Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA.

BACKGROUND: Amivantamab-lazertinib significantly prolonged progression-free survival (PFS) versus osimertinib in patients with epidermal growth factor receptor (EGFR)-mutant advanced non-small-cell lung cancer [NSCLC; hazard ratio (HR) 0.70; P < 0.001], including those with a history of brain metastases (HR 0.69). Patients with TP53 co-mutations, detectable circulating tumor DNA (ctDNA), baseline liver metastases, and those without ctDNA clearance on treatment have poor prognoses. We evaluated outcomes in these high-risk subgroups. PATIENTS AND METHODS: This analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR). RESULTS: Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004]. CONCLUSIONS: Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC.

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.

Stereotactic body radiation therapy (SBRT) as salvage treatment for early stage lung cancer with interstitial lung disease (ILD): An observational and exploratory case series of non-asian patients.

Interstitial lung disease (ILD) can coexist with early-stage lung cancer (LC) and may compromise surgery and worsen patients' outcomes. Stereotactic body radiation therapy (SBRT) is the gold standard treatment for medically inoperable early-stage lung cancer, but radiation therapy is contra-indicated for patients with ILD because of the higher risk of severe radiation-induced pneumonitis. SBRT may spare healthy lung tissue, but data are scarce in this rare population. Our exploratory case series aimed to retrospectively identify patients treated with SBRT in this setting: 19 patients were diagnosed with early-stage LC-ILD over the past 6 years and 9 received SBRT. Most of them were smokers with a median age of 71, 4 had no pathological documentation. After SBRT, 5 patients had grade I-II respiratory adverse events (AEs), but none had treatment-related grade III-IV respiratory AEs. Two patients died within 6 months of SBRT, and for both, death was related to metastatic relapse. In this case series, the radiological evolution of ILD before radiotherapy and the evolution of the radiotherapy scar on CT-Scan were also explored with different evolutionary models. This exploratory study shows available data that could be studied in a larger retrospective cohort to identify risk factors for SBRT in the LC-ILD population. The use of dosimetric data as a risk factor for SBRT should be done with cautiousness due to heterogeneous and complex dose delivery and different fractionation schedule.

[Immunotherapy adaptation in lung cancer during the COVID-19 pandemic]. / COVID-19 et cancer bronchique : adaptation des schémas d'immunothérapie et qualité de vie.

INTRODUCTION: COVID-19 pandemics required changes in medical practices. In thoracic oncology, pembrolizumab was doubled to 400mg every 6weeks, nivolumab to 480mg every 4weeks. The objective of our study was to assess the impact on quality of life, and on psychological state, as well as the tolerance, of this new schedule. METHODS: Thoracic oncologic patients who underwent these therapeutic changes in our center during the first COVID-19 epidemic wave were included. Their quality of life was assessed using the Quality of Life Questionnaire-30, their psychological state by the Hospital Anxiety Depression (HAD) scale. We also reported the preferred administration schedule, as well as adverse events. RESULTS: Thirty patients were included. The overall quality of life was preserved. Rates on HAD scale were low. Tolerance was acceptable. In majority, patients preferred the new procedure. They had a significantly better quality of life compared to those who preferred the old one. CONCLUSIONS: This new immunotherapy schedule in thoracic oncology is well tolerated and allows a preservation of quality of life. This therapeutic option may be favored in the context of COVID-19 pandemics.

Quantitative mathematical modeling of clinical brain metastasis dynamics in non-small cell lung cancer.

Brain metastases (BMs) are associated with poor prognosis in non-small cell lung cancer (NSCLC), but are only visible when large enough. Therapeutic decisions such as whole brain radiation therapy would benefit from patient-specific predictions of radiologically undetectable BMs. Here, we propose a mathematical modeling approach and use it to analyze clinical data of BM from NSCLC. Primary tumor growth was best described by a gompertzian model for the pre-diagnosis history, followed by a tumor growth inhibition model during treatment. Growth parameters were estimated only from the size at diagnosis and histology, but predicted plausible individual estimates of the tumor age (2.1-5.3 years). Multiple metastatic models were further assessed from fitting either literature data of BM probability (n = 183 patients) or longitudinal measurements of visible BMs in two patients. Among the tested models, the one featuring dormancy was best able to describe the data. It predicted latency phases of 4.4-5.7 months and onset of BMs 14-19 months before diagnosis. This quantitative model paves the way for a computational tool of potential help during therapeutic management.

[Autoimmune-related bleeding occurring during combined immunotherapy for lung cancer - Case report]. / Complication hémorragique inattendue pour un cancer bronchique sous double immunothérapie.

