Hajime Asahina

A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations

Retrospective analysis has shown that activating mutations in exons 18–21 of the epidermal growth factor receptor (EGFR) gene are a predictor of response to gefitinib. We conducted a phase II trial to evaluate the efficacy and safety of gefitinib as first-line therapy for advanced non-small cell lung cancer (NSCLC) with EGFR mutations. Patients with stage IIIB or IV chemotherapy-naïve NSCLC with EGFR mutation were treated with 250 mg gefitinib daily. For mutational analysis, DNA was extracted from paraffin-embedded tissues and EGFR mutations were analysed by direct sequence of PCR products. Twenty (24%) of the 82 patients analysed had EGFR mutations (deletions in or near E746-A750, n=16; L858R, n=4). Sixteen patients were enrolled and treated with gefitinib. Twelve patients had objective response and response rate was 75% (95% CI, 48–93%). After a median follow-up of 12.7 months (range, 3.1–16.8 months), 10 patients demonstrated disease progression, with median progression-free survival of 8.9 months (95% CI, 6.7–11.1 months). The median overall survival time has not yet been reached. Most of the toxicities were mild. This study showed that gefitinib is very active and well tolerated as first-line therapy for advanced NSCLC with EGFR mutations.

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.

Combined survival analysis of prospective clinical trials of gefitinib for non-small cell lung cancer with EGFR mutations.

Purpose: Somatic mutations of the epidermal growth factor receptor (EGFR) gene are associated with an increased response to gefitinib in patients with non–small cell lung cancer. We have examined the impact of gefitinib on progression-free survival and overall survival in patients with EGFR mutation–positive non–small cell lung cancer. Experimental Design: We searched for all clinical trials that prospectively evaluated the efficacy of gefitinib for advanced non–small cell lung cancer with EGFR mutations in Japan. We did a combined analysis based on individual patient data from the identified trials. Results: Seven eligible trials were identified for a total of 148 non–small cell lung cancer patients with EGFR mutations. The overall response rate to gefitinib was 76.4% [95% confidence interval (95% CI), 69.5-83.2]. The median progression-free survival and overall survival were 9.7 months (95% CI, 8.2-11.1) and 24.3 months (95% CI, 19.8-28.2), respectively. Good performance status and chemotherapy-naïve status were significantly associated with a longer progression-free survival or overall survival. Of the 148 patients, 87 received gefitinib as a first-line therapy, whereas 61 received systemic chemotherapy before gefitinib treatment. The median progression-free survival after the start of first-line therapy was significantly longer in the gefitinib-first group than in the chemotherapy-first group (10.7 versus 6.0 months; P < 0.001), whereas no significant difference in median overall survival was apparent between the two groups (27.7 versus 25.7 months; P = 0.782). Conclusions: Gefitinib monotherapy confers substantial clinical benefit in terms of progression-free survival and overall survival in non–small cell lung cancer patients with EGFR mutations. Randomized trials comparing chemotherapy with gefitinib as a first-line treatment are warranted in such patients.

Endobronchial ultrasonography with guide-sheath for peripheral pulmonary lesions

The usefulness of endobronchial ultrasonography (EBUS) with guide-sheath (GS) as a guide for transbronchial biopsy (TBB) for diagnosing peripheral pulmonary lesions (PPL)s and for improving diagnostic accuracy was evaluated in this study. EBUS-GS-guided TBB was performed in 24 patients with 24 PPLs of ≤30 mm in diameter (average diameter=18.4 mm). A 20-MHz radial-type ultrasound probe, covered with GS was inserted via a working bronchoscope channel and advanced to the PPL in order to produce an EBUS image. The probe with the GS was confirmed to reach the lesion by EBUS imaging and X-ray fluoroscopy. When the lesion was not identified on the EBUS image, the probe was removed and a curette was used to lead the GS to the lesion. After localising the lesion, the probe was removed, and TBB and bronchial brushing were performed via the GS. Nineteen peripheral lesions (79.2%) were visualised by EBUS. All patients whose PPLs were visible on EBUS images subsequently underwent an EBUS-GS-guided diagnostic procedure. A total of 14 lesions (58.3%) were diagnosed. Even when restricted to PPLs <20 mm in diameter, the diagnostic sensitivity was 53%. In conclusion, endobronchial ultrasonography with guide sheath-guided transbronchial biopsy was feasible and effective for diagnosing peripheral pulmonary lesions.

