Motesanib Fails in a Phase III Trial for NSCLC

The gist: New research results have dashed hopes that a drug called motesanib (AMG 706) might be an effective treatment for Asian people with stage IV, non-squamous non-small cell lung cancer (NSCLC). In 2011, the drug failed testing in patients, but data showed there might be some benefit for certain Asian patients. Testing continued in a group of patients from Japan, South Korea, Taiwan, and Hong Kong. However, the new results show that motesanib does not improve standard treatment with the drugs paclitaxel and carboplatin.


Adding Higher Dose Radiation or Cetuximab Doesn't Benefit Stage III NSCLC Patients Receiving Chemoradiation

The gist: An attempt to improve treatment for stage III non-small cell lung cancer (NSCLC) patients failed when it was tested in a clinical trial. People with stage III NSCLC are normally treated with radiation and chemotherapy. Researchers wondered if giving higher-dose radiation or adding the drug cetuximab (Erbitux) would improve the standard treatment. However, when tested in patients, neither approach worked better than the standard approach.

“As reported in The Lancet Oncology by Bradley and colleagues, the phase III Radiation Therapy Oncology Group 0617 trial showed no survival benefit of high- vs standard-dose radiotherapy or for addition of cetuximab (Erbitux) to concurrent paclitaxel-carboplatin chemoradiation in patients with inoperable stage IIIA or IIIB non–small cell lung cancer (NSCLC).

“In the open-label 2×2 factorial trial, patients from the United States and Canada were randomly assigned 1:1:1:1 between November 2007 and November 2011 to receive 60 Gy radiotherapy (n = 166), 74 Gy radiotherapy (n = 121), 60 Gy radiotherapy and cetuximab (n = 147), or 74 Gy radiotherapy and cetuximab (n = 110) with all patients receiving concurrent once-weekly chemotherapy with paclitaxel at 45 mg/m2 and carboplatin at area under the curve (AUC) 2. Two weeks after chemoradiation, patients received two cycles of consolidation paclitaxel at 200 mg/m2 and carboplatin at AUC 6 separated by 3 weeks. Radiation was given in 2-Gy daily fractions with either intensity-modulated or three-dimensional conformal radiation therapy. Cetuximab was given at 400 mg/m2 on day 1 followed by 250 mg/m2 weekly continued through consolidation therapy. The primary endpoint was overall survival.

“Patients had a median age of 64 years, and most were male (55%–64%), white (82%–89%), had Zubrod performance status of 0 (55%–59%), were current smokers (43%–51%), received three-dimensional conformal radiotherapy (47%–54%), underwent positron-emission tomography (PET) staging (89%–91%), had squamous histology (42%–47%), and had stage IIIA disease (63%–66%).”


Linifanib With Chemotherapy Delays Disease Worsening in Advanced Non-Squamous NSCLC

The gist: People with advanced non-squamous non-small cell lung cancer (NSCLC) might do better if a drug called linifanib is added to chemo treatment with the drugs carboplatin and paclitaxel. In a clinical trial with volunteer patients, people who took all three drugs went for several weeks longer without their disease worsening than patients who took only carboplatin and paclitaxel.

“The addition of linifanib to a carboplatin and paclitaxel regimen offered significantly improved progression-free survival (PFS) over placebo in a randomized phase II trial of patients with advanced non-squamous non–small-cell lung cancer (NSCLC).

“Previous work has shown that adding inhibitors of VEGF to standard chemotherapy can improve survival outcomes in advanced NSCLC. Linifanib (Abbott Laboratories) is a tyrosine kinase inhibitor with activity against VEGF and PDGF receptors. “Single-agent activity of linifanib in phase I and II clinical studies in patients with advanced NSCLC encouraged further evaluation of linifanib as a component of therapy for these patients,” wrote study authors led by Suresh S. Ramalingam, MD, of Winship Cancer Institute of Emory University in Atlanta…

“ ‘Although additional studies of linifanib in NSCLC are not currently planned, further evaluation of linifanib in patients with the identified biomarker signature is warranted,’ the authors concluded. ‘These findings are also of potential significance for other antiangiogenic agents presently under development for NSCLC.’ ”


Two Treatments Yield Similar Survival Rates in Stage III NSCLC

The gist: A recent study showed similar survival rates for two different drug combinations for stage III non-small cell lung cancer (NSCLC). The study compared  EP (treatment with the drugs etoposide and cisplatin) with CP (carboplatin plus paclitaxel). Both drug combinations were given along with radiation therapy. The study showed that EP might cause worse side effects, but the researchers say that more research will be needed to determine whether either EP or CP is better for treating stage III NSCLC.

“An analysis of Veterans Health Administration patients showed that etoposide/cisplatin (EP) and carboplatin/paclitaxel (CP) yielded similar overall survival along with radiotherapy in patients with stage III non–small-cell lung cancer (NSCLC), but EP was associated with increased morbidity. Prospective studies are still needed to determine the optimal treatment in these patients.

“ ‘There is considerable concern that CP, although better tolerated than EP, may be inferior in terms of disease control,’ wrote study authors led by Rafael Santana-Davila, MD, of the University of Washington in Seattle. To better understand the differences between the regimens, researchers looked into outcomes of patients in the VA Central Cancer Registry.

