New Antibody-Drug Conjugate Shows Early Promise for Patients with Metastatic HER2-Positive Breast Cancer

“An investigational antibody-drug conjugate called MM-302 was safe, tolerable, and showed signs of clinical activity in heavily pretreated patients with metastatic, HER2-positive breast cancer, according to data from a phase I clinical trial presented here at the AACR Annual Meeting 2015, April 18-22.

“MM-302 is an antibody-drug conjugate composed of a HER2-targeted antibody linked to the cytotoxic chemotherapy liposomal doxorubicin. The HER2 antibody delivers the liposomal doxorubicin to HER2-positive breast cancer cells.

” ‘The main purpose of our study was to establish whether MM-302, alone or in combination with trastuzumab, was safe and tolerable for patients with metastatic, HER2-positive breast cancer whose disease had progressed following numerous prior treatments,’ said Patricia LoRusso, DO, associate director of innovative medicine and professor of medicine (medical oncology) at Yale Cancer Center in New Haven, Connecticut, and professor of medicine in the Division of Oncology at Yale University. ‘We found that the drug was well tolerated when administered to these women.’ “


Risks, Benefits Must Be Balanced When Choosing Optimal Therapy for Node-Negative, HER-2–Positive Breast Cancer

“On May 16, 2005, at about 1:30 p.m. local time, I was one of several hundred fortunate persons crowded into a conference hall at the ASCO Annual Meeting when the wide separation of the DFS curves in the joint analysis of NCCTG 9831 and NSABP B-31 was first shown.

“The benefit of adjuvant trastuzumab was dramatic, and the results changed clinical practice that very next Monday morning.

“Because there was a known cardiac risk of trastuzumab, patients with smaller lymph node-negative breast cancers either were excluded or underrepresented in the initial adjuvant trastuzumab studies, thus making extrapolation of these impressive results somewhat problematic for patients at lower risk for invasive recurrence.”


Tykerb Still Falls Short in HER2-Positive Breast Ca

“In HER2-positive breast cancer, lapatinib (Tykerb) combined with a taxane was linked to shorter progression-free survival (PFS) and more toxicity compared with trastuzumab (Herceptin) plus a taxane, according to results from an international trial.

“In the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) MA.31 study, the median intention-to-treat (ITT) PFS was 9.0 months with lapatinib versus 11.3 months with trastuzumab when paired with a taxane, according to Karen A. Gelmon, MD, of the British Columbia Cancer Agency in Vancouver, and colleagues.

“In addition, lapatinib plus a taxane was associated with more toxicity in patients with centrally confirmed HER2-positive tumors, and overall survival (OS) was worse in the confirmed HER2-positive group treated with lapatinib (ITT hazard ratio 1.28, 95% CI 0.95-1.72, P=0.11), they wrote in the Journal of Clinical Oncology.

” ‘Our results support the use of trastuzumab over lapatinib in the HER2 treatment-naive first-line metastatic setting,’ Gelmon’s group stated. ‘The NCIC CTG MA.31 trial was the first head-to-head comparison to our knowledge of trastuzumab and lapatinib in locally determined metastatic HER2-positive breast cancer, with separate analysis for centrally determined HER2 disease.’ “


Puma Biotechnology Initiates Phase II Trial of PB272 in Early Stage HER2-Positive Breast Cancer

“Puma Biotechnology, Inc. PBYI, +2.74% a development stage biopharmaceutical company, announced the initiation of a Phase II trial of Puma’s investigational drug PB272 (neratinib) for the extended adjuvant treatment of breast cancer.

“The 70 patient study will be an open label single arm Phase II trial of PB272 monotherapy administered to patients with HER2-positive early stage breast cancer who have previously received adjuvant treatment with trastuzumab. Patients will receive extended adjuvant treatment with neratinib for a period of one year. Patients will receive primary prophylaxis with high dose loperamide (16 mg per day initially) in order to attempt to reduce the neratinib-related diarrhea. The primary endpoint of the trial is reduction in the incidence and severity of diarrhea.

“ ‘We are pleased to initiate this Phase II trial,’ said Alan H. Auerbach, Chief Executive Officer and President. ‘Because the ExteNET Phase III trial was run prior to the implementation of loperamide prophylaxis in clinical trials of neratinib, in the ExteNET Phase III trial neratinib was administered without loperamide prophylaxis. The results from this Phase II study will give us a better understanding of the safety of neratinib in the extended adjuvant setting with concurrent high dose loperamide administered and, importantly, to what degree the grade 3 neratinib-related diarrhea can be reduced. We anticipate that initial results from this trial should be available by yearend 2015 and would enable us to include this data in our NDA filing for neratinib in the extended adjuvant setting, which is currently anticipated for the first quarter of 2016.’ “


Kadcyla given after Chemotherapy Does Not Cause Cardiac Side Effects

“In a study reported in the Journal of Clinical Oncology, Krop et al found that ado-trastuzumab emtansine (Kadcyla) had an acceptable cardiac safety profile when used after anthracycline-based (neo)adjuvant therapy in women with early-stage HER2-positive breast cancer.

