Tarek Mekhail

First-line crizotinib versus chemotherapy in ALK-positive lung cancer.

BACKGROUND The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).

Validation and Extension of the Memorial Sloan-Kettering Prognostic Factors Model for Survival in Patients With Previously Untreated Metastatic Renal Cell Carcinoma

PURPOSE To validate the Motzer et al prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma (RCC) and to identify additional independent prognostic factors. PATIENTS AND METHODS Data were collected on 353 previously untreated metastatic RCC patients enrolled onto clinical trials between 1987 and 2002. RESULTS Four of the five prognostic factors identified by Motzer were independent predictors of survival. In addition, prior radiotherapy and presence of hepatic, lung, and retroperitoneal nodal metastases were found to be independent prognostic factors. Using the number of metastatic sites as surrogate for individual sites (none or one v two or three sites), Motzers definitions of risk groups were expanded to accommodate these two additional prognostic factors. Using this expanded criteria, favorable risk is defined as zero or one poor prognostic factor, intermediate risk is two poor prognostic factors, and poor risk is more than two poor prognostic factors. According to Motzers definitions, 19% of patients were favorable risk, 70% were intermediate risk, and 11% were poor risk; median overall survival times for these groups were 28.6, 14.6, and 4.5 months, respectively (P < .0001). Using the expanded criteria, 37% of patients were favorable risk, 35% were intermediate risk, and 28% were poor risk; median overall survival times of these groups were 26.0, 14.4, and 7.3 months, respectively (P < .0001). CONCLUSION These data validate the model described by Motzer et al. Additional independent prognostic factors identified were prior radiotherapy and sites of metastasis. Incorporation of these additional prognostic factors into the Motzer et al model can help better define favorable risk, intermediate risk, and poor risk patients.

Alectinib in Crizotinib-Refractory ALK-Rearranged Non–Small-Cell Lung Cancer: A Phase II Global Study

PURPOSE Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC. PATIENTS AND METHODS Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC). RESULTS Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2. CONCLUSION Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.

Durvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer

Background Most patients with locally advanced, unresectable, non–small‐cell lung cancer (NSCLC) have disease progression despite definitive chemoradiotherapy (chemotherapy plus concurrent radiation therapy). This phase 3 study compared the anti–programmed death ligand 1 antibody durvalumab as consolidation therapy with placebo in patients with stage III NSCLC who did not have disease progression after two or more cycles of platinum‐based chemoradiotherapy. Methods We randomly assigned patients, in a 2:1 ratio, to receive durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months. The study drug was administered 1 to 42 days after the patients had received chemoradiotherapy. The coprimary end points were progression‐free survival (as assessed by means of blinded independent central review) and overall survival (unplanned for the interim analysis). Secondary end points included 12‐month and 18‐month progression‐free survival rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. Results Of 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). The median progression‐free survival from randomization was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12‐month progression‐free survival rate was 55.9% versus 35.3%, and the 18‐month progression‐free survival rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Conclusions Progression‐free survival was significantly longer with durvalumab than with placebo. The secondary end points also favored durvalumab, and safety was similar between the groups. (Funded by AstraZeneca; PACIFIC ClinicalTrials.gov number, NCT02125461.)

A Phase I Study with Neratinib (HKI-272), an Irreversible Pan ErbB Receptor Tyrosine Kinase Inhibitor, in Patients with Solid Tumors

Purpose: The dose-limiting toxicities, maximum tolerated dose, pharmacokinetic profile, and preliminary antitumor activity of neratinib (HKI-272), an irreversible pan ErbB inhibitor, were determined in patients with advanced solid tumors. Experimental Design: Neratinib was administered orally as a single dose, followed by a 1-week observation period, and then once daily continuously. Planned dose escalation was 40, 80, 120, 180, 240, 320, 400, and 500 mg. For pharmacokinetic analysis, timed blood samples were collected after administration of the single dose and after the first 14 days of continuous daily administration. Results: Dose-limiting toxicity was grade 3 diarrhea, which occurred in one patient treated with 180 mg and in four patients treated with 400 mg neratinib; hence, the maximum tolerated dose was determined to be 320 mg. Other common neratinib-related toxicities included nausea, vomiting, fatigue, and anorexia. Exposure to neratinib was dose dependent, and the pharmacokinetic profile of neratinib supports a once-a-day dosing regimen. Partial response was observed for 8 (32%) of the 25 evaluable patients with breast cancer. Stable disease ≥24 weeks was observed in one evaluable breast cancer patient and 6 (43%) of the 14 evaluable non–small cell lung cancer patients. Conclusion: The maximum tolerated dose of once-daily oral neratinib is 320 mg. The most common neratinib-related toxicity was diarrhea. Antitumor activity was observed in patients with breast cancer who had previous treatment with trastuzumab, anthracyclines, and taxanes, and tumors with a baseline ErbB-2 immunohistochemical staining intensity of 2+ or 3+. The antitumor activity, tolerable toxicity profile, and pharmacokinetic properties of neratinib warrant its further evaluation.

