Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

TTCC-2019-02: real-world evidence of first-line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck.

Objectives: The aim of this study was to confirm the efficacy of the ERBITAX scheme (paclitaxel 80 mg/m2 weekly and cetuximab 400 mg/m2 loading dose, and then 250 mg/m2 weekly) as first-line treatment for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) who are medically unfit for cisplatin-based (PT) chemotherapy. Materials and methods: This retrospective, non-interventional study involved 16 centers in Spain. Inclusion criteria were to have started receiving ERBITAX regimen from January 2012 to December 2018; histologically confirmed SCCHN including oral cavity, oropharynx, hypopharynx, and larynx; age ≥18 years; and platinum (PT) chemotherapy ineligibility due to performance status, comorbidities, high accumulated dose of PT, or PT refractoriness. Results: A total of 531 patients from 16 hospitals in Spain were enrolled. The median age was 66 years, 82.7% were male, and 83.5% were current/former smokers. Patients were ineligible to receive PT due to ECOG 2 (50.3%), comorbidities (32%), PT cumulative dose ≥ 225 mg/m2 (10.5%), or PT refractoriness (7.2%). Response rate was 37.7%. Median duration of response was 5.6 months (95% CI: 4.4-6.6). With a median follow-up of 8.7 months (95% CI: 7.7-10.2), median PFS and OS were 4.5 months (95% CI: 3.9-5.0) and 8.9 months (95% CI: 7.8-10.3), respectively. Patients treated with immunotherapy after ERBITAX had better OS with a median of 29.8 months compared to 13.8 months for those who received other treatments. The most common grade ≥ 3 toxicities were acne-like rash in 36 patients (6.8%) and oral mucositis in 8 patients (1.5%). Five (0.9%) patients experienced grade ≥ 3 febrile neutropenia. Conclusion: This study confirms the real-world efficacy and tolerability of ERBITAX as first-line treatment in recurrent/metastatic SCCHN when PT is not feasible. Immunotherapy after treatment with ERBITAX showed remarkable promising survival, despite potential selection bias.

Neoadjuvant immunotherapy in resectable head and neck cancer: oral cavity carcinoma as a potential research model.

Squamous cell carcinoma of oral cavity (OCSCC) accounts for approximately 25% of cases of head and neck squamous cell carcinoma (HNSCC). Tobacco and alcohol consumption are the main risk factors for both cancers. Surgical resection, combined with adjuvant radiotherapy or radiochemotherapy in patients with high risk of relapse, is the key element in management in the initial stages. However, despite the availability of aggressive multidisciplinary treatments, advanced resectable OCSCC carries poor prognosis; only half of the patients are disease-free 5 years after the surgery. Immunotherapy based on the use of immune checkpoint inhibitors has been proven to be effective in a wide variety of tumours, including recurrent and metastatic HNSCC. These positive results resulted in investigations into its effectiveness in earlier stages of the disease with OCSCC emerging as an interesting research model because of the accessible location of the tumours. This article reviews the potential advantages of emerging immunotherapeutic agents [mainly monoclonal antibodies against programmed cell death-1 (PD-1) immune checkpoint inhibitors] as neoadjuvant treatment for OCSCC at locoregional stages as well as the ongoing clinical trials, challenges in evaluating tumour response, and possible predictive biomarkers of response with highlights regarding the role of oral microbiota as modulators of immune response. The efficacy and safety of anti-PD-1 drugs in these patients have been proven in preliminary trials. If there is a decrease in the relapse rate and an improvement in the overall survival after surgical resection in ongoing trials, preoperative immunotherapy may be established as a treatment option for patients with early stages of the disease.

Trabectedin in patients with advanced non-small-cell lung cancer (NSCLC) with XPG and/or ERCC1 overexpression and BRCA1 underexpression and pretreated with platinum.

