Roche's Perjeta Regimen Approved in Europe for Use Before Surgery in Early Stage Aggressive Breast Cancer

“Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced that the European Commission (EC) has approved the use of Perjeta® (pertuzumab) in combination with Herceptin® (trastuzumab) and chemotherapy for the neoadjuvant treatment (use before surgery) of adult patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer at high risk of recurrence. The Perjeta regimen is the first neoadjuvant breast cancer treatment approved by the EC based on pCR data.

“Every year in Europe nearly 100,000 people are diagnosed with HER2-positive breast cancer, an aggressive type of the disease that is more likely to progress than HER2-negative cancer.1,2 Treating people with breast cancer early, before the cancer has spread, may improve the chance of preventing the disease from returning. Neoadjuvant treatment is given before surgery and is aimed at reducing tumour size so it is easier to surgically remove. pCR is achieved when there is no tumour tissue detectable at the time of surgery in the affected breast or in the affected breast and local lymph nodes. It is a common measure of neoadjuvant treatment effect in breast cancer and it can be assessed more quickly than traditional endpoints in eBC.

“ ‘Today’s approval is a significant milestone in the neoadjuvant treatment of HER2-positive early breast cancer, bringing Perjeta to patients years earlier than typical adjuvant treatment,’ said Sandra Horning, M.D., Roche’s Chief Medical Officer and Head, Global Product Development. ‘We are committed to making the Perjeta regimen available to appropriate patients in the EU as early as possible.’ “


Neoadjuvant T-DM1 Shows Promising pCR Rates in HER2+/HR+ Early Breast Cancer

“Chemotherapy-free neoadjuvant treatment with trastuzumab emtansine (T-DM1; Kadcyla) demonstrated a pathological complete response (pCR) rate of 40.5% in patients with HER2+ and HR+ early breast cancer, according to findings from the phase II ADAPT trial presented at the 2015 ASCO Annual Meeting.

” ‘After 12 weeks without systemic chemotherapies we observed more than a 40% pCR in both the breast and nodes in our T-DM1-treated HER+/HR+ patients,’ said lead investigator Nadia Harbeck, MD, PhD, head of the Breast Center, Oncological Therapy and Clinical Trials Unit, University of Munich, Germany. ‘We did see very low overall toxicity, and did not detect any new safety signals.’

“The ADAPT trial is a large umbrella trial that has enrolled 5000 patients with various breast cancer phenotypes. In the arm of the trial presented at ASCO, 376 patients with HER2+ and HR+ breast cancer were randomized to receive neoadjuvant T-DM1 at 3.6 mg/kg with or without endocrine therapy or trastuzumab plus endocrine therapy. Treatment was administered for 4 cycles followed by surgery and 1-year of standard adjuvant chemotherapy plus trastuzumab.”


Higher Tumor-Infiltrating Lymphocyte Level Associated With Better Outcomes in HER2-Positive Early Breast Cancer Independent of Neoadjuvant Treatment

“In an analysis of the NeoALTTO trial reported in JAMA Oncology, Salgado et al found that a higher level of tumor-infiltrating lymphocytes was associated with improved pathologic compete response rate and event-free survival independent of neoadjuvant treatment received in patients with HER2-positive early breast cancer.

“In NeoALTTO, 455 patients were randomly assigned to receive neoadjuvant trastuzumab (Herceptin), lapatinib (Tykerb), or the combination for 6 weeks followed by the addition of weekly paclitaxel for 12 weeks and three cycles of fluorouracil, epirubicin, and cyclophosphamide after surgery. Percentage of tumor-infiltrating lymphocytes were measured by hematoxylin-eosin stained core biopsy sections taken at diagnosis.”


German Breast Group (GBG) Studies Demonstrate Subanalyses of Tumor DNA Repair Mutations Can Help Guide Treatment Selection and Predict Response in Preoperative Breast Cancer

“The German Breast Group (GBG) presented two analyses that can serve as predictors of response to treatment by further subdividing preoperative (neoadjuvant) patients with HER 2 positive breast cancer and those with triple negative breast cancer based on tumor DNA repair capabilities and related factors.

“Prof. Dr. Gunter von Minckwitz, president of the GBG Research Institute, noted, ‘Taken together these studies demonstrate that a deeper understanding of the variations among breast cancer types that go beyond hormone response and BRCA gene mutations can inform treatment options with increased precision.’

“One study (Abstract No: 1004) fromlead author Dr. von Minckwitz found cancer-related BRCA mutations in the tumor are more common (30.3%) than inherited BRCA mutations (19.8%) in patients with triple-negative breast cancer. The homologous recombination (HR) assay measures DNA repair capacity beyond those related to BRCA mutation. HR deficiency defined as having either a BRCA mutation of the tumor or a high HR score was found in 70.5% of the patients. These findings can affect treatment options. Patients with a tumor BRCA mutation and/or a high HR score showed a high complete response to preoperative (neoadjuvant) chemotherapy. Our findings suggest those patients are also benefiting more from the additional use of carboplatin than tumors without HR deficiency.”


High TIL Levels Predict Positive Outcomes in HER-2–Positive Breast Cancer

“High levels of tumor-infiltrating lymphocytes served as an independent positive predictive marker for EFS and pathological complete response in HER-2–positive early breast cancer treated with chemotherapy and anti-HER–2 agents, according a secondary analysis of the NeoALTTO trial.

