5%) cases and ALK mutation was positive in two (4.5%) cases. Metastasis to pleura with pleural effusion was the common presentation (n = 41, 93%). Chemotherapy was administered as the first line in 19 cases (43.2%) while 25 cases (56.8%) received chemoimmunotherapy. The commonest chemoimmunotherapy regimen used was carboplatin-pemetrexed-pembrolizumab in 16 (36.4%), followed by carboplatin-paclitaxel-pembrolizumab in 9 (20.5%) cases. The response to initial systemic therapy was as follows disease progression, stable disease, and complete remission in 10 (22.7%), 33 (75.0%), and 1 (2.3%), respectively. Median progression-free survival was 8.7 months (interquartile range (IQR): 5.7-11.4), and the median overall survival was 12.3 months (IQR: 11.1-13.4). Among the total documented 36 (81.8%) dead cases, disease progression was the main cause of death in 25 cases (56.8%). Using chemoimmunotherapy as the first-line therapy was associated with numerical survival improvement compared to using chemotherapy alone (HR: 0.75; 95% CI: 0.39-1.46) however, it was not statistically significant (p = 0.397).
CONCLUSION
In this study, the majority of lung cancer patients were male and over 70 years old. Adenocarcinoma was the most common histological type. Metastasis to pleura with pleural effusion was the common presentation. The most common treatment used was chemoimmunotherapy with a regimen of carboplatin-pemetrexed-pembrolizumab. Addressing the possible causes of delayed diagnosis of lung cancer is crucial for improved survival outcomes.
PubMed: 38770472
DOI: 10.7759/cureus.58602 -
The Oncologist May 2024The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how...
BACKGROUND
The role of tyrosine kinase inhibitors (TKIs) in early-stage and metastatic oncogene-driven non-small cell lung cancer (NSCLC) is established, but it remains unknown how best to integrate TKIs with concurrent chemoradiotherapy (cCRT) in locally advanced disease. The phase 2 ASCENT trial assessed the efficacy and safety of afatinib and cCRT with or without surgery in locally advanced epidermal growth factor receptor (EGFR)-mutant NSCLC.
PATIENTS AND METHODS
Adults ≥18 years with histologically confirmed stage III (AJCC 7th edition) NSCLC with activating EGFR mutations were enrolled at Mass General and Dana-Farber/Brigham Cancer Centers, Boston, Massachusetts. Patients received induction afatinib 40 mg daily for 2 months, then cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 IV every 3 weeks during RT (definitive or neoadjuvant dosing). Patients with resectable disease underwent surgery. All patients were offered consolidation afatinib for 2 years. The primary endpoint was the objective response rate (ORR) to induction TKI. Secondary endpoints were safety, conversion to operability, progression-free survival (PFS), and overall survival (OS). Analyses were performed on the intention-to-treat population.
RESULTS
Nineteen patients (median age 56 years; 74% female) were enrolled. ORR to induction afatinib was 63%. Seventeen patients received cCRT; 2/9 previously unresectable became resectable. Ten underwent surgery; 6 had a major or complete pathological response. Thirteen received consolidation afatinib. With a median follow-up of 5.0 years, median PFS and OS were 2.6 (95% CI, 1.4-3.1) and 5.8 years (2.9-NR), respectively. Sixteen recurred or died; 6 recurrences were isolated to CNS. The median time to progression after stopping consolidation TKI was 2.9 months (95% CI, 1.1-7.2). Four developed grade 2 pneumonitis. There were no treatment-related deaths.
CONCLUSION
We explored the efficacy of combining TKI with cCRT in oncogene-driven NSCLC. Induction TKI did not compromise subsequent receipt of multimodality therapy. PFS was promising, but the prevalence of CNS-only recurrences and rapid progression after TKI discontinuation speak to unmet needs in measuring and eradicating micrometastatic disease.
PubMed: 38761385
DOI: 10.1093/oncolo/oyae107 -
Internal Medicine (Tokyo, Japan) May 2024Objective Pembrolizumab plus platinum and pemetrexed (Pemb-Plt-PEM) combination therapy is an effective first-line treatment for advanced non-squamous non-small-cell...
