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Annals of Oncology : Official Journal... Jan 2024Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor...
Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.
BACKGROUND
Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial.
PATIENTS AND METHODS
A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion.
RESULTS
All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy.
CONCLUSIONS
Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.
Topics: Humans; Acrylamides; Aniline Compounds; Antibodies, Bispecific; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Carcinoma, Non-Small-Cell Lung; Disease Progression; ErbB Receptors; Indoles; Lung Neoplasms; Morpholines; Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines
PubMed: 37879444
DOI: 10.1016/j.annonc.2023.10.117 -
Journal of Thoracic Oncology : Official... Feb 2024Treatment with 3 years of adjuvant osimertinib is considered a new standard in patients with completely resected stage I to IIIA NSCLC harboring a common sensitizing... (Review)
Review
Treatment with 3 years of adjuvant osimertinib is considered a new standard in patients with completely resected stage I to IIIA NSCLC harboring a common sensitizing EGFR mutation. This therapeutic approach significantly prolonged the disease-free survival and the overall survival versus placebo and revealed a significant role in preventing the occurrence of brain metastases. However, many unanswered questions remain, including the optimal duration of this therapy, whether all patients benefit from adjuvant osimertinib, and the role of adjuvant chemotherapy in this population. Indeed, there is a renewed interest in neoadjuvant strategies with targeted therapies in resectable NSCLC harboring oncogenic drivers. In light of these considerations, we discuss the past and current treatment options, and the clinical challenges that should be addressed to optimize the treatment outcomes in this patient population.
Topics: Humans; Lung Neoplasms; Protein Kinase Inhibitors; ErbB Receptors; Neoplasm Staging; Carcinoma, Non-Small-Cell Lung; Mutation; Acrylamides; Aniline Compounds; Indoles; Pyrimidines
PubMed: 37783386
DOI: 10.1016/j.jtho.2023.09.1451 -
JAMA Oncology Feb 2024A series of high-profile clinical trials for patients with resectable early-stage non-small cell lung cancer (NSCLC) have recently changed the standard of care in this... (Review)
Review
IMPORTANCE
A series of high-profile clinical trials for patients with resectable early-stage non-small cell lung cancer (NSCLC) have recently changed the standard of care in this setting. Specifically, studies have demonstrated statistically and clinically significant improvements in efficacy with the targeted therapy for adjuvant osimertinib in patients with resected NSCLC harboring an epidermal growth factor receptor (EGFR) genomic abnormality (GA), whereas trials with chemotherapy combined with nivolumab in the neoadjuvant setting and others testing atezolizumab or pembrolizumab as adjuvant therapy have all demonstrated improvements in event-free survival (EFS) (for neoadjuvant therapy) or disease-free survival (DFS) (for adjuvant therapy). These trials introduce many open questions about how to apply these findings in clinical practice.
OBSERVATIONS
Treatment with adjuvant osimertinib for 3 years was associated with significant improvement in both DFS and overall survival (OS), but the erosion of the DFS benefit after the duration of treatment ends suggests a potential value for more longitudinal treatment. The potential value of highly effective targeted therapies as adjuvant therapy for other GAs has a compelling rationale but no data at this time. Adjuvant atezolizumab or pembrolizumab, generally administered for 1 year after postoperative chemotherapy, are appropriate considerations, but only atezolizumab for patients with tumor programmed death-ligand 1 (PD-L1) levels of 50% has demonstrated a benefit in OS. Neoadjuvant chemotherapy with nivolumab offers a strong EFS benefit, a shorter interval of treatment, and radiographic and pathologic feedback for patients with resectable stage IB to IIIA NSCLC, although very recent randomized clinical trials of perioperative immunotherapy both combined with chemotherapy preoperatively and administered postoperatively highlight the debatable value of adjuvant immunotherapy after prior chemoimmunotherapy. Improved tumor shrinkage rates with neoadjuvant chemoimmunotherapy suggest the possibility that criteria for resectability may potentially be redefined in anticipation of a good response to neoadjuvant chemoimmunotherapy.