INTRODUCTION: Specific immune-related adverse events in lung cancer treatment are rare and it is important that they are identified as they may have important adverse consequences. We report such a case here. CASE REPORT: A Caucasian female diagnosed with KRAS mutant advanced adenocarcinoma of the lung was enrolled in a phase Ib trial assessing the combination of an anti cytotoxic T-lymphocyte- associated protein 4 antibody and a programmed death-Ligand 1 inhibitor. For several years, she had also been taking warfarin for recurrent pulmonary embolism. At day 15 of treatment, she presented with grade 1 haematomas and signs of grade 2 hyperthyroidism. Blood tests revealed a normal number of platelets but an INR increased to 6.5. Thyroid function tests and auto antibodies confirmed the presence of an autoimmune thyroitidis. The study treatment was then stopped and the patient received 1mg/kg of prednisone and 40mg of propranolol. At day 28, the thyroid function and symptoms were normalized. No direct interactions exist between immunotherapy and vitamin K antagonists (VKA) but hyperthyroidism, through pharmacokinetic and metabolic mechanisms, can boost VKA plasma levels and increase INR, leading to hemorrhagic complications. CONCLUSIONS: This case emphasizes that special consideration should be given to patients with VKA treatment planned to receive immunotherapy.

[Lung neuroendocrine large cell carcinoma in young women. An unusual presentation]. / Cancer neuroendocrine à grandes cellules de la femme jeune : une présentation inhabituelle.

INTRODUCTION: Lung neuroendocrine large cell carcinoma is a rare tumor with a poor prognosis. There are very few guidelines for treating this cancer but a better knowledge of its markers could improve the treatment and the prognosis. OBSERVATIONS: We report two patients who presented initially with an early stage carcinoid tumor treated with surgery. Both patients had further new neuroendocrine disease diagnosed because of intermittent carcinoid syndrome, predominantly occurring at the same time as menstruation. They were then diagnosed with metastatic lung neuroendocrine large cell carcinoma and treated with first-line cisplatin-etoposide and second-line octreotide with estrogen plus progestin. They both had a good prognosis with no disease progression to date. CONCLUSIONS: The clinical characteristics of these cases raise several questions about the pathophysiology of lung neuroendocrine large cell carcinoma and may suggest potential new treatment options. The unusual clinical presentation and good prognosis may be explained either by the second-line treatment choice or by potential molecular or hormonal biomarkers. There is a need to investigate these potential biomarkers further since they could be new therapeutic targets.

[Lung neuroendocrine large-cell carcinoma in young women - An unusual presentation]. / Cancer neuroendocrine à grandes cellules de la femme jeune : une présentation inhabituelle.

INTRODUCTION: Lung neuroendocrine large-cell carcinoma (LNELCC) is a rare tumour with a poor prognosis. There are very few guidelines for LNELCC treatment but a better knowledge of its biology could improve the treatment and prognosis of this malignancy. OBSERVATIONS: We present the cases of 2 patients who presented initially with early stage carcinoid tumours treated with surgery. Both patients had further new neuroendocrine disease diagnosed because of intermittent carcinoid syndrome, predominantly occurring at the same time as menstruation. They were then diagnosed with metastatic LNELCC. They were treated with first-line cisplatin-etoposide and second-line octreotide based on the protocol used for treatment of gastro-intestinal neuroendocrine tumours. They both had a good prognosis with no disease progression to date. CONCLUSIONS: The clinical characteristics of these cases raise several questions about the pathophysiology of LNELCC and may suggest potential new treatment options. The unusual clinical presentation and good prognosis may be explained either by the second-line treatment choice or by potential molecular or hormonal biomarkers. There is a need to investigate these potential biomarkers further since they could be new therapeutic targets.

Adrenal surgery for oligometastatic tumors improves survival in selected cases.

INTRODUCTION: Oligometastatic cancer prognosis is distinct from polymetastatic cancer prognosis and surgery can improve survival. The objective of this study was to assess the role of adrenalectomy and to look for prognostic or predictive factors for the treatment of patients with oligometastatic solid tumors and adrenal metastasis. MATERIAL AND METHODS: Patients with oligometastatic solid tumors undergoing adrenalectomy were selected. Clinical data were retrieved from electronic patients records. Progression-free survival (PFS), overall survival (OS) and clinical outcomes were assessed. RESULTS: Forty patients were analyzed. Median PFS was 7.4 months and PFS was longer for metachronous versus synchronous adrenal metastasis (10.8 versus 4.5 months; P=0.008). Median OS was 22.8 months and OS was better with laparoscopic adrenalectomy versus open adrenalectomy (24.4 versus 11.2 months; P=0.05). DISCUSSION: Adrenalectomy part of the treatment plan of oligometastatic solid tumors but patients have to be selected. Surgery might be indicated for metachronous metastasis when laparoscopic adrenalectomy is possible.