Objective Pembrolizumab plus platinum and pemetrexed (Pemb-Plt-PEM) combination therapy is an effective first-line treatment for advanced non-squamous non-small-cell lung cancer (NSCLC), regardless of programmed death ligand 1 expression. However, the effectiveness and feasibility of first-line Pemb-Plt-PEM therapy in elderly patients (≥75 years old) remain unclear. Therefore, this study investigated the safety and efficacy of first-line Pemb-Plt-PEM in elderly patients with nonsquamous NSCLC. Methods We retrospectively evaluated the data of patients ≥75 years old with non-squamous NSCLC who were treated with first-line Pemb-Plt-PEM from December 2018 to December 2020 at 10 institutes in Japan. Data on patient characteristics, efficacy of pemb-Plt-PEM therapy, and the type and severity of adverse events were reviewed. Results Thirty patients [20 men and 10 women; median age: 76 (range: 75-82) years old] were included in the analysis. The overall response rate, disease control rate, median progression-free survival (PFS), and median overall survival (OS) were 40.0%, 66.7%, and 7.5 and 24.0 months, respectively. The treatment-related deaths were caused by pneumonitis. First-line Pemb-Plt-PEM was associated with the PFS, based on the neutrophil-to-lymphocyte ratio (NLR). The PFS for low and high NLR values was 10.1 and 2.0 months, respectively. Furthermore, the sex and NLR influenced the association between Pemb-Plt-PEM and the OS. The OS for low and high NLR values was 32.8 and 2.6 months, respectively. Conclusion First-line pemb-Plt-PEM therapy is effective and feasible in elderly patients with non-squamous NSCLC.
PubMed: 38749728
DOI: 10.2169/internalmedicine.3649-24 -
South Asian Journal of Cancer Jan 2024Ranjith K.The objective of this study was to compare the efficacy, safety, pharmacokinetics, and immunogenicity of a proposed bevacizumab biosimilar (DRL_BZ) with the...
Comparison of Efficacy and Safety of a Bevacizumab Biosimilar, in Combination with Chemotherapies, in Nonresectable Metastatic Colorectal Cancer and in Advanced Nonsquamous Non-Small Cell Lung Cancer: A Randomized, Double-Blind, Phase III Study.
Ranjith K.The objective of this study was to compare the efficacy, safety, pharmacokinetics, and immunogenicity of a proposed bevacizumab biosimilar (DRL_BZ) with the innovator Avastin (reference medicinal product [RMP]) in patients with nonresectable metastatic colorectal cancer (mCRC) over a period of 9 months and advanced nonsquamous non-small cell lung cancer (NSCLC) over 6 months. The study was planned as a randomized, double-blind trial. In part A, a total of 117 mCRC patients were intended to receive 5 mg/kg of bevacizumab every 2 weeks along with mFOLFOX6 chemotherapy for a maximum of 18 cycles. In part B, 60 NSCLC patients were to receive 15 mg/kg of bevacizumab every 3 weeks along with pemetrexed and carboplatin for the initial four cycles, followed by pemetrexed for another four cycles. The primary endpoint was the progression-free survival rate at 6 months (PFS6) in both subparts. The anticipated sample size was 106 evaluable mCRC patients to achieve 85% statistical power for concluding noninferiority with a margin of half the difference (18.8%) between DRL_BZ and Avastin, along with a pilot study involving 60 evaluable NSCLC patients. Safety comparison included assessing adverse events (AEs), infusion reactions, and lab abnormalities. Immunogenicity comparison involved the incidence of antidrug antibodies (ADAs) and neutralizing antibodies (NAbs). Pharmacokinetic comparison was planned after the first and fourth dosing cycles of treatment in 24 NSCLC patients. The PFS6 for mCRC patients treated with DRL_BZ and RMP was 57.8% and 50% respectively, with a difference in efficacy of 7.8 (-8.7, 23.7). The PFS9 was 31.1% and 22.9%, with a difference of 8.2% (-6.9%, 22.9%). The objective response rate (ORR) for DRL_BZ and RMP was 28.8% and 22.4%, while the disease control rate (DCR) was 44.2% and 37.9% respectively. For NSCLC patients, the PFS6 was 44% and 45%, showing a difference of -1.0 (-4.2, 22.1). The ORR was 41.4% and 48.1%, and the DCR was 62.1% and 63%. The frequency, type, and severity of AEs were similar in both indications. Blood levels during the first and fourth dosing cycles exhibited comparable values. All NSCLC patients tested negative for ADA, while no mCRC patients on DRL_BZ tested positive for ADA. Low incidences of ADA (8%) and NAbs (4.0%) were reported in patients on RMP. Overall, the efficacy, safety, immunogenicity, and pharmacokinetic parameters of DRL_BZ and RMP were found to be comparable. Clinical Trial Registration For BZ-01-002: CTRI/2016/01/006481.