Diagnosis of lung cancer by the analysis of exhaled breath with a colorimetric sensor array

Background: The pattern of volatile organic compounds (VOCs) in the exhaled breath of patients with lung cancer may be unique. New sensor systems that detect patterns of VOCs have been developed. One of these sensor systems, a colorimetric sensor array, has 36 spots composed of different chemically sensitive compounds impregnated on a disposable cartridge. The colours of these spots change based on the chemicals with which they come into contact. In this proof of principle study, the ability of this sensor system to detect a pattern of VOCs unique to lung cancer is assessed. Methods: Individuals with lung cancer, those with other lung diseases and healthy controls performed tidal breathing of room air for 12 min while exhaling into a device designed to draw their breath across a colorimetric sensor array. The colour changes that occurred for each individual were converted into a numerical vector. The vectors were analysed statistically, using a random forests technique, to determine whether lung cancer could be predicted from the responses of the sensor. Results: 143 individuals participated in the study: 49 with non-small cell lung cancer, 18 with chronic obstructive pulmonary disease 15 with idiopathic pulmonary fibrosis 20 with pulmonary arterial hypertension 20 with sarcoidosis and 21 controls. A prediction model was developed using observations from 70% of the subjects. This model was able to predict the presence of lung cancer in the remaining 30% of subjects with a sensitivity of 73.3% and a specificity of 72.4% (p = 0.01). Conclusions: The unique chemical signature of the breath of patients with lung cancer can be detected with moderate accuracy by a colorimetric sensor array.

Paclitaxel in cancer therapy

The last decade witnessed the introduction of exciting new chemotherapeutic agents. Among these, paclitaxel emerged as one of the most powerful compounds. Paclitaxel promotes the polymerisation of tubulin, thereby causing cell death by disrupting the normal microtubule dynamics required for cell division and vital interphase processes. Mechanisms of acquired resistance to paclitaxel include alterations of tubulin structure and the amplification of membrane phosphoglycoproteins that function as drug-efflux pumps. Toxicities associated with paclitaxel include hypersensitivity reaction, neurotoxicity and haematological toxicities. Toxicities may be both dose- and schedule-dependent. Paclitaxel has activity against a broad band of tumour types, including breast, ovarian, lung, head and neck cancers. Paclitaxel also has activity in other malignancies that are refractory to conventional chemotherapy, including previously-treated lymphoma and small cell lung cancers and oesophageal, gastric endometrial, bladder and germ cell tumours. Paclitaxel is also active against AIDS-associated Kaposi’s sarcoma.

Metastatic Sarcomatoid Renal Cell Carcinoma Treated With Vascular Endothelial Growth Factor–Targeted Therapy