“In the study, 153 patients with a pretreatment left ventricular ejection fraction > 55% received (neo)adjuvant doxorubicin-cyclophosphamide for four cycles or fluorouracil, epirubicin, and cyclophosphamide for three or four cycles followed by ado-trastuzumab emtansine 3.6 mg/kg every 3 weeks for four cycles. Patients could then receive three or four cycles of docetaxel with or without trastuzumab (Herceptin). Ado-trastuzumab emtasine treatment was then resumed with optional sequential or concurrent radiotherapy for up to 1 year (17 cycles)…

“The investigators concluded: ‘Use of [ado-trastuzumab emtansine] for approximately 1 year after anthracycline-based chemotherapy was feasible and generally well tolerated by patients with HER2-positive [early-stage breast cancer], providing support for phase III trials of [ado-trastuzumab emtansine] in this setting.’ “


Genentech Distribution Shift for Cancer Meds Delays Patient Care: Survey

“A new survey of hospitals and academic medical centers finds that a recent move by Genentech to switch distribution of three widely used cancer treatments – Avastin, Rituxan and Herceptin – is resulting in higher costs, reduced access to the medications and delays in treating patients. And the institutions are hoping the results will prompt the drug maker, which says it’s unaware of such problems, to revert to its earlier distribution program.

“Here’s the background: Last fall, Genentech began using just a few distributors that specialize in handling such medicines. Until then, the Roche unit used dozens of wholesalers, although the specialty distributors are actually divisions of some of those same wholesalers. Genentech says the change was made to save money, but also make distribution more efficient and prevent the possibility of shortages.

“However, most of the institutions – 93% – say they had not experienced shortages, and the move has disrupted not only their finances, but patient care. The survey also found that 81% say the switch will have a moderate to significant impact on their expenses. Meanwhile, 63% say deliveries have been unreliable and 88% reported a delay in patient treatment because one of the drugs was unavailable.

“The institutions say they are forced to increase inventories to hedge against any supply disruptions that may occur because shipping can take longer, depending upon the location of the distributor. Some institutions say they cannot afford to keep large amounts of drug on hand, which can result in delays in treating new patients or unexpected events. And previous discounts may no longer be available.”


Combined Therapy Can Reduce Chance of Recurrence in Women with Small, HER2-Positive Breast Tumors

The gist: After surgery to remove their tumors, women with stage I, HER2-positive breast cancer might benefit from a combination of lower-intensity chemotherapy and the targeted drug trastuzumab (Herceptin). In a clinical trial, patients received post-surgery (adjuvant) treatment with the drugs paclitaxel and Herceptin. After three years, 98.7% were alive and had not experienced return of invasive breast cancer.

“In a phase 2 clinical trial, women with small (stage 1), HER2-positive breast tumors who received a combination of lower-intensity chemotherapy and a targeted drug following surgery were highly unlikely to have the cancer recur within three years of treatment, investigators at Dana-Farber Cancer Institute and other institutions report in a paper published today by the New England Journal of Medicine.

“The findings may help establish the therapy – which combines the agent paclitaxel and the targeted drug trastuzumab (Herceptin) – as the first standard treatment approach for this group of patients, the authors state.

” ‘Many previous studies excluded women with small (less than 2 cm in diameter) HER2-positive that hadn’t spread to nearby lymph nodes from clinical trials of trastuzumab, because it wasn’t considered prudent to expose them to an investigational drug, given the relatively low risk that the disease would recur. Without a single, standard treatment for this group of patients, treatment approaches have varied widely. (Breast cancers are classified as HER2-positive if their cells have surplus human epidermal growth factor receptors on their surface, making them extra-sensitive to signals to grow and divide.)”


PIK3CA Mutations Matter in HER2-Positive Breast Cancer

The gist: Recent research suggests that women whose tumors have a mutation in the PIK3CA gene may be resistant to treatment with the drugs trastuzumab (Herceptin) and lapatinib. However, two new studies say that PIK3CA mutations can’t be used to predict how well Herceptin and lapatinib will work.

“While preclinical studies indicate that PIK3CA mutations result in resistance to the two HER2-targeted therapies trastuzumab and lapatinib, two recently published studies suggest that this mutation cannot be used as a predictive biomarker to guide therapy.

“The first study found that PIK3CA mutations are associated with a decreased benefit to neoadjuvant HER2-directed therapies. The second study showed that PIK3CA mutations did not affect outcomes for HER2-positive patients receiving adjuvant trastuzumab treatment.

“Preclinical studies using HER2-positive cell lines have previously shown that an additional mutation in PIK3CA, the alpha-catalytic subunit of PI3K, results in downstream constitutive signaling, making breast tumor cells that harbor both aberrations resistant to trastuzumab and lapatinib. PIK3CA is among the most commonly mutated oncogene in breast cancer and is present in about one-fourth of all HER2-positive breast cancers. Because of this prevalence and the effect of PI3K pathway activation on HER2 therapy, clinicians have posited that PIK3CA mutations may serve as predictive biomarkers, both preventing ineffectual therapy in some patients and guiding appropriate treatment choices.”


Subcutaneous, IV Trastuzumab Similarly Safe, Effective for HER-2-Positive Early Breast Cancer

The gist: Breast cancer patients being treated with the drug trastuzumab (Herceptin) receive the same benefits whether they take it intravenously (by IV) or as an injection.

“Subcutaneous trastuzumab demonstrated comparable safety and efficacy to IV trastuzumab in patients with HER-2–positive early breast cancer, according to results of an international randomized, open-label phase 3 study.

“Christian Jackisch, MD, PhD, of the Breast Cancer and Gynecology Cancer Center at Sana Klinikum Offenbach GmbH in Germany, and colleagues compared the pharmacokinetics, efficacy and safety of subcutaneous vs. IV trastuzumab (Herceptin, Genentech). The study included 596 women with HER-2–positive, operable, locally advanced or inflammatory breast cancer in the neoadjuvant/adjuvant setting.

“All women underwent treatment with eight cycles of neoadjuvant chemotherapy administered concurrently with trastuzumab. Trastuzumab was administered either via 3-weekly fixed doses of 600 mg or via the standard weight-based method.

“Patients continued treatment with trastuzumab for 1 year after surgery.”