Clinical benefit of readministration of gefitinib for initial gefitinib-responders with non-small cell lung cancer

BackgroundGefitinib, an oral agent of epidermal growth factor receptor tyrosine kinase inhibitor, has a certain efficacy against non-small cell lung cancer (NSCLC). Several predictive factors of gefitinib sensitivity have been well described. However, few studies have investigated the clinical features of gefitinib-responders. In the present study, we analyzed the response and disease progression of primary and metastatic lesions to gefitinib in responders and the results of gefitinib readministration following temporary cessation of gefitinib upon progression of initial gefitinib treatment and other treatments.MethodWe retrospectively evaluated the clinical courses of 27 NSCLC patients who received gefitinib and achieved either a complete or partial response.ResultsThe best-response rate and disease-control rate against the initial chemotherapy for the gefitinib-responders were 27.3% and 77.3%, respectively. Favorable efficacy was observed in the primary lesion and metastases to the lung, liver and brain, while there was no obvious effect on bone metastasis. The primary lesion and intrapulmonary metastasis were the sites of major recurrence. Median progression-free survival was 13.8 months, median duration of gefitinib treatment was 17.0 months and median overall survival was 29.2 months. Some of the patients who experienced disease progression after responding to gefitinib were again sensitive to readministration of gefitinib following temporary cessation of gefitinib and other treatments.ConclusionPatients may still be expected to have prolonged survival if they once responded to gefitinib and then underwent various subsequent treatments followed by readministration of gefitinib. These findings might provide valuable information for the management of gefitinib-responders.

STK11/LKB1 Deficiency Promotes Neutrophil Recruitment and Proinflammatory Cytokine Production to Suppress T-cell Activity in the Lung Tumor Microenvironment

STK11/LKB1 is among the most commonly inactivated tumor suppressors in non-small cell lung cancer (NSCLC), especially in tumors harboring KRAS mutations. Many oncogenes promote immune escape, undermining the effectiveness of immunotherapies, but it is unclear whether the inactivation of tumor suppressor genes, such as STK11/LKB1, exerts similar effects. In this study, we investigated the consequences of STK11/LKB1 loss on the immune microenvironment in a mouse model of KRAS-driven NSCLC. Genetic ablation of STK11/LKB1 resulted in accumulation of neutrophils with T-cell-suppressive effects, along with a corresponding increase in the expression of T-cell exhaustion markers and tumor-promoting cytokines. The number of tumor-infiltrating lymphocytes was also reduced in LKB1-deficient mouse and human tumors. Furthermore, STK11/LKB1-inactivating mutations were associated with reduced expression of PD-1 ligand PD-L1 in mouse and patient tumors as well as in tumor-derived cell lines. Consistent with these results, PD-1-targeting antibodies were ineffective against Lkb1-deficient tumors. In contrast, treating Lkb1-deficient mice with an IL6-neutralizing antibody or a neutrophil-depleting antibody yielded therapeutic benefits associated with reduced neutrophil accumulation and proinflammatory cytokine expression. Our findings illustrate how tumor suppressor mutations can modulate the immune milieu of the tumor microenvironment, and they offer specific implications for addressing STK11/LKB1-mutated tumors with PD-1-targeting antibody therapies.

A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors†‡

Olaparib (AZD2281) is an orally active Poly(ADP‐ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose‐finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single‐dose on day 1, followed by twice‐daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400‐mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose‐limiting toxicities were not observed up to and including the 400‐mg b.i.d. dose level. Following twice‐daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single‐dose pharmacokinetics. PARP‐1 inhibition was observed from the 100‐mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post‐dose on day 1 during the multiple‐dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400‐mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400‐mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed. (Cancer Sci 2012; 103: 504–509)

Phase II Study of Gefitinib Readministration in Patients with Advanced Non-Small Cell Lung Cancer and Previous Response to Gefitinib

