Clovis Oncology Enters Into Oncology Clinical Trial Collaboration With GlaxoSmithKline

The gist: Scientists hope that a promising drug called rociletinib could be combined with a drug called trametinib to treat people with non-small cell lung cancer (NSCLC) whose tumors have mutations in the EGFR gene. Both drugs are targeted therapy drugs. The combination might help treat people whose tumors are resistant to other targeted treatments, due to EGFR T790M mutations. The combination will be tested soon in a clinical trial with volunteer patients. Later, other clinical trials might try combining rociletinib with other drugs.

“ ‘We have seen significant activity in EGFR mutant NSCLC patients treated with rociletinib monotherapy, and so an important next step in our research is to examine rociletinib in combination with other targeted therapies that may also impact acquired resistance to EGFR inhibitors,’ said Lecia V. Sequist, MD, MPH, Massachusetts General Hospital Cancer Center and Associate Professor of Medicine at Harvard Medical School and the lead investigator for this combination study.

“ ‘As we continue to see compelling activity for rociletinib single-agent therapy at our selected dose, we look forward to exploring combination trials in both T790M-positive and T790M-negative patients,’ said Patrick J. Mahaffy, President and CEO of Clovis Oncology. ‘We believe that given the tolerability profile of rociletinib, particularly its lack of cutaneous toxicity, it may be a good candidate for combination therapy with trametinib, and other relevant targeted therapies. We intend to announce additional combination studies over the next few months.’ “


Dabrafenib–Trametinib Combination Extended Survival in Metastatic Melanoma

The gist: A recent clinical trial with volunteer patients compared two treatments for metastatic melanoma. It showed that one of the treatments might give longer survival times for people whose tumors have mutations called BRAF V600E or BRAF V600K. This treatment combines the drugs dabrafenib and trametinib. In the trial, some patients were treated with the combination, and some were treated with only the drug vemurafenib (aka Zelboraf). People who took dabrafenib and trametinib lived several months longer than people who took vemurafenib. None of the patients had taken any previous treatments for their melanoma.

“The combination of dabrafenib and trametinib significantly extended OS compared with vemurafenib monotherapy in patients with treatment-naive metastatic melanoma who harbored BRAF V600E or V600K mutations, according to results of a randomized, open-label phase 3 study.

“The regimens demonstrated comparable toxicity profiles, researchers wrote.

“ ‘Together with the previously reported phase 2 and 3 trials of dabrafenib plus trametinib as compared with dabrafenib monotherapy, these data provide clear evidence for the benefit of this combination therapy over BRAF monotherapy in prolonging survival,’ Caroline Robert, MD, PhD, head of the dermatology unit at Institut Gustave-Roussy in Paris, and colleagues wrote.”


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. ‘ “


Trial Expands the Eligible Patient Population and Overall NeuVax Clinical Trial Portfolio

The gist: In a new clinical trial, the first patient has been given a new treatment meant to keep their cancer from returning (recurrence). The treatment combines the drug Herceptin with a new drug called NeuVax (aka nelipepimut-S). It is being tested in volunteer patients with HER2 3+ and/or HER2 gene-amplified breast cancer that has a high risk of recurrence.

“Galena Biopharma, Inc. (Nasdaq:GALE), a biopharmaceutical company developing and commercializing innovative, targeted oncology treatments that address major medical needs across the full spectrum of cancer care, today announced the dosing of the first patient in a new NeuVax™ (nelipepimut-S) Phase 2 clinical trial to prevent breast cancer recurrence in high risk HER2 3+ and/or HER2 gene-amplified breast cancer patients in combination with Herceptin® (trastuzumab; Genentech/Roche). The patients will be defined as 3+ by immunohistochemistry (IHC) or are HER2 2+ and/or fluorescence in situ hybridization (FISH) > 2.0, also described as gene-amplified. The multi-center, prospective, randomized, single-blinded, placebo-controlled, Phase 2 trial will enroll 100 patients with a diagnosis of HER2 3+ or gene-amplified breast cancer, are HLA A2+ or HLA A3+, and are determined to be at high-risk for recurrence.

