Brigatinib Achieves Brain Metastases Control for Over 80% of ALK-Positive NSCLC Patients

“Brigatinib (AP26113), an investigational ALK tyrosine kinase inhibitor, demonstrated significant intracranial antitumor activity in patients with ALK-positive non–small cell lung cancer (NSCLC) and brain metastases, according to findings presented at the European Lung Cancer Conference.1

“A post hoc analysis conducted by Ariad Pharmaceuticals, the company developing brigatinib, looked at 49 NSCLC patients identified as having baseline brain metastasis. The analysis determined that intracranial disease control was achieved with brigatinib in 87% of patients with measurable brain metastases and in 87% of patients with nonmeasurable brain metastases. Intracranial response was reported in 53% of patients with measurable brain metastases and in 30% of patients with nonmeasurable lesions.

“Following treatment, 45 patients achieved median intracranial progression–free survival (PFS) of 22.3 months. The median duration of intracranial response was 18.9 months.

“Adverse events were mild to moderate in severity and included nausea, diarrhea, and fatigue that were reported by 29 (59%), 28 (57%), and 24 (49%) patients, respectively.”

NKTR-102 Improves Survival in Women with Brain and Liver Metastases from Breast Cancer

“Nektar Therapeutics (NASDAQ: NKTR) announced topline results from its Phase 3 BEACON study evaluating single-agent NKTR-102 in patients with advanced breast cancer. BEACON compared NKTR-102 to an active control arm comprised of a single chemotherapy agent of physician’s choice (TPC) in patients who were heavily pre-treated with a median of three prior therapies for metastatic disease. In a topline analysis of 852 patients from the trial, NKTR-102 provided a 2.1 month improvement in median overall survival (OS) over TPC (12.4 months for patients receiving NKTR-102 compared to 10.3 months for patients receiving TPC). Based on a stratified log-rank analysis, the primary endpoint measuring the Hazard Ratio (HR) for survival in the NKTR-102 group compared to the active control arm was 0.87 with a p-value of 0.08, which did not achieve statistical significance.

“In a pre-specified subgroup of patients with a history of brain metastases, NKTR-102 showed an improvement of 5.2 months in median OS (10.0 months compared to 4.8 months, n=67, HR 0.51, p-value <0.01). The proportion of patients with brain metastases with 12-month survival was 44.4% in the NKTR-102 arm as compared to 19.4% in the control arm.”

Localized Radiation for Brain Mets Has Similar Recurrence Rate at Tumor Site as Whole-Brain Radiation, but More New Mets over Time

“In patients who had undergone surgery for brain metastases, the rate of recurrence at the resected site was similar between patients who received adjuvant whole-brain radiotherapy vs those who underwent adjuvant localized radiotherapy, according to a retrospective study by Hsieh et al in the journal Neurosurgery. However, localized radiotherapy was associated with a higher incidence of distant metastases.

“Surgery followed by adjuvant whole-brain radiotherapy is a well-established treatment for brain metastases, particularly in patients who have a limited number of brain metastases. Yet discussions continue as to whether these patients require whole-brain radiotherapy or can be treated with localized radiotherapy. Localized radiotherapy is associated with fewer side effects compared with whole-brain radiotherapy, but some studies have documented an association with an increased risk for development of new intracranial metastases.

“Thus, the investigators  conducted a study to examine the rate of brain metastases recurrence between patients treated with whole-brain radiotherapy vs localized radiotherapy. They also analyzed overall survival and the risk of development of leptomeningeal disease…

“The investigators stated, ‘Our results support the conclusion that adjuvant treatment with localized radiotherapy instead of whole-brain radiotherapy as adjuvant provides equivalent control at the resection cavity and radiosurgically treated lesions, with no detectable difference in overall survival.’ ”

Improved Survival for Patients with Brain Mets Who Are 50 and Younger and Receive SRS Alone

“Cancer patients with limited brain metastases (one to four tumors) who are 50 years old and younger should receive stereotactic radiosurgery (SRS) without whole brain radiation therapy (WBRT), according to a study available online, open-access, and published in the March 15, 2015 issue of the International Journal of Radiation Oncology * Biology * Physics (Red Journal), the official scientific journal of the American Society for Radiation Oncology (ASTRO). For patients 50 years old and younger who received SRS alone, survival was improved by 13 percentage points when compared to those patients 50 years old and younger who received both SRS and WBRT.