“The study included a total of 1,842 patients treated with concurrent radiotherapy and either EP or CP between 2001 and 2010. EP was used in 27% of the full cohort…

“Though the similar survival and increased morbidity with EP suggest CP may be the preferred treatment, Santana-Davila said in an email that “the study is not able to provide a firm recommendation. It has many limitations, and although we tried to adjust for confounders with several techniques, it is still a retrospective study.”

“Those limitations include a lack of data on dose or duration of therapy, and there were treatment differences such as an increased rate of consolidation chemotherapy with CP patients. The reliance on coded administrative data to identify toxicities is also less reliable than methods used in clinical trials.

“ ‘The only way we could provide firm recommendations would be with a phase III randomized trial,’ Santana-Davila said. In the meantime, the authors concluded that these results may simply help guide treatment decisions in stage III NSCLC patients.”


No Survival Difference but Greater Morbidity With Etoposide/Cisplatin vs Carboplatin/Paclitaxel With Concurrent Radiotherapy for Stage III NSCLC

The gist: Recent research comparing two drug combinations for stage III non-small cell lung cancer (NSCLC) suggests that the drug combo etoposide/cisplatin does not help people live longer than carboplatin/paclitaxel does, and it also may result in more side effects. Both drug combos are taken alongside radiation treatment.

“In an analysis of Veterans Health Administration data reported in the Journal of Clinical Oncology, Santana-Davila et al found that etoposide/cisplatin resulted in no overall survival difference but greater morbidity compared with carboplatin/paclitaxel used concurrently with radiotherapy in patients with stage III non–small cell lung cancer (NSCLC).

“The analysis involved 1,842 patients treated with etoposide/cisplatin (n = 499) or carboplatin/paclitaxel (n = 1,343) between 2001 and 2010. In a Cox proportional hazard model, age (hazard ratio [HR] = 1.08, P = .0258), percentage weight loss (HR = 1.04, P < .0001), baseline anemia (HR = 1.19, P = .0064), hypoalbuminemia (HR = 1.29; 95% confidence interval [CI] = 1.14–1.46; P < .001), and treatment era (HR = 0.89 for 2005-2007 and 0.83 for 2008-2010 vs 2001-2004, P = .028) were independently associated with overall survival, whereas chemotherapy regimen (median overall survival = 17.3 months for etoposide/cisplatin vs 14.6 months for carboplatin/paclitaxel, HR = 0.97, P = .6327), stage (HR = 1.08, P = .185, for IIIB vs IIIA), and National Cancer Institute combined index score (HR = 1.17, P = .0503) were not associated with survival…

“The investigators concluded: ‘After accounting for prognostic variables, patients treated with [etoposide/cisplatin vs carboplatin/paclitaxel] had similar overall survival, but [etoposide/cisplatin] was associated with increased morbidity.’ ”


Olaparib Tablet Found Safe and Effective in Heavily Pretreated Patients With Ovarian Cancer

The gist: Patients with advanced ovarian cancer who have already had three to eight treatments might benefit from a new treatment that combines the drugs olaparib, paclitaxel, and carboplatin. That was the insight from a recent clinical trial—a research study with volunteer patients. The clinical trial found the combination treatment to be safe and effective at shrinking tumors, especially for women with BRCA mutations.

“A phase Ib clinical trial of the tablet form of olaparib, a PARP inhibitor, in combination with paclitaxel and carboplatin chemotherapy in heavily pretreated patients with advanced-stage ovarian cancer finds the drug to be safe and effective, especially in those women with BRCA gene mutations. The study by Rivkin et al was presented at the Marsha Rivkin Center for Ovarian Cancer Research–AACR 10th Biennial Ovarian Cancer Research Symposium, held September 8 to 9, in Seattle…

“The purpose of this study was to establish the maximum-tolerated dose of olaparib and to evaluate dose-limiting toxicities and response to therapy of the tablet form of olaparib plus carboplatin and paclitaxel in women with stage III or IV ovarian cancer. The researchers enrolled 14 heavily pretreated (from three to eight prior therapies) patients in the study, aged 42 to 77. All the patients were tested for BRCA2 and BRCA2 gene mutations.

“Patients received paclitaxel and carboplatin weekly for 3 out of 4 weeks, with increasing doses of olaparib. The maximum tolerated dose of olaparib was found to be 150 mg twice daily for 3 consecutive days of each week of each cycle.”


Breast Cancer Specialist Reports Advance in Treatment of Triple-Negative Breast Cancer

“Because of its rapid growth rate, many women with triple-negative breast cancer receive chemotherapy to try to shrink it before undergoing surgery. With the standard treatment, the cancer is eliminated from the breast and lymph nodes in the armpit before surgery in about one third of women. This is referred to as a pathologic complete response (pCR). In patients who achieve pCR, the cancer is much less likely to come back, spread to other parts of the body, and cause the patient’s death than if the cancer survives the chemotherapy.

“Sikov and his collaborators studied the addition of other drugs – carboplatin and/or bevacizumab – to the standard treatment regimen to see if they could increase response rates. More than 440 women from cancer centers across the country enrolled in this randomized clinical trial.

” ‘Adding either of these medications significantly increased the percentage of women who achieved a pCR with the preoperative treatment. We hope that this means fewer women will relapse and die of their cancer, though the study is not large enough to prove this conclusively. Of the two agents we studied, we are more encouraged by the results from the addition of carboplatin, since it was associated with fewer and less concerning additional side effects than bevacizumab,’ Sikov explains.”

Editor’s note: This article describes the results of a clinical trial—a research study with volunteer patients.