CONCLUSIONS AND RELEVANCE
Developments in resectable NSCLC have arrived so rapidly that they have also created practical challenges of identifying optimal patients and prioritizing options among these new competing standards. In some cases, practical management requires clinical judgment and discussion with the patient to cover the gaps in prospective data. Caution should be exerted when extrapolating beyond the available data.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Nivolumab; Prospective Studies; Acrylamides; Aniline Compounds; Indoles; Pyrimidines
PubMed: 38153722
DOI: 10.1001/jamaoncol.2023.5276 -
Journal of Clinical Oncology : Official... Mar 2024We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor ()-mutated advanced... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor ()-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status.
METHODS
Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR).
RESULTS
On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR.
CONCLUSION
Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with -mutated advanced NSCLC, including those with CNS metastases.
Topics: Humans; Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Central Nervous System Neoplasms; ErbB Receptors; Indoles; Lung Neoplasms; Mutation; Pemetrexed; Platinum; Protein Kinase Inhibitors; Pyrimidines
PubMed: 38042525
DOI: 10.1200/JCO.23.02219 -
JAMA Oncology Jan 2024Non-small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations.
IMPORTANCE
Non-small cell lung cancer (NSCLC) with uncommon EGFR mutations is a rare subgroup, composing 14% of all EGFR mutations.
OBJECTIVE
To determine the usefulness of osimertinib in previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations, excluding exon 20 insertion mutations.
DESIGN, SETTING, AND PARTICIPANTS
This multicenter, open-label, single-group, phase 2 nonrandomized clinical trial enrolled patients from April 10, 2020, to May 31, 2022, with a follow-up of 6 months from the date the last patient was enrolled. The study enrolled 42 patients with uncommon EGFR mutations, of whom 40 were eligible.
INTERVENTION
Osimertinib, 80 mg once daily, was administered orally to patients.
MAIN OUTCOMES AND MEASURES
The primary end point was the overall response rate (ORR). The secondary end points were disease control rate (DCR), progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), duration of response (DoR), and safety of osimertinib. Patients were included in the study on an intention-to-treat basis.
RESULTS
Of the 40 eligible patients, 22 were men (55.0%) and the median age was 72 years (range, 39.0-88.0 years). The most common mutations were G719X (20 [50.0%]), S768I (10 [25.0%]), and L861Q (8 [20.0%]). The ORR was 55.0% (90% CI, 40.9%-68.5%) and the DCR was 90.0% (95% CI, 76.3%-97.2%). The median PFS was 9.4 months (95% CI, 3.7-15.2 months) after a median follow-up of 12.7 months (range, 2.7-30.7 months). The median TTF was 9.5 months (95% CI, 5.6-30.3 months), median OS was not reached (NR; 95% CI, 19.3 months to NR), and median DoR was 22.7 months (95% CI, 9.5 months to NR). The ORR for patients with solitary or compound uncommon EGFR mutations was 45.5% (90% CI, 26.9%-65.3%) and 66.7% (90% CI, 43.7%-83.7%), respectively. Median PFS for patients with solitary or compound uncommon EGFR mutations was 5.4 months (95% CI, 3.6-22.7 months) and 9.8 months (95% CI, 5.1 months to NR), respectively. Median OS for patients with solitary or compound uncommon EGFR mutations was 23.0 months (95% CI, 12.3 months to NR) and NR, respectively. Median DoR for patients with solitary or compound uncommon EGFR mutations was 22.7 months (95% CI, 3.6-22.7 months) or NR (95% CI, 5.7 months to NR), respectively. Grade 3 or 4 adverse events were reported by 11 patients (27.5%), and 5 patients (12.5%) developed interstitial lung disease. All adverse events were manageable, and there were no treatment-related deaths.
CONCLUSIONS AND RELEVANCE
Osimertinib showed clinical activity with manageable toxic effects among previously untreated patients with metastatic NSCLC harboring uncommon EGFR mutations other than exon 20 insertion mutations. The results support the use of osimertinib as a treatment option for this patient population.
TRIAL REGISTRATION
Japan Registry of Clinical Trials Identifier: jRCTs071200002.
Topics: Male; Humans; Aged; Female; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein Kinase Inhibitors; ErbB Receptors; Mutation; Acrylamides; Aniline Compounds; Indoles; Pyrimidines
PubMed: 37991747
DOI: 10.1001/jamaoncol.2023.5013 -
Angewandte Chemie (International Ed. in... Dec 20235-Methylcytosine (m C) is an RNA modification prevalent on tRNAs, where it can protect tRNAs from endonucleolytic cleavage to maintain protein synthesis. The NSUN family...