” This trial is a significant addition to our portfolio of NeuVax clinical trials that are exploring the potential of the agent to prevent recurrence in a variety of cancer settings,’ said Mark W. Schwartz, Ph.D., President and Chief Executive Officer. ‘Herceptin has shown efficacy in HER2 3+ patients; however, those patients who fall into the high risk category are at much greater risk for a recurrence following standard of care treatment. Based on early studies and pre-clinical data, the combination of NeuVax and Herceptin has shown that the two agents utilize different mechanisms of action to target the same protein, leading to a potentially strong synergistic effect that may provide clinical benefit in this high-risk population. We are excited for the potential to help these high risk patients.’ “


CLEOPATRA Analysis Shows That HER2 Is Sole Marker Suitable for Selection of Pertuzumab/Trastuzumab-Based Treatment in Metastatic Breast Cancer

The gist: Some metastatic breast cancer patients can be treated with a combination of the drugs pertuzumab (Perjeta) and trastuzumab (Herceptin). New research shows that, when deciding whether to use the combo for a patient, the only tumor mutation an oncologist must consider is HER2. HER2 is one of many tumor mutations that could potentially be used to predict whether a certain treatment will work. The new research showed that, while only HER2 is necessary for the treatment decision, other biomarkers like HER3 and PIK3CA might help predict how well the treatment will work for a patient.

“In an analysis in the CLEOPATRA trial population reported in the Journal of Clinical Oncology, Baselga et al found that HER2 was the only biomarker suitable for use in selecting patients for first-line pertuzumab (Perjeta)/trastuzumab (Herceptin)-based treatment in patients with HER2-positive metastatic breast cancer…

“The study involved analysis of mandatory tumor and serum samples from 808 patients receiving first-line pertuzumab, trastuzumab, and docetaxel vs trastuzumab and docetaxel in CLEOPATRA. Samples were assessed (58%–99.8% assessable) for amphiregulin, betacellulin, EGF, transforming growth factor alpha,  EGFR, HER2, HER3, insulin-like growth factor 1 receptor, PTEN, phosphorylated AKT, PIK3CA, CMYC, serum HER2 extracellular domain (sHER2), and FCγR. The CLEOPATRA trial showed significant increases in progression-free survival and overall survival with the addition of pertuzumab…

“The investigators concluded: ‘Through comprehensive prospective analyses, CLEOPATRA biomarker data demonstrate that HER2 is the only marker suited for patient selection for the trastuzumab plus pertuzumab-based regimen in HER2-positive metastatic breast cancer. HER2, HER3, and PIK3CA were relevant prognostic factors.’ “


Everolimus–Exemestane Combination Failed to Significantly Extend OS in Advanced Breast Cancer

The gist: A clinical trial with volunteer patients tested a treatment for postmenopausal women with HR-positive, HER-2–negative advanced breast cancer. The treatment combines the drugs everolimus and exemestane. The clinical trial compared it to exemestane alone. The combination did NOT appear to give longer overall survival rates than exemestane alone.

“The addition of everolimus to exemestane extended OS in postmenopausal women with HR-positive, HER-2–negative advanced breast cancer, but the difference was not statistically significant, according to results of the BOLERO-2 study.

“BOLERO-2 is a randomized phase 3, double blind, international trial.

“Prior results showed the addition of 10 mg daily everolimus (Afinitor, Novartis) — an inhibitor of mammalian target of rapamycin (mTOR) — to 25 mg daily exemestane significantly extended PFS compared with exemestane alone (7.8 months vs. 3.2 months; P<.001).

“In the current study, Martine Piccart, MD, PhD, professor of oncology at the Université Libre de Bruxelles in Belgium and director of medicine at Institut Jules Bordet, and colleagues presented OS outcomes as part of a prospectively planned secondary-endpoint analysis.

“Results showed patients assigned the combination demonstrated longer median OS (31 months vs. 26.6 months; HR=0.89; 95% CI, 0.73-1.1), but the difference was not statistically significant.

“ ‘Ongoing translational research should further refine the benefit of mTOR inhibition and related pathways in this treatment setting,’ Piccart and colleagues wrote.”


Neoadjuvant Chemotherapy Plus Two Anti-HER2 Agents Optimal for HER2-Positive Breast Cancer

The gist: Before surgery to remove a tumor, breast cancer patients might take neoadjuvant therapy to shrink the tumor or otherwise help ensure a more successful surgery. A recent study concludes that combining two HER2-targeted drugs with chemotherapy might be the best neoadjuvant treatment choice for women with HER2-positive breast cancer. The researchers compared data from patients who received different combinations of chemotherapy, trastuzumab (Herceptin), and lapatinib (Tykerb). Patients who received all three had the highest chance of having no more signs of an invasive tumor after the treatment.