“ ‘Increasingly, oncogenic addiction, in which tumors become dependent on a sole oncogenic pathway for growth, is thought to promote a tumor microenvironment conducive to immune escape,’ Sherene Loi, MD, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne, and colleagues wrote. ‘Although this had not been shown yet for HER-2 oncogenic signaling, one could speculate that anti-HER–2 therapy may not only work in a cell-intrinsic manner but may also reserve HER-2–induced immunosuppression as a mechanism for action.’

“The NeoALTTO trial included 455 women with HER-2–positive early-stage breast cancer between 2008 and 2010. The researchers randomly assigned patients to neoadjuvant treatment with trastuzumab (Herceptin, Genentech), lapatinib (Tykerb, GlaxoSmithKline) or both.

“Patients received the initial treatment for 6 weeks, followed by weekly paclitaxel for 12 weeks and three treatment cycles of fluorouracil, epirubicin and cyclophosphamide after surgery.”


Erlotinib Trial Indicates That It Could Be Used Before Surgery in Stage III Lung Cancer

“Erlotinib showed promise as neoadjuvant therapy in patients with epidermal growth factor receptor (EGFR) mutant stage IIIA-N2 non-small-cell lung cancer (NSCLC) who demonstrated good disease control with tolerable toxicity following treatment.

“Dr Baohui Han, Pulmonary Department, Shanghai Chest Hospital, Shanghai, China presented findings from a single arm, phase II clinical trial during the New Treatment Avenues Proffered Papers session at the European Lung Cancer Conference, 15 to 18 April 2015 in Geneva, Switzerland. The trial aimed to evaluate efficacy and safety of erlotinib as neoadjuvant treatment in patients with stage IIIA-N2 NSCLC and activating EGFR mutation.

“The trial’s primary endpoint was radical resection rate. Secondary endpoints included pathological complete response rate (pCR), objective response rate (ORR), disease free survival (DFS), overall survival (OS), safety profile, and explorative biomarkers.

“This study screened 155 patients and subsequently enrolled 44 patients with stage IIIA N2 NSCLC and 25 patients with IIIA N2 NSCLC plus activating EGFR (exon 19 or 21) mutations. All patients had ECOG performance status 1 and had been previously untreated for stage IIIA-N2 NSCLC, that was confirmed by endobronchial ultrasound.”


Neoadjuvant Chemotherapy for Breast Cancer Increases Chances of Lumpectomy, Decreases Chances of Mastectomy

“Patients with larger malignant tumors of the breast who undergo chemotherapy before a breast cancer operation are more likely to undergo a lumpectomy than a mastectomy, according to a study published by Killelea et al in the Journal of the American College of Surgeons.

“Study investigators from Yale University School of Medicine and Yale University Comprehensive Cancer Center also determined that rates of neoadjuvant chemotherapy had increased significantly through the 5-year study period, possibly because of the FDA approval of new chemotherapy agents…

“ ‘Going forward, it will be interesting to see whether or not the use of neoadjuvant therapy continues to rise as newer drugs and agents are being developed all the time,’ Dr. Killelea said. ‘It will also be interesting to watch what happens to the rate of breast conservation over time. We don’t know. That’s why it’s so important for us to have a database like NCDB.’ ”


A Breast Cancer Tumor's Immune Signature Could Predict Response to Neoadjuvant Therapy

“In a study reported in the Journal of Clinical Oncology, Denkert et al found that increased tumor-infiltrating lymphocytes and the presence of lymphocyte-predominant breast cancer were associated with increased rates of pathologic complete response in patients receiving neoadjuvant anthracycline-taxane treatment with or without carboplatin. Higher rates were observed with carboplatin, with treatment interactions being significant among all patients and among those with HER2-positive disease but not among those with triple-negative disease. mRNA profiles for immune-related genes also distinguished pathologic complete response rates.

“The study involved 580 tumors from patients in the GeparSixto trial, which assessed the effects on pathologic complete response rates of adding carboplatin to neoadjuvant anthracycline plus taxane treatment. The current analysis assessed the effects on pathologic complete response of tumor-infiltrating lymphocyte levels, the presence of lymphocyte–predominant disease, and levels of immune-activating (CXCL9, CCL5, CD8A, CD80, CXCL13, IGKC, CD21) and immunosuppressive genes (IDO1, PD-1, PD-L1, CTLA4, FOXP3).”


Neoadjuvant HER-2–Targeted Breast Cancer Therapies Less Effective in Patients with PIK3CA Mutations

The gist: Women with HER2-positive breast cancer whose tumors also have a mutation called PIK3CA might not respond as well to HER2-targeted treatments. Scientists looked at tumor samples from patients who had taken the drugs trastuzumab (Herceptin) and/or lapatinib (Tykerb). They had also taken neoadjuvant (before surgery) chemotherapy. Patients whose tumors had PIK3CA mutations had a significantly lower rate of treatment success. These findings highlight the need for more research into PIK3CA-targeted therapy. They also echo findings from other researchers.

“Patients with HER-2–positive breast cancer who harbored activating mutations in PIK3CA were considerably less likely to achieve total pathologic complete response to neoadjuvant HER-2–targeted therapies than patients who did not have PIK3CA mutations, according to findings in the randomized, phase 3 NeoALTTO trial.

“PIK3CA activating mutations are present in all subtypes of breast cancer. However, they are enriched in HER-2–positive and ER-positive disease, according to study background.

“José Baselga, MD, PhD, physician-in-chief and chief medical officer at Memorial Sloan Kettering Cancer Center, and colleagues investigated whether an association existed between PIK3CA mutation status and patients’ response to HER-2–targeted therapy.”