PURPOSE Metastatic renal cell carcinoma (mRCC) with sarcomatoid differentiation is an aggressive disease that is associated with poor outcomes to chemotherapy or immunotherapy. The utility of vascular endothelial growth factor (VEGF)-targeted therapy in patients with this disease is unknown. PATIENTS AND METHODS Patients who had mRCC with sarcomatoid features in the primary tumor and who were treated with VEGF-targeted therapy were retrospectively identified. Pathology slides were reviewed to determine the percentage of sarcomatoid differentiation. Objective response rate, percentage of tumor burden shrinkage, progression-free survival (PFS), and overall survival (OS) were determined. RESULTS Forty-three patients who had sarcomatoid mRCC were identified. The median percentage of sarcomatoid features was 14% (range, 3% to 90%). Patients were treated with either sunitinib (49%), sorafenib (28%), bevacizumab (19%), or sunitinib plus bevacizumab (5%). Partial responses were observed in eight patients (19%); 21 patients (49%) had stable disease; and 14 patients (33%) had progressive disease as their best response. Partial responses were limited to patients who had underlying clear-cell histology and less than 20% sarcomatoid elements. Median tumor shrinkage was -2% (range, -85% to 127%), and 53% achieved some degree of tumor shrinkage on therapy. Median PFS and OS were estimated to be 5.3 months and 11.8 months, respectively. CONCLUSION Patients who have mRCC and sarcomatoid differentiation can demonstrate objective responses and tumor shrinkage to VEGF-targeted therapy. Patients who have clear-cell histology and a lower percentage of sarcomatoid differentiation may have better outcomes with VEGF-targeted therapy.

F-18 Fluorodeoxyglucose Positron Emission Tomography in the Evaluation of Distant Metastases From Renal Cell Carcinoma

PURPOSE We conducted a study to evaluate the role of F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) in the detection of distant metastases from renal cell carcinoma (RCC). MATERIALS AND METHODS Twenty-four patients with histologically proven clear-cell RCC undergoing surgical evaluation for possible resection of recurrent disease were investigated. All patients had suspected distant metastases based on conventional anatomic imaging techniques (computed tomography and magnetic resonance imaging). A total of 36 distant metastatic sites were identified. Pathology for all sites was obtained by biopsy or after surgical resection. RESULTS Histologically documented distant metastases from RCC were present in 33 sites (21 patients). Overall sensitivity, specificity, and positive predictive value of FDG-PET for the detection of distant metastases from RCC was 63.6% (21 of 33), 100% (three of three), and 100% (21 of 21), respectively. The mean size of distant metastases in patients with true-positive FDG-PET was 2.2 cm (95% CI, 1.7 to 2.6 cm) compared with 1.0 cm in patients with false-negative FDG-PET (95% CI, 0.7 to 1.4 cm; P =.001). CONCLUSION FDG-PET is not a sensitive imaging modality for the evaluation of metastatic RCC and may not adequately characterize small metastatic lesions. However, positive FDG-PET is predictive for the presence of RCC in lesions imaged, may complement anatomic radiologic imaging modalities, and may alleviate the need for a biopsy in selected situations. A negative FDG-PET, however does not rule out active malignancy.

A Comparison of Two Stereotactic Body Radiation Fractionation Schedules for Medically Inoperable Stage I Non-small Cell Lung Cancer: The Cleveland Clinic Experience

Purpose: To assess the impact of fractionation upon tumor control and toxicity in medically inoperable early stage lung cancer patients treated with stereotactic body radiotherapy. Methods: We reviewed 94 consecutive stereotactic body radiotherapy treatments (86 patients) with medically inoperable stage I non-small cell lung cancer receiving either 50 Gy in five fractions (n = 56) or 60 Gy in three fractions (n = 38) from October 2003 to August 2007. Institutional practice was 10 Gy × 5 before March 1, 2006, when it changed to 20 Gy × 3 to conform to Radiation Therapy Oncology Group 0236 unless otherwise dictated clinically. Results: Median age was 73 years and median Karnofsky performance status 80. A total of 69 lesions were T1, 24 were T2 lung cancer. Median follow-up was 15.3 months. For the 50- and 60-Gy cohorts at 1 year, local control was 97.3% versus 100%, nodal failure 7.3% versus 3.4%, distant metastasis rate 21.8% versus 29.5%, and overall survival 83.1% versus 76.9% (p = 0.68, 0.54, 0.56, and 0.54, respectively). There was no difference in overall survival for patients with histologic (n = 61) compared with radiographic (n = 33) diagnosis. There was no impact of fractionation in the subset of T2 tumors. We observed two cases (2.2%) of clinical grade 2 pneumonitis. Mild late chest wall toxicity (grade 1 or 2) was seen in nine patients (10%) at a median of 8.4 months after treatment and was more common in the 60-Gy group (7 of 38 [18%] versus 2 of 56 [4%], p = 0.028). Conclusions: Local control, overall survival, nodal failure, and distant failure were not affected by fractionation. Chest wall toxicity was more common with 60-Gy group.