[Oncogenic drivers in daily practice improve overall survival in patients with lung adenocarcinoma]. / Bénéfice à l'évaluation moléculaire en routine pour les cancers bronchiques métastatiques.

BACKGROUND: EGFR tyrosine kinase inhibitors and crizotinib are nowadays the optimal treatment for metastatic lung cancer with activation of EGFR mutations and ALK rearrangement. In addition, several targeted agents are in development for lung cancer with other oncodrivers. In France, since 2011, six oncodrivers are routinely tested in patients with stage IV. The aim of this study was to assess whether systematic detection of oncodrivers and matched targeted therapy improve overall survival in patients with advanced lung adenocarcinoma. METHODS: This study included all consecutive patients treated in our department for advanced lung adenocarcinoma from January 2012 to December 2013. We studied the impact in survival according to the presence of the driver and the targeted therapy. RESULTS: Among the 261 patients included, oncodrivers alterations were found in 43.5% of patients: EML4-ALK fusion genes (2.1%), EGFR (10.3%), KRAS (27.7%), BRAF (2.5%), HER2 (0.8%), and PI3KCA (0.8%) mutations. Twenty-nine percent of patients (n=32) with oncodrivers received matched targeted therapy. Patient treated by targeted agent appropriate to an oncogenic driver had a median survival of 21.1 months (95% CI: 14.7-27.5). The patients (n=79) who did not receive targeted therapy had a median survival of 6.6 months (95% CI: 4.3-8.9). The patients (n=150) without identified driver had a median survival of 9.7 months (95% CI: 6.7-11.7); P<0.001. CONCLUSION: An actionable oncodriver was routinely detected in nearly half of patients with advanced lung adenocarcinoma. This systematic detection may influence treatment outcomes, notably with matched targeted therapy.

[Ipilimumab and metastatic lung cancer: Can we change the natural history of the disease?]. / Ipilimumab et cancer bronchique métastatique : peut-on changer l'histoire naturelle de la maladie ?

INTRODUCTION: Ipilimumab (anti CTLA-4 antibody) aims to activate antitumor immunity. This treatment is being evaluated in non-small cell lung cancer. CASE REPORT: We report a case of a stage IV adenocarcinoma patient randomized in 2008 in the phase II trial CA 184-104 evaluating the combination of ipilimumab to chemotherapy with carboplatin and paclitaxel. After an initial partial response to chemotherapy, the patient achieved a complete response with ipilimumab as maintenance therapy. However, it was complicated by grade 3 gastro-intestinal toxicity leading to stop the ipilimumab. However, this complete response persists after 6 years. CONCLUSIONS: Our case illustrates the contribution of immunotherapy at least in some patients. The mechanisms of action, relationship between efficacy and toxicity and predictors of efficacy remain to be defined.

Rare EGFR exon 18 and exon 20 mutations in non-small-cell lung cancer on 10 117 patients: a multicentre observational study by the French ERMETIC-IFCT network.

BACKGROUND: There is scarce data available about epidermal growth factor receptor (EGFR) mutations other than common exon 19 deletions and exon 21 (L858R) mutations. PATIENTS AND METHODS: EGFR exon 18 and/or exon 20 mutations were collected from 10 117 non-small-cell lung cancer (NSCLC) samples analysed at 15 French National Cancer Institute (INCa)-platforms of the ERMETIC-IFCT network. RESULTS: Between 2008 and 2011, 1047 (10%) samples were EGFR-mutated, 102 (10%) with rare mutations: 41 (4%) in exon 18, 49 (5%) in exon 20, and 12 (1%) with other EGFR mutations. Exon 20 mutations were related to never-smoker status, when compared with exon 18 mutations (P < 0.001). Median overall survival (OS) of metastatic disease was 21 months [95% confidence interval (CI) 12-24], worse in smokers than in non-smoker patients with exon 20 mutations (12 versus 21 months; hazard ratio [HR] for death 0.27, 95% CI 0.08-0.87, P = 0.03). Under EGFR-tyrosine kinase inhibitors (TKIs), median OS was 14 months (95% CI 6-21); disease control rate was better for complex mutations (6 of 7, 86%) than for single mutations (16 of 40, 40%) (P = 0.03). CONCLUSIONS: Rare EGFR-mutated NSCLCs are heterogeneous, with resistance of distal exon 20 insertions and better sensitivity of exon 18 or complex mutations to EGFR-TKIs, probably requiring individual assessment.

[Anti-angiogenic factors in thoracic oncology: successes, failures and prospects]. / Traitements antiangiogéniques en oncologie thoracique: succès, échecs et perspectives.