“This study, ‘Phase 3 Trials of Stereotactic Radiation Surgery With or Without Whole-Brain Radiation Therapy For 1 to 4 Brain Metastases: Individual Patient Data Meta-Analysis,’ analyzed patient data from the three largest randomized clinical trials (RCT) of SRS and WBRT conducted to-date: the Asian trial (JROSG99-1) by Aoyama et al.[1], published in 2006; the North American trial (MDACC NCT00548756) by Chang et al.[2], published in 2009; and the European trial (EORTC 22952-26001) by Kocher et al.[3], published in 2011. A total of 364 patients from the three RCTs were evaluated for this meta-analysis. Of those 364 patients, 51 percent (186) were treated with SRS alone, and 49 percent (178) received both SRS and WBRT. Nineteen percent of patients (68) were 50 years old and younger, and 61 percent (19) of these patients had a single brain metastasis. Twenty percent of all patients (72) had local brain failure, which is the occurrence of progression of previously treated brain metastases; and 43 percent (156) experienced distant brain failure, which is the occurrence of new brain metastases in areas of the brain outside the primary tumor site(s).

“The impact of age on treatment effectiveness revealed SRS alone yielded improved overall survival (OS) in patients 50 years old and younger. Patients 50 years old and younger who received SRS alone had a median survival of 13.6 months after treatment, a 65 percent improvement, as opposed to 8.2 months for patients 50 years old and younger who were treated with SRS plus WBRT. Patients >50 years old had a median survival of 10.1 months when treated with SRS alone, and 8.6 months for those who received SRS plus WBRT.”

Crizotinib Shows Promise against Brain Metastases in Patients with NSCLC

The gist: A drug called crizotinib (Xalkori) has shown promise for some people with non-small cell lung cancer (NSCLC) that has metastasized to the brain. Xalkori is already used to treat NSCLC in patients whose tumors have a genetic abnormality known as “ALK rearrangement.” A recent study focused specifically on people whose NSCLC had spread to the brain. The researchers found that Xalkori may help patients whose brain metastases have not yet caused any symptoms.

Puma Shrugs off an 'Expected' Phase II Failure for Its Breast Cancer Drug

The gist: A new breast cancer drug called neratinib works just as well as Herceptin for some HER2-positive patients. It may also reduce the chances of metastases in the central nervous system; for example, in the brain. Researchers recently tested neratinib in volunteer patients in a clinical trial. They compared it to the drug Herceptin, which is already used by many breast cancer patients. In the trial, neratinib was tested in combination with the chemotherapy drug paclitaxel in people with HER2-positive breast cancer. People who took the neratinib combination had similar survival rates as people who took Herceptin. They had a 52.6% reduction in central nervous system metastases.

“Puma Biotechnology’s ($PBYI) closely watched neratinib failed to beat out the blockbuster Herceptin in a mid-stage breast cancer trial, a miss the company said was no surprise as it touted success on a secondary goal.

“The company recruited 479 patients with HER2- positive breast cancer, testing whether a combination of neratinib and paclitaxel could better prolong progression-free survival (PFS) than a cocktail of Roche’s ($RHHBY) Herceptin and paclitaxel. In the end, median PFS for Puma’s drug came in at 16.6 months, while Herceptin clocked 16.7. And neratinib fared no better on its secondary endpoint, charting a 74.8% overall response rate compared to Herceptin’s 75.1%.

“But Puma is ‘very pleased with the results,’ CEO Alan Auerbach said in a statement, pointing to the secondary endpoint in which neratinib succeeded. The drug contributed to a 52.6% reduction in the incidence of central nervous system metastases–for instance cancer spreading to the brain–compared to the Herceptin arm, a statistically significant result that Puma believes could help differentiate neratinib on the market for breast cancer therapies.

” ‘As expected, there was no statistically significant difference in progression-free survival and objective response rate for the paclitaxel plus neratinib arm compared to the paclitaxel plus trastuzumab arm,’ Auerbach said. ‘However … while the development of other HER2-targeted drugs has produced a clinically meaningful benefit to patients with HER2 positive breast cancer, these drugs have had little impact on CNS metastases. As a result, we believe that there remains an unmet clinical need for reducing the incidence of CNS metastases, and the results of the NEfERTT study demonstrate that we may be able to provide this type of improvement with neratinib. ‘ “

Adding Ziv-Aflibercept to Topotecan Improves Progression-Free Survival but Increases Toxicity in Platinum-Treated Small Cell Lung Cancer

Editor’s note: A recent clinical trial with volunteer patients tested whether a treatment that combines a drug called ziv-aflibercept (Zaltrap) with the drug topotecan would be better than toptecan alone for people with small cell lung cancer (SCLC). All participating patients had previously been treated with platinum-based chemotherapy and had been treated for brain metastases. Patients were randomly assigned to be treated with either topotecan alone, or the topotecan/ziv-aflibercept combination. The researchers found that the combination treatment significantly increased the number of patients who survived three months or more without their disease worsening. However, the combo treatment had worse side effects and did not improve overall survival.