“For women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, combining two anti-HER2 agents with chemotherapy is the most effective treatment modality in the neoadjuvant setting, according to a meta-analysis published in the Journal of the National Cancer Institute.

“The study by Nagayama et al found that chemotherapy with trastuzumab (Herceptin) plus lapatinib (Tykerb), or with trastuzumab plus pertuzumab (Perjeta), resulted in a statistically significantly larger number of patients achieving pathologic complete response than did chemotherapy alone, chemotherapy with a single targeted therapy, or two anti-HER agents without chemotherapy. Ranking of treatment arms indicated that chemotherapy with trastuzumab plus pertuzumab “had the highest probability of being the best treatment arm in terms of [pathologic complete response],” the investigators stated.

“ ‘The growing number of HER2-targeted agents has created the need to define the optimal neoadjuvant therapy for HER2-positive breast cancer,’ the researchers wrote in explaining the rationale for the study. While other trials have been conducted to compare treatments, ‘it is difficult to integrate information on the relative efficacy of all tested regimens, since each trial has compared only a few treatments,’ the investigators noted.”


Immune System-Activating Drugs in Combination Treatments May Be Next Big Thing for Melanoma


Among solid tumors, the curative potential of immunotherapies has been explored most in melanoma. One reason for this is that melanoma tumors often contain so-called immune infiltrates—patches of T cells, the killer cells of the immune system. It seems that these fighter cells arrive at the ‘battlefield’ to target tumor cells for killing, but instead become ‘frozen,’ unable to attack.  How to activate the tumor-killing potential of T cells has been an area of intense and fruitful research, leading to the development of several immunotherapy drugs. Continue reading…


Pfizer Announces FDA Acceptance of Palbociclib New Drug Application with Priority Review

The gist: In the U.S., a drug must be approved by the U.S. Food and Drug Administration (FDA) in order for it to be prescribed to patients with specific diseases. Particularly promising drugs might be granted Priority Review, meaning that the FDA agrees to work with the drug manufacturer to accelerate the approval process. The FDA recently granted priority review to a drug meant to treat certain breast cancer patients. The drug is called palbociclib. It is meant to be combined with another drug called letrozole as a treatment for “postmenopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who have not received previous systemic treatment for their advanced disease.”  The FDA’s decision was based on promising results for the treatment in a clinical trial that tested it in volunteer patients. People who are interested in getting the treatment before it is approved can look into participating in Pfizer’s expanded access trial.

“Pfizer Inc. today announced the New Drug Application (NDA) for palbociclib has been accepted for filing and granted Priority Review by the United States Food and Drug Administration (FDA). This NDA requests FDA approval of palbociclib, in combination with letrozole, as a first-line treatment for postmenopausal women with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who have not received previous systemic treatment for their advanced disease. The submission is based on the final results of PALOMA-1, a randomized, Phase 2 trial comparing palbociclib plus letrozole versus letrozole alone in this population of patients.

“The FDA’s Priority Review status accelerates the review time from 10 months to a goal of six months from the day of acceptance of filing and is given to drugs that may offer major advances in treatment or may provide a treatment where no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is April 13, 2015.

“Palbociclib received Breakthrough Therapy designation from the FDA in April 2013, for the first-line systemic treatment of women with advanced or metastatic ER+, HER2- breast cancer.

“ ‘If approved as a first-line therapy in combination with letrozole, palbociclib will be an important new option for the thousands of women in the U.S. who are living with metastatic breast cancer,’ said Garry Nicholson, president, Pfizer Oncology. ‘We look forward to continuing to work closely with the FDA through the review process.’

“Pfizer recently announced the initiation of a multi-center, open-label expanded access program (EAP) in the United States for palbociclib. Through the program, palbociclib is available to post-menopausal women with hormone receptor-positive (HR+), HER2- advanced breast cancer who are eligible for letrozole therapy and for whom enrolling in other palbociclib clinical trials is not an option. Healthcare professionals and patients can learn more about the palbociclib EAP by visiting www.clinicaltrials.gov (trial number: NCT02142868).”