BACKGROUND: Previous studies in sarcoma found that a composite gene signature, including high expression of nucleotide excision repair (NER) genes (XPG and/or ERCC1) and low expression of homologous recombination repair (HR) genes (BRCA1), identifies a highly sensitive population of patients with significantly improved outcome to trabectedin. This exploratory phase II trial evaluated a customized trabectedin treatment according to this gene signature in patients with non-small cell lung cancer (NSCLC) after the failure of standard platinum-based treatment. METHODS: Patients were selected according to their mRNA expression (elevated XPG and/or ERCC1, with low BRCA1) using the following values as cutoff: XPG=0.99, ERCC1=3.47 and BRCA1=12.00. Trabectedin was administered as a 1.3mg/m(2) 3-hour intravenous infusion every 3 weeks (q3wk). The primary efficacy endpoint was the progression-free survival rate at 3 months. Objective response according to the Response Evaluation Criteria in Solid Tumors (RECIST) was a secondary efficacy endpoint. RESULTS: Two of 18 evaluable patients (11.1%; 95% CI, 1.38-34.7%) achieved progression-free survival rate at 3 months. The primary efficacy objective (at least 3 of 18 patients being progression-free at 3 months) was not met, and therefore the trial was early finalized. No objective responses per RECIST were achieved. Four patients had stable disease. Median PFS was 1.3 months, and median overall survival was 5.9 months. Trabectedin was usually well tolerated, with a safety profile similar to that described in patients with other tumor types. CONCLUSIONS: Customized treatment with trabectedin 1.3mg/m(2) 3-h q3wk according to composite gene signature (XPG and/or ERCC1 overexpression, and BRCA1 underexpression) was well tolerated, but had modest activity in NSCLC patients pretreated with platinum. Therefore, further clinical trials with trabectedin as single agent in this indication are not warranted.

Gemcitabine and vinorelbine followed by weekly docetaxel in patients with advanced non-small-cell lung cancer: a phase II trial of sequential chemotherapy.

UNLABELLED: Objective. We conducted this phase II trial to evaluate the efficacy and toxicity of the sequential nonplatinum combination chemotherapy consisting of gemcitabine (GEM) and vinorelbine (VNR) followed by weekly docetaxel (DOC) in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods. ELIGIBILITY CRITERIA: stage IV NSCLC, Performance status =/< 2, adequate renal, hepatic and bone marrow function. Treatment consisted on: VNR 25 mg/m(2) plus gemcitabine 1000 mg/m(2), on days 1 and 8 of each 21-day cycle, followed by docetaxel 36 mg/m(2) weekly until progression or unacceptable toxicity. Results. 21 stage IV patients were enrolled. All patients are evaluable for treatment response and toxicity profile. The mean age of the patients was 63 years (range: 51 to 72) with 18 (86%) males and 3 (14%) females. Histology types were: adenocarcinoma in 8 patients (38%), large cell carcinoma in 1 patients (5%) and squamous cell carcinoma in 12 patients (57%). The majority of the patients had and ECOG PS of 1. Eight patients (38%) did not complete six cycles of gemcitabine-navelbine. The median number of cycles of gemcitabine-navelbine was 4 (range 2-6) Of the 13 patients (61%) who completed six cycles of gemcitabine-navelbine, all of them went on to receive weekly docetaxel and received at least 3 cycles, with a median number of 8 cycles (range 3- 16). The overall response rate was 33%. Respect survival, the minimum follow-up was 6 months (range, 6-25 months). The median survival time (MST) was 7.9 months, and the 1-year survival was 30%, and the median progression-free survival was 4.7 months. Toxicity was mild, well tolerated and mostly hematologic. In the GEM/VNR cycle, grade 3/4 neutropenia occurred in 14%, two patients with febrile neutropenia. Grade 3 anaemia in 1 patients (5%) and grade 3 thrombocytopenia in 1 patient (5%). Nonhematologic toxicity was also mild: 1 patient with Grade 3 skin toxicity with docetaxel, 1 patient with grade 3 infection, 2 patients with grade 3 astenia and 1 patient with a mild allergic reaction postchemotherapy treatment with docetaxel. Conclusion. The sequential triplet nonplatinum chemotherapy consisted of GEM/VNR followed by weekly DOC is active and can be administered safely in advanced NSCLC. Our results are similar with other sequential regimens and did not represent a significant improvement in the treatment of this disease.