5-Methylcytosine (m C) is an RNA modification prevalent on tRNAs, where it can protect tRNAs from endonucleolytic cleavage to maintain protein synthesis. The NSUN family (NSUN1-7 in humans) of RNA methyltransferases are capable of installing the methyl group onto the C position of cytosines in RNA. NSUNs are implicated in a wide range of (patho)physiological processes, but selective and cell-active inhibitors of these enzymes are lacking. Here, we use cysteine-directed activity-based protein profiling (ABPP) to discover azetidine acrylamides that act as stereoselective covalent inhibitors of human NSUN2. Despite targeting a conserved catalytic cysteine in the NSUN family, the NSUN2 inhibitors show negligible cross-reactivity with other human NSUNs and exhibit good proteome-wide selectivity. We verify that the azetidine acrylamides inhibit the catalytic activity of recombinant NSUN2, but not NSUN6, and demonstrate that these compounds stereoselectively disrupt NSUN2-tRNA interactions in cancer cells, leading to a global reduction in tRNA m C content. Our findings thus highlight the potential to create isotype-selective and cell-active inhibitors of NSUN2 with covalent chemistry targeting a conserved catalytic cysteine.
Topics: Humans; Acrylamides; Azetidines; Cysteine; Methylation; Methyltransferases; Proteomics; RNA, Transfer; tRNA Methyltransferases; Enzyme Inhibitors
PubMed: 37909922
DOI: 10.1002/anie.202311924 -
Journal of Thoracic Oncology : Official... Mar 2024Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or...
INTRODUCTION
Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification, and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance.
METHODS
H1975/EGFR (L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity, and self-renewal capacity.
RESULTS
We reveal that MUC1-C is up-regulated in H1975 osimertinib drug-tolerant persister cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are found to be dependent on MUC1-C for induction of (1) phospho (p)-EGFR, p-ERK, and p-AKT, (2) EMT, and (3) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK, and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (1) MET-amplified MGH170-1D #2 cells and (2) MGH121 Res#2/EGFR (T790M/C797S) cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. In support of these results, high MUC1 mRNA and MUC1-C protein expression is associated with a poor prognosis for patients with EGFR-mutant NSCLCs.
CONCLUSIONS
Our findings reveal that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib-resistant NSCLCs.
Topics: Humans; Lung Neoplasms; ErbB Receptors; Mutation; Proto-Oncogene Proteins c-akt; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Carcinoma, Non-Small-Cell Lung; Aniline Compounds; Mucin-1; Acrylamides; Indoles; Pyrimidines
PubMed: 37924972
DOI: 10.1016/j.jtho.2023.10.017 -
Journal of Thoracic Oncology : Official... Jun 2024Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for...
Consolidation Osimertinib Versus Durvalumab Versus Observation After Concurrent Chemoradiation in Unresectable EGFR-Mutant NSCLC: A Multicenter Retrospective Cohort Study.
INTRODUCTION
Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown.
METHODS
In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology Criteria for Adverse Events version 5.0. Multivariable Cox regression analysis was used.
RESULTS
Of 136 patients with stage III EGFRmut NSCLC treated with definitive concurrent CRT, 56 received consolidation durvalumab, 33 received consolidation osimertinib, and 47 was on observation alone. Baseline characteristics were similar across the three cohorts. With a median follow-up of 46 months for the entire cohort, the median duration of treatment was not reached (NR) for osimertinib (interquartile range: NR-NR) and was 5.5 (interquartile range: 2.4-10.8) months with durvalumab. After adjusting for nodal status, stage III A/B/C, and age, patients treated with consolidation osimertinib had significantly longer 24-month rwPFS compared to those treated with durvalumab or in the observation cohorts (osimertinib: 86%, durvalumab: 30%, observation: 27%, p < 0.001 for both comparisons). There was no difference in rwPFS between the durvalumab and the observation cohorts. No significant difference in overall survival across the three cohorts was detected, likely due to the limited follow-up. Any-grade trAE occurred in 52% (2 [6.1%] grade ≥3) and 48% (10 [18%] grade ≥3) of patients treated with osimertinib and durvalumab, respectively. Of 45 patients who progressed on consolidation durvalumab, 37 (82%) subsequently received EGFR tyrosine kinase inhibitors. Of these, 14 (38%) patients developed trAEs including five patients with pneumonitis (14%; 2 [5.4%] grade ≥3) and five patients with diarrhea (14%; 1 [2.7%] grade ≥3).