“The phase II Southwest Oncology Group (SWOG) S0802 trial reported in the Journal of Clinical Oncology by Allen et al showed that adding ziv-aflibercept (Zaltrap) to topotecan improved 3-month progression-free survival, but increased toxicity and had no effect on overall survival, in patients with platinum-treated small cell lung cancer (SCLC)…

“In the trial, 189 patients who had experienced disease progression after one line of platinum-based chemotherapy and had treated brain metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, and no recent vascular events or bleeding diatheses were randomly assigned to receive weekly topotecan at 4 mg/m2 with (n = 97) or without (n = 92) ziv-aflibercept at 6 mg/kg every 21 days. Patients were stratified as platinum-refractory (n = 55 vs 51) or platinum-sensitive (n = 42 vs 41). Progression-free survival at 3 months was the primary endpoint.”

Prophylactic Cranial Irradiation Increased DFS in Patients with Stage III NSCLC

Editor’s note: People who are at risk of having their cancer spread (metastasize) to the brain can receive “prophylactic cranial irradiation” to help prevent it. In this procedure, the head is treated with radiation to kill any cancer cells that may have already spread there but are not yet detectable. A recent study investigated the benefits of prophylactic cranial irradiation for people with fully resected (surgically removed), stage IIIA N2 non-small cell lung cancer (NSCLC). The study involved volunteer patients at high risk of brain metastases whose lung tumors had been surgically removed and who had received post-surgery chemotherapy to keep the cancer from returning. Some of the patients were given prophylactic cranial irradiation, and some were not. The researchers found that patients who received prophylactic cranial irradiation had a decreased risk of brain metastases and also had a longer period of survival without return of their cancer.


“Prophylactic cranial irradiation prolonged disease-free survival and decreased the incidence for brain metastases in patients with fully-resected stage IIIA N2 non–small cell lung cancer at high-risk for cerebral metastases after completing adjuvant chemotherapy, according to results presented at the ASCO Annual Meeting.

“Si-Yu Wang, MD, of the department of thoracic surgery at the Sun Yat-sen University Cancer Center in China and colleagues assessed whether prophylactic cranial irradiation improves survival in this population of patients.

“Between 2005 and 2009, researchers randomly assigned 156 patients to 30 Gy prophylactic cranial irradiation in 10 fractions (n=81) or observation (n=75). DFS served as the primary outcome measure; secondary outcome measures included the incidence for brain metastases, OS and adverse events. The study was halted early due to slow accrual.

“Patients treated with prophylactic cranial irradiation experienced a decreased risk for brain metastases (5-year brain relapse rate, 13.6% vs. 41.3%; OR=0.223; 95% CI, 0.102-0.489).

“DFS was significantly higher in patients assigned prophylactic cranial irradiation (28.5 months) compared with controls (21.2 months; HR=0.67; 95% CI, 0.46-0.98). Three-year DFS was 42% and 5-year DFS was 26.1% in the prophylactic cranial irradiation group vs. 29.8% at 3 years and 18.5% at 5 years for controls.”

ASCO Clinical Practice Guideline: Systemic Therapy for Patients With Advanced HER2-Positive Breast Cancer

“Approximately 15% of patients with breast cancer have tumors that overexpress the HER2 protein and these patients can benefit from HER2-targeted therapies. The American Society of Clinical Oncology recently released a clinical practice guideline on systemic therapy for patients with advanced HER2-positive breast cancer, published in the Journal of Clinical Oncology. The rationale for the guideline is that several new agents have become available for treatment of metastatic HER2-positive breast cancer since the approval of trastuzumab (Herceptin).

“Up to half of all patients with HER2-positive metastatic breast cancer develop brain metastases over time. Recommendations for the management of brain metastases in patients with HER2-positive breast cancer are detailed in another recently released companion guideline.”

Editor’s note: Click through to the full article (arrow button to the right of the title) to see the recommendations.