Objective: Salvage treatment for acquired resistance to gefitinib has yet to be developed. We conducted the first prospective phase II study of gefitinib readministration in previous gefitinib responders. Methods: Gefitinib (250 mg/day) was readministered to patients with advanced/metastatic non-small cell lung cancer who had achieved objective response to initial gefitinib and subsequently received cytotoxic chemotherapy after disease progression with initial gefitinib. The primary endpoint was the objective response rate with gefitinib readministration. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), quality of life, and toxicity. Changes in lung cancer-related symptoms were evaluated using the seven-item lung cancer subscale of the questionnaire. Results: Sixteen patients were enrolled between February 2005 and January 2008. Most had received ≧3 regimens of chemotherapy. Response and disease-control rates for all patients were 0 and 44%. Median PFS and OS were 2.5 and 14.7 months, respectively. Four of 7 patients with stable disease experienced a long duration (≧6 months) of disease control without severe toxicity. Symptom improvement was observed in 2 of 12 patients (17%) for whom quality of life was evaluable. Conclusion: Gefitinib represents a useful therapeutic option for selected previous gefitinib responders.

Innovator and generic cisplatin formulations: Comparison of renal toxicity

To compare the incidence and degree of renal toxicity associated with innovator and generic cisplatin formulations, increase in the serum creatinine (CRN) levels (mg/dL) and incidence of grade 2–3 CRN elevation during the first and all cycles of chemotherapy were retrospectively evaluated in patients treated with innovator (group 1, n = 296) and generic (group 2, n = 321) cisplatin formulations. There were no differences in the sex, age, performance status or number of chemotherapy cycles between groups 1 and 2. The median increases in CRN levels during the first cycle were 0.20 mg/dL regardless of the sex or group. There was no difference in the incidence of grade 2–3 CRN elevation between groups 1 and 2 among female or male patients. The median increases in CRN levels during all cycles were 0.2 (0–1.0) and 0.3 (0–1.8) in the female patients of groups 1 and 2, respectively (P = 0.68), and 0.3 (0–2.1) and 0.5 (0–3.6) in the male patients of groups 1 and 2, respectively (P < 0.001). Grade 2–3 CRN elevation was observed in 18.1% and 24.7% of the female patients in groups 1 and 2, respectively (P = 0.33), and 9.4% and 20.9% of the male patients in groups 1 and 2, respectively (P < 0.001). Renal toxicity was slightly more severe in patients treated with the generic cisplatin formulation than in those treated with the innovator formulation, especially among the male patients. (Cancer Sci 2011; 102: 162–165)

Endobronchial Ultrasonography With a Guide Sheath in the Diagnosis of Benign Peripheral Diseases

BACKGROUND For appropriate treatment, such as the selection of antibiotics or initiation of steroid therapy, correctly diagnosing benign pulmonary diseases located at the periphery is vital. This study assessed the usefulness of bronchoscopy using endobronchial ultrasonography with a guide sheath (EBUS-GS) in the diagnosis of benign pulmonary diseases, especially those presenting peripheral nodular lesions. METHODS We retrospectively reviewed 159 patients with 171 peripheral pulmonary lesions (PPLs) that were subsequently diagnosed as benign diseases. To examine the role of bronchoscopy with EBUS-GS, the contribution of bronchoscopy was classified into 4 categories. We also retrospectively reviewed 24 patients with 25 PPLs that were subsequently diagnosed as benign diseases by bronchoscopy without EBUS-GS (historical control). RESULTS The ultimate diagnosis of 171 PPLs included 45 cases of mycobacteriosis, 45 cases of bronchiolitis obliterans organizing pneumonia/chronic organized pneumonia (BOOP), 23 cases of bacterial pneumonia, 13 abscesses, 11 cases of sarcoidosis, and 34 other benign diseases. Among them, a definitive diagnosis was obtained by bronchoscopy with EBUS-GS in 99 lesions (58%). Lesions in which the probe was positioned within the lesion had a higher diagnostic yield (64%) than did lesions in which the probe was positioned adjacent to the lesion (52%) or outside the lesion (20%; P=0.01). The diagnostic yield of bronchoscopy with EBUS-GS was higher compared with that of the historical control (58% versus 28%; P=0.04). CONCLUSIONS Bronchoscopy using EBUS-GS is a reasonable option as a diagnostic procedure for PPLs, even if they are suspected to be benign in nature.