Poziotinib in Treatment-Naive NSCLC Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4).

INTRODUCTION: ERBB2 or HER2 alterations are found in approximately 2% to 5% of NSCLCs; most are exon 20 insertion mutations. The efficacy and safety of poziotinib, an oral tyrosine kinase inhibitor, were assessed in patients with treatment-naive NSCLC whose tumors harbor HER2 exon 20 insertions. METHODS: ZENITH20 is an open-label, multicohort, multicenter, global, phase 2 trial. ZENITH20-C4 enrolled treatment-naive patients with NSCLC with tumors harboring HER2 exon 20 insertions. Poziotinib was administered 16 mg once daily (QD) or 8 mg twice daily (BID). The primary end point was objective response rate (ORR) by independent central review. Secondary and exploratory end points included disease control rate, duration of response, progression-free survival, and safety. RESULTS: A total of 80 patients (16 mg QD, n = 47; 8 mg BID, n = 33) were treated in ZENITH20-C4. ORR was 39% (95% confidence interval [CI]: 28%-50%; 31 of 80), with a disease control rate of 73% (95% CI: 61%-82%; 58 of 80); 80% of the patients experienced tumor reduction. Median duration of response was 5.7 (95% CI: 4.6-11.9) months, and median progression-free survival was 5.6 (95% CI: 5.4-7.3) months. The most common grade 3 treatment-related adverse events were rash (QD, 45%; BID, 39%), stomatitis (QD, 21%; BID, 15%), and diarrhea (QD, 15%; BID, 21%). Among all subtypes of HER2 exon 20 insertions, seven patients (9%) harboring tumors with G778_P780dupGSP had the best clinical outcomes (ORR, 71%). CONCLUSIONS: Poziotinib was found to have clinically meaningful efficacy with a manageable toxicity profile for patients with treatment-naive NSCLC harboring HER2 exon 20 mutations.

Patient-Reported Health-Related Quality of Life in KEYNOTE-604: Pembrolizumab or Placebo Added to Etoposide and Platinum as First-Line Therapy for Extensive-Stage SCLC.

Introduction: In the phase 3 KEYNOTE-604 study (NCT03066778), pembrolizumab plus etoposide and platinum chemotherapy (EP) significantly (p = 0.0023) improved progression-free survival versus placebo plus EP in previously untreated extensive-stage SCLC (ES-SCLC). We present health-related quality of life (HRQoL) results from KEYNOTE-604. Methods: Patients with stage IV SCLC were randomized 1:1 to pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles plus four cycles of EP. Secondary end points included mean change from baseline to week 18 in the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire-Core 30 (QLQ-C30) global health status/quality of life (GHS/QoL) scale and time to deterioration in the composite outcome of cough, chest pain, or dyspnea from QLQ-C30 and QLQ-Lung Cancer Module 13. Two-sided, nominal p values are reported. Results: A total of 439 patients completed at least one QLQ-C30 and QLQ-Lung Cancer Module 13 assessment (pembrolizumab + EP, n = 221; placebo + EP, n = 218). GHS/QoL scores improved from baseline to week 18: least squares mean (95% confidence interval [CI]) changes were 8.7 (5.3-12.1) for pembrolizumab plus EP and 4.2 (0.9-7.5) for placebo plus EP. Between-group differences in least squares mean scores were improved for pembrolizumab plus EP (4.4 [95% CI: 0.2-8.7], p = 0.040]). Median time to deterioration for the composite end point was not reached and 8.7 (95% CI: 5.9-not reached) months, respectively (hazard ratio = 0.80 [95% CI: 0.56-1.14], p = 0.208). Conclusions: First-line pembrolizumab plus EP therapy maintained HRQoL in patients with ES-SCLC and may be associated with greater improvement than placebo plus EP. Together with the efficacy and safety findings in KEYNOTE-604, HRQoL data support the benefit of pembrolizumab in ES-SCLC.

Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study.

PURPOSE: Pembrolizumab monotherapy has shown antitumor activity in patients with small-cell lung cancer (SCLC). The randomized, double-blind, phase III KEYNOTE-604 study compared pembrolizumab plus etoposide and platinum (EP) with placebo plus EP for patients with previously untreated extensive-stage (ES) SCLC. METHODS: Eligible patients were randomly assigned 1:1 to pembrolizumab 200 mg once every 3 weeks or saline placebo for up to 35 cycles plus 4 cycles of EP. Primary end points were progression-free survival (PFS; RECIST version 1.1, blinded central review) and overall survival (OS) in the intention-to-treat population. Objective response rate (ORR) and duration of response were secondary end points. Prespecified efficacy boundaries were one-sided P = .0048 for PFS and .0128 for OS. RESULTS: Of the 453 participants, 228 were randomly assigned to pembrolizumab plus EP and 225 to placebo plus EP. Pembrolizumab plus EP significantly improved PFS (hazard ratio [HR], 0.75; 95% CI, 0.61 to 0.91; P = .0023). Twelve-month PFS estimates were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. Although pembrolizumab plus EP prolonged OS, the significance threshold was not met (HR, 0.80; 95% CI, 0.64 to 0.98; P = .0164). Twenty-four-month OS estimates were 22.5% and 11.2%, respectively. ORR was 70.6% in the pembrolizumab plus EP group and 61.8% in the placebo plus EP group; the estimated proportion of responders remaining in response at 12 months was 19.3% and 3.3%, respectively. In the pembrolizumab plus EP and placebo plus EP groups, respectively, any-cause adverse events were grade 3-4 in 76.7% and 74.9%, grade 5 in 6.3% and 5.4%, and led to discontinuation of any drug in 14.8% and 6.3%. CONCLUSION: Pembrolizumab plus EP significantly improved PFS compared with placebo plus EP as first-line therapy for patients with ES-SCLC. No unexpected toxicities were seen with pembrolizumab plus EP. These data support the benefit of pembrolizumab in ES-SCLC.