Many growth factors involved in tumor angiogenesis are potential targets in thoracic oncology. This work is a review of the literature on the effectiveness of anti-angiogenic treatments in non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) and malignant pleural mesothelioma (MM). Thirty-four articles and 15 abstracts were identified. Currently, bevacizumab is the only drug that has demonstrated an impact on overall survival in first line treatment for stage IV non-squamous NSCLC, but VEGFR-TKI such as cediranib, aflibercept, vandetanib, pazopanib have shown encouraging results in phase II or III clinical trials. In extensive-disease SCLC and inoperable MM, bevacizumab is the most studied molecule, but again, clinical trials are still ongoing. Current data on potential predictors for efficacy are disappointing, but some biomarkers or radiological techniques might be useful for guiding the use of anti-angiogenic therapies in the future. In conclusion, bevacizumab is the most studied anti-angiogenic agent in thoracic oncology. It is the only approved drug with an indication in first-line and maintenance treatment for stage IV non-squamous NSCLC. The indications for the use of VEGFR-TKI in clinical practice remain to be defined.

[Pleural metastases from bronchial carcinoma: is a cure possible?]. / Métastases pleurales des cancers bronchiques: une guérison est-elle possible?

INTRODUCTION: The 2009 TNM classification of lung cancer reclassified patients with pleural invasion from stage IIIB (T4) to stage IV (M+). However, the 2009 TNM separates patients with pleural metastases (M1a) from patients with others visceral metastases (M1b), the patients with stage M1a having the better prognosis. CASE REPORTS: Two cases are reported of patients with non-small cell lung cancer (NSCLC) metastatic to the pleura, having a long disease free survival (50 and 34 months). CONCLUSIONS: Patients with pleural metastases from NSCLC seem to have a better prognosis than other patients with stage IV disease, maybe because of a subgroup of patients with long survival. This long survival is probably related to specific biological characteristics of certain pleural disorders that need to be identified. This would allow a more aggressive treatment of this subgroup of patients regarded today as incurable.

[Ureteral hematoma complicating anticoagulant treatment]. / Hématomes urétéraux compliquant un traitement anticoagulant.

Submucosal hemorrhage of the ureters, are a very uncommon quoted cause of hematuria when overdosing anticoagulants. We report two cases, CT shows some very typical aspects but can also highlight, as reported formerly, another associated complication: parietal hematoma of the small bowel.

[Bladder herniation in a inguinal-scrotal hernia complicated by acute renal insufficiency]. / Extériorisation vésicale dans une hernie inguino-scrotale compliquée d'une insuffisance rénale aiguë.

We report one case of massive inguino-scrotal bladder herniation which was responsible for an acute obstructive renal insufficiency. The different types of bladder hernias and their anatomic factors are described. The clinical-radiological findings and surgical management are discussed.

[Spontaneous intramural hematoma of the esophagus. Apropos of a case]. / Hématome spontané intramural de l'oesophage. A propos d'un cas.

The authors report a case of spontaneous intramural haematoma of the oesophagus. This is a rare observation which usually occurs in association with oesophageal hyperpressure and sometimes with impaired haemostasis. The strategy for diagnosis is based on tomodensitography and also endosonography and magnetic resonance imagery.

[Ischemic cerebral vascular accidents in young subjects and livedo reticularis. Apropos of a case of Sneddon's syndrome or Divry-Van Bogaert's syndrome]. / Accidents vasculaires cérébraux ischémiques du sujet jeune et livedo réticulaire. A propos d'un cas de syndrome de Sneddon ou de Divry-Van Bogaert.

The authors report the case of a 28-year-old patient presenting with successive ischaemic cerebral vascular accidents, preceded by the appearance of a livedo reticulare, without any laboratory signs of an inflammatory syndrome. Since Sneddon, and before him Divry and Von Bogaert, patients with this dermatosis are known to have an increased frequency of ischaemic cerebral vascular accidents. This syndrome, considered for a long time to be minimally aggressive, appears to be a very serious disease, leading to a bedridden state and dementia. The prognosis for these patients, all young (30-40 years), therefore appears to be very poor. Any case of livedo reticulare requires the search for cerebral neurological lesions. After a complete neurological examination, imaging therefore has an important major in the assessment of cerebral lesions due to this corticomeningeal angiomatosis. CT scan and MRI are useful in this initial assessment and in the subsequent follow-up of patients. In cases with frank neurological lesions, cerebral arterial exploration is essential with demonstration of lesions of the midcerebral arteries and activation of collateral vascular anastomoses and their helicine vessels. The prognosis is based on the extent of these lesions. Cerebral biopsy may demonstrate a non-inflammatory endothelial cellular proliferation of midcerebral vessels.