Cisplatin plus continuous infusion vinorelbine for the treatment of advanced non-small cell lung cancer: a phase I-II study

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Backbround. In this Phase I/II trial, the maximumtolerateddose (MTD) and activity of cisplatin plusvinorelbine (VRL) administered in continuous infusionas first-line treatment of advanced non smallcell lung cancer (NSCLC) was determined in 12consecutive chemotherapy-naive patients with advancedNSCLC.Patients and methods. The dose of cisplatin was100 mg/m2 in all patients, and vinorelbine was administeredas an initial intravenous (iv) bolus of 8mg/m2 on day 1 followed by a 4-day continuous ivinfusion at 4 different 24 h dose levels (DLs) to berepeated every 21 days. All 12 patients (47 cycles)were evaluable for response and toxicity.Results. The MTD was 8 mg/m2 bolus followed by acontinuous iv infusion of 8 mg/m2 per day over 4days. The dose limiting toxicities (DLT) were febrileneutropenia in 4 patients and grade 3 mucositis in 1patient. There was less neuro-toxicity and comparedto the weekly bolus scheme. There was nosignificant cumulative toxicity after 3 cycles. Partialresponses were observed in 6 patients; an overall responserate of 50% (95% CI: 30-65%). Median time toprogression was 5,5 months (95% CI: 1,5-11 months)and median survival was 11 months (95% CI: 5-20months).Conclusions. The results demonstrate that, in thissetting of first-line treatment of NSCLC, cisplatinplus vinorelbine at 8 mg/m2 bolus followed by acontinuous infusion of 8 mg/m2 per day over 4 daysis the recommended schedule. Further trials wouldbe useful to establish activity of this combination

Solitary metastasis in a nasal fossa as the first manifestation of a renal carcinoma.

Renal cell carcinoma is an uncommon tumor in adults. Metastasis in the nasal fossa is rare, and can become apparent as a result of repeated epistaxis. We report a patient with renal cell carcinoma presenting with epistaxis secondary to a metastasis in the right nasal fossa. The primary tumor was treated with nephrectomy and the nasal fossa metastasis was treated successfully with embolization, chemoimmunotherapy, surgery, and radiotherapy. The presence of repeated epistaxis may very occasionally be the first symptom of renal cell carcinoma, and systemic treatment combined with local treatment may enable adequate control of the disease.

Bronchiolitis obliterans organizing pneumonia simulating progression in bronchioloalveolar carcinoma.

Bronchiolitis obliterans organizing pneumonia (BOOP) is a clinicopathologic syndrome with characteristic features. The diagnosis of BOOP requires the presence of a combination of pathological, clinical, and radiological features. We report the case of a lung cancer patient with bronquiloalveolar carcinoma (BAC) presenting with BOOP after chemotherapy with docetaxel and gemcitabine producing severe respiratory insufficiency, and simulating a progression of the tumor.

Solitary metastasis in a nasal fossa as the first manifestation of a renal carcinoma

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Renal cell carcinoma is an uncommon tumor inadults. Metastasis in the nasal fossa is rare, and canbecome apparent as a result of repeated epistaxis.We report a patient with renal cell carcinoma presentingwith epistaxis secondary to a metastasis inthe right nasal fossa. The primary tumor was treatedwith nephrectomy and the nasal fossa metastasiswas treated successfully with embolization, chemoimmunotherapy,surgery, and radiotherapy. Thepresence of repeated epistaxis may very occasionallybe the first symptom of renal cell carcinoma, andsystemic treatment combined with local treatmentmay enable adequate control of the disease