Local recurrence following adjuvant chemotherapy without radiotherapy in completely resected stomach and gastroesophageal junction adenocarcinoma.

BACKGROUND: The gold standard of adjuvant treatment after surgical resection of adenocarcinoma of the stomach or gastroesophageal junction (GEJ) is chemoradiotherapy. We retrospectively evaluated chemotherapy without radiotherapy in stomach and GEJ adenocarcinoma, using a combination of etoposide, adriamycin and cisplatin (modified EAP). PATIENTS AND METHODS: Sixty-five patients with completely resected gastric or GEJ adenocarcinoma and positive regional lymph nodes were treated with modified EAP over an 8-year period. RESULTS: Recurrent disease was diagnosed in 38/58 (69%) patients evaluable for analysis. Only two (5%) had locoregional recurrence. The main toxicity was hematological, with 22 (34%) patients developing neutropenic fever and 12 (18%) anemia requiring blood transfusion. The median survival for the entire group was 20 months, with a median time to recurrence of 11 months. Seventeen (26%) patients are alive for a median of 7+ years, with no evidence of recurrent disease. CONCLUSION: Our data cast doubt on the benefit of radiotherapy adjuvant to chemotherapy.

[Treatment of gastrointestinal stromal tumors with imatinib mesylate: a center-based study of 13 patients].

Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors, with specific histological characteristics. These tumors are resistant to conventional radiation and chemotherapy treatment and therefore, patients with unresectable or metastatic GIST have a poor prognosis. Imatinib, a c-kit tyrosine kinase inhibitor, has recently been found to be highly effective for patients with advanced GIST. We report on 13 consecutive patients, aged 43-78 years, treated at our center between the years 2001-2004. Two patients were given imatinib as neoadjuvant treatment and the other 11 patients were treated with palliative intent. Response to imatinib was evaluable in 11 out of 13 patients. Objective response was seen in 10 patients (91%) and included complete response in two of them (18%). After a follow-up of 4-33 months (median 7 months), the median time to tumor progression has not yet been reached. The treatment was generally well tolerated. The most common adverse events included edema of the periorbital and lower extremities. We conclude that imatinib is a safe and highly effective therapy for GIST patients with unresectable or metastatic disease, providing new hope for durable remission in these patients.

PET/CT using 18F-FDG in suspected lung cancer recurrence: diagnostic value and impact on patient management.

UNLABELLED: The goal of this study was to assess the value of hybrid imaging using a combined PET/CT device with 18F-FDG in the diagnosis and clinical management of suspected recurrent lung cancer. METHODS: Forty-two patients with non-small cell lung cancer (NSCLC) with suspected recurrence due to new clinical, biochemical, and radiologic findings were prospectively evaluated. PET/CT results were compared with PET interpreted with side-by-side CT data. A final diagnosis of recurrence was confirmed by histologic tissue sampling during surgery or biopsy or by further clinical and radiologic work-up. The impact of PET/CT on patient management was assessed. RESULTS: Twenty-four of 27 positive PET/CT studies (89%) were proven to have recurrent disease. Fourteen of 15 negative PET/CT studies (93%) had no evidence of disease. The sensitivity, specificity, and positive and negative predictive values of PET/CT for diagnosis of recurrence were 96%, 82%, 89%, and 93% compared with 96%, 53%, 75%, and 90%, respectively, for PET. PET/CT changed the PET lesion classification in 22 patients (52%), by determining the precise localization of sites of increased 18F-FDG uptake. PET/CT changed the management of 12 patients (29%) by eliminating previously planned diagnostic procedures (5 patients), by initiating a previously unplanned treatment option (4 patients), or by inducing a change in the planned therapeutic approach (3 patients). CONCLUSION: In patients with a suspected recurrence of NSCLC, PET/CT provides a better anatomic localization of suspicious lesions compared with PET interpreted with side-by-side CT data. This improved diagnostic performance of PET/CT has a further impact on the clinical management and treatment planning of the patients.