CONCLUSIONS
This study suggests that among patients with stage III unresectable NSCLC with a sensitizing EGFR mutation, consolidation osimertinib was associated with a significantly longer rwPFS compared to durvalumab or observation. No unanticipated safety signals were observed with consolidation osimertinib.
Topics: Humans; Retrospective Studies; Carcinoma, Non-Small-Cell Lung; Male; Female; Lung Neoplasms; Acrylamides; Antibodies, Monoclonal; Middle Aged; Aged; Chemoradiotherapy; ErbB Receptors; Aniline Compounds; Mutation; Consolidation Chemotherapy; Indoles; Pyrimidines
PubMed: 38278303
DOI: 10.1016/j.jtho.2024.01.012 -
Cancer Discovery Aug 2023The final overall survival (OS) results for the ADAURA trial show that osimertinib reduces the risk of death by 51% in patients with EGFR-mutated non-small cell lung...
The final overall survival (OS) results for the ADAURA trial show that osimertinib reduces the risk of death by 51% in patients with EGFR-mutated non-small cell lung cancer. For stage II or IIIA disease, the 5-year OS was 85% in patients who received osimertinib and 73% in the control group. The findings were nearly identical when patients with stage IB tumors were included in the analysis.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Acrylamides; Aniline Compounds; Mutation; Protein Kinase Inhibitors
PubMed: 37276331
DOI: 10.1158/2159-8290.CD-NB2023-0045 -
Journal of Endocrinological... Aug 2023Acrylamide (AA) is a potential carcinogen that mainly comes from fried, baked and roasted foods, and Hb adducts of AA (HbAA) and its metabolite glycidamide (HbGA) are...
PURPOSE
Acrylamide (AA) is a potential carcinogen that mainly comes from fried, baked and roasted foods, and Hb adducts of AA (HbAA) and its metabolite glycidamide (HbGA) are the biomarkers of its exposure. Increasing evidence suggests that AA is associated with various hormone-related cancers. This study aims to explore the association of HbAA and HbGA with female serum sex hormone concentrations.
METHODS
942 women from the National Health and Nutrition Examination Survey cycles (2013-2016) were included in this cross-sectional study. The associations between HbAA or HbGA or HbGA/HbAA and sex hormones were assessed by the multiple linear regression. Further stratified analyses were conducted to figure out the effects of menopausal status, BMI and smoking status on sex hormone levels.
RESULTS
Among all participants, 597 were premenopausal and 345 were postmenopausal. HbAA was positively associated with both two androgen indicators. Specifically, a ln-unit increase in HbAA was associated with 0.41 ng/dL higher ln(total testosterone, TT) (95% CI 0.00, 0.27) and 0.14 ng/dL higher ln(free testosterone) (95%CI 0.00, 0.28), respectively. However, HbGA concentrations had no association with sex hormones in the overall population. Additionally, HbGA/HbAA was negatively associated with TT and SHBG in the overall population as well as postmenopausal women. In stratified analysis, higher HbAA was associated with rising TT in postmenopausal women (β = 0.29, 95%CI 0.04, 0.53) and underweight/normal-weight women (β = 0.18, 95%CI 0.03, 0.33). Other indicators had no significant association detected in estradiol and sex hormone-binding globulin.
CONCLUSION
Our results revealed that HbAA was positively associated with androgen concentrations, especially in postmenopausal and BMI < 25 women.
Topics: Humans; Female; Nutrition Surveys; Hemoglobins; Acrylamide; Androgens; Cross-Sectional Studies; Postmenopause; Gonadal Steroid Hormones; Testosterone; Sex Hormone-Binding Globulin
PubMed: 36602706
DOI: 10.1007/s40618-022-01976-3