Bronchiolitis obliterans organizing pneumonia simulating progression in bronquioloalveolar carcinoma

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Bronchiolitis obliterans organizing pneumonia(BOOP) is a clinicopathologic syndrome withcharacteristic features. The diagnosis of BOOPrequires the presence of a combination of pathological,clinical, and radiological features. We reportthe case of a lung cancer patient with bronquiloalveolarcarcinoma (BAC) presenting withBOOP after chemotherapy with docetaxel andgemcitabine producing severe respiratory insufficiency,and simulating a progression of the tumor

Subcutaneous metastasis as the first manifestation of a solid-pseudopapillary tumor of the pancreas

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Secondary signet-ring cell tumour of the prostate derived from a primary gastric malignancy.

Primary signet-ring cell carcinoma of the prostate is infrequent and even more so as secondary spread of this pathologic sub-type to the prostate. We describe the sixth reported case with a diagnosis of a secondary signet-ring cell tumour of the prostate secondary to a gastric cancer. Five years post-gastrectomy to resect signet-ring cell carcinoma, we detected a secondary intra-prostatic spread with urinary tract obstruction. The physical appearance of the tumour cells was similar to that of the previously-resected signet-cell carcinoma of the stomach. There were no metastases in other sites and the patient was treated with radiotherapy. When confronted with intra-prostatic signet-ring cell adenocarcinoma it is necessary to distinguish between primary and secondary aetiology since this would reflect in the choice of treatment and prognosis.

Secondary signet-ring cell tumour of the prostate derived from a primary gastric malignancy

Primary signet-ring cell carcinoma of the prostate is infrequent and even more so as secondary spread of this pathologic sub-type to the prostate. We describe the sixth reported case with a diagnosis of a secondary signet-ring cell tumour of the prostate secondary to a gastric cancer. Five years post-gastrectomy to resect signet-ring cell carcinoma, we detected a secondary intra-prostatic spread with urinary tract obstruction. The physical appearance of the tumour cells was similar to that of the pre-viously-resected signet-cell carcinoma of the stomach. There were no metastases in other sites and the patient was treated with radiotherapy. When confronted with intra-prostatic signet-ring cell adenocarcinoma it is necessary to distinguish between primary and secondary aetiology since this would reflect in the choice of treatment and prognosis

Continuous-infusion vinorelbine for the treatment of advanced non-small-cell lung cancer: a phase I/II study.

BACKGROUND: In this phase I/II trial, the maximum tolerated dose (MTD) and activity of vinorelbine administered in continuous infusion as first-line treatment for advanced non-small-cell lung cancer (NSCLC) was determined in 25 consecutive chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Vinorelbine was administered as an initial intravenous (I.V.) bolus of 8 mg/m(2) on day 1 followed by a 4-day continuous I.V. infusion at 5 different 24-hour dose levels to be repeated every 21 days. All 25 patients (159 cycles) were evaluable for response. The MTD was 8 mg/m(2) bolus followed by a continuous I.V. infusion of 11 mg/m(2) per day over 4 days. RESULTS: The dose-limiting toxicities were febrile neutropenia in 6 patients and grade 3 mucositis in 2 patients. There was less neurotoxicity and constipation and more mucositis compared with the weekly bolus scheme. There was no significant cumulative toxicity after 3 cycles. Treatment responses were observed in 6 patients: 1 complete response and 5 partial responses. The overall response rate was 24% (95% confidence interval [CI], 8%-40%). Median time to progression was 4 months (95% CI, 2-11 months), and median survival was 6 months (95% CI, 2-18 months). CONCLUSION: The results demonstrate that, in this setting of first-line treatment of NSCLC, vinorelbine administered as an 8 mg/m(2) bolus followed by a continuous infusion of 11 mg/m(2) per day over 4 days is the recommended schedule. Further trials are necessary to establish activity and possible benefits of combination with other agents.