PubMed: 38721097
DOI: 10.1055/s-0043-1774403 -
Frontiers in Oncology 2024Leptomeningeal metastasis (LM) is a complication of non-small cell lung cancer (NSCLC) characterized by poor prognosis and short survival. A variety of therapeutic...
Double-dose osimertinib combined with intrathecal injection of pemetrexed improves the efficacy of EGFR-mutant non-small cell lung cancer and leptomeningeal metastasis: case report and literature review.
Leptomeningeal metastasis (LM) is a complication of non-small cell lung cancer (NSCLC) characterized by poor prognosis and short survival. A variety of therapeutic approaches have been sought to improve the efficacy of LM. Here we present a clinical case and conduct a literature review to investigate the effectiveness and safety of double-dose osimertinib combined with a pemetrexed intrathecal injection. This is an older man who underwent thoracoscopic pneumonectomy and was diagnosed with stage IIA lung adenocarcinoma with EGFR21 L858R mutation. He experienced thoracic vertebral metastases 33 months postoperatively and received first-line treatment with gefitinib combined with radiotherapy for vertebral metastases. However, the patient developed a grade 3 rash with unacceptable toxicity and his CEA levels were significantly increased 22 months later, leading to a targeted treatment adjustment to 80 mg of osimertinib orally once daily. Four months later, the patient developed LM and osimertinib dosage was increased to 160 mg once daily; however, neurological symptoms did not improve, and cerebrospinal fluid (CSF) tumor cells remained detected. Accordingly, the patient received an intrathecal injection of pemetrexed (dose 30 mg) every 2-3 months, 2-3 times per course (4-6 days each time), and continued to receive a double dose of osimertinib. After three courses of intrathecal chemotherapy, CSF tumor cells were eliminated, and neurological symptoms significantly improved. During the treatment, he experienced a one-degree rash, leukopenia, thrombocytopenia, and fatigue. This patient has been alive and well with disease control for 28 months since the diagnosis of meningeal metastases. Combining double-dose osimertinib and an intrathecal injection of pemetrexed demonstrated therapeutic efficacy and manageable adverse effects in this patient with advanced NSCLC with EGFR-mutant and LM.
PubMed: 38711856
DOI: 10.3389/fonc.2024.1377451 -
JAMA Network Open May 2024Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end... (Observational Study)
Observational Study
IMPORTANCE
Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to assess therapeutic response in clinical trials but not in routine care; thus, RECIST-based end points are difficult to include in observational studies. Clinician-anchored approaches for measuring clinical response have been validated but not widely compared with clinical trial data, limiting their use as evidence for clinical decision-making.
OBJECTIVE
To compare response- and progression-based end points in clinical trial and observational cohorts of patients with non-small cell lung cancer (NSCLC).
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study used patient-level data from the IMpower132 trial (conducted April 7, 2016, to May 31, 2017) and a nationwide electronic health record (EHR)-derived deidentified database (data collected January 1, 2011, to March 31, 2022). Patients in the observational cohort were selected according to the inclusion and exclusion criteria of the IMpower132 trial. All patients in the observational cohort had stage IV NSCLC.
EXPOSURE
All patients were randomized to or received first-line carboplatin or cisplatin plus pemetrexed.
MAIN OUTCOMES AND MEASURES
End points included response rates, duration of response, and progression-free survival, compared between the trial and observational cohorts before and after weighting. Response rates for the observational cohort were derived from the EHR.
RESULTS
A total of 769 patients met inclusion criteria, 494 in the observational cohort (median [IQR] age, 67 [60-74] years; 228 [46.2%] female; 45 [9.1%] Black or African American; 352 [71.3%] White; 53 [10.7%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial) and 275 in the trial cohort (median [IQR] age, 63 [56-68] years; 90 [32.7%] female; 4 [1.5%] Black or African American; 194 [70.5%] White; 65 [23.6%] American Indian or Alaska Native, Asian, Hawaiian or Pacific Islander, or multiracial). All 3 end points were comparable between the study cohorts. Trial patients had a higher number of response assessments compared with patients in the weighted observational cohort. The EHR-derived response rate was numerically higher than the objective response rate after weighting (100.3 of 249.3 [40.2%] vs 105 of 275 [38.2%]) due to higher rates of observed partial response than RECIST-based partial response. Among patients with at least 1 response assessment, the EHR-derived response rate remained higher than the objective response rate (100.3 of 193.4 [51.9%] vs 105 of 256 [41.0%]) due to a higher proportion of patients in the observational cohort with no response assessment.
CONCLUSIONS AND RELEVANCE
In this study, response- and progression-based end points were similar between clinical trial and weighted observational cohorts, which increases confidence in the reliability of observational end points and can inform their interpretation in relation to trial end points. Additionally, the difference observed in response rates (including vs excluding patients with no response assessment) highlights the importance of future research adopting this 2-way approach when evaluating the relationship of EHR-derived and objective response rates.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Female; Male; Lung Neoplasms; Middle Aged; Aged; Retrospective Studies; Carboplatin; Disease Progression; Cisplatin; Pemetrexed; Cohort Studies; Response Evaluation Criteria in Solid Tumors; Antineoplastic Combined Chemotherapy Protocols; Progression-Free Survival
PubMed: 38700864
DOI: 10.1001/jamanetworkopen.2024.9286 -
Frontiers in Oncology 2024Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing...
BACKGROUND
Front-line therapy with an EGFR tyrosine kinase inhibitor (TKI) is the standard of care for treating patients with advanced nonsquamous NSCLC with the common sensitizing exon 19 deletion and exon 21 L858R point mutations. However, EGFR TKI resistance inevitably develops. The optimal subsequent therapy remains to be identified, although platinum-containing chemotherapy regimens are often administered. Our objectives were to describe baseline characteristics, survival, and subsequent treatment patterns for patients with advanced nonsquamous NSCLC with exon 19 deletion or L858R mutation who received a platinum-based combination regimen after front-line EGFR TKI therapy.
METHODS
This retrospective study used a nationwide electronic health record-derived deidentified database to select adult patients with advanced nonsquamous NSCLC, evidence of exon 19 deletion or L858R mutation, and ECOG performance status of 0-2 who initiated platinum-containing chemotherapy, with or without concomitant immunotherapy, from 1-January-2011 to 30-June-2020 following receipt of any EGFR TKI as first-line therapy or, alternatively, a first- or second-generation EGFR TKI (erlotinib, afatinib, gefitinib, dacomitinib) as first-line therapy followed by the third-generation EGFR TKI osimertinib as second-line therapy. Data cut-off was 30-June-2022. The Kaplan-Meier method was used to estimate overall survival (OS) after initiation of pemetrexed-platinum (n=119) or any platinum-based combination regimen (platinum cohort; n=311).
RESULTS
The two cohorts included two-thirds women (65%-66%) and 57%-58% nonsmokers; median ages were 66 and 65 years in pemetrexed-platinum and platinum cohorts, respectively. Median OS was 10.3 months (95% CI, 8.1-13.9) from pemetrexed-platinum initiation and 12.4 months (95% CI, 10.2-15.2) from platinum initiation; 12-month survival rates were 48% and 51%, respectively; 260 patients (84%) had died by the end of the study.
CONCLUSION
The suboptimal survival outcomes recorded in this study demonstrate the unmet need to identify more effective subsequent treatment regimens for patients with -mutated advanced nonsquamous NSCLC after EGFR TKI resistance develops.
PubMed: 38699642
DOI: 10.3389/fonc.2024.1285280