On December 6, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that results from the subgroup of patients with hormone receptor positive (HR-positive) breast cancer from the Company’s Phase III ExteNET Trial of neratinib for early stage HER2-Amplified breast cancer are being presented at the 2018 San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 6, 2018, View Source [SID1234531919]). The presentation entitled, "Efficacy of neratinib in hormone receptor-positive patients who initiated treatment within 1 year of completing trastuzumab-based adjuvant therapy in HER2+ early stage breast cancer: subgroup analyses from the phase III ExteNET trial," is being presented at a poster session by Dr. Frankie Ann Holmes, Texas Oncology/US Oncology Research, Houston Texas on Thursday, December 6 from 7:00 – 9:00 a.m. CST. A copy of this poster is posted on Puma’s website at www.pumabiotechnology.com.

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In September 2018, the European Commission (EC) granted marketing authorisation for NERLYNX (neratinib) for the extended adjuvant treatment of adult patients with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy. This poster presentation highlights the data that was the basis for the EC approval.

ExteNET was a Phase III multicenter, randomized, double-blind, placebo-controlled trial of neratinib in adult patients (n=2,840) with early stage HER2-positive breast cancer following adjuvant trastuzumab treatment. Participants were randomized to receive either neratinib (n=1420) or placebo (n=1420) for one year.

In the subgroup of 1334 patients with hormone receptor positive disease and who were less than one year from the completion of prior adjuvant trastuzumab based therapy, the data, presented in the poster, demonstrated that after two years of follow-up, invasive disease-free survival (iDFS) was 95.3% in the patients treated with neratinib compared with 90.8% in those receiving placebo (hazard ratio = 0.49; 95% CI: (0.30, 0.78); p=0.002). The presentation also showed that after five years of follow-up, invasive disease-free survival (iDFS) was 90.8% in the patients treated with neratinib compared with 85.7% in those receiving placebo (hazard ratio = 0.58; 95% CI: (0.41, 0.82); p=0.002).

The poster highlighted that in this same subgroup, distant disease-free survival (DDFS) was 96.1% in the patients treated with neratinib compared with 92.9% in those receiving placebo (hazard ratio = 0.53, 95% CI: (0.31, 0.88); p=0.015) after two years of follow-up. After five years of follow-up, distant disease-free survival (DDFS) was 92.4% in the patients treated with neratinib compared with 87.7% in those receiving placebo (hazard ratio = 0.57; 95% CI: (0.39, 0.83); p=0.003).

Additionally, in this population, there were 295 patients who did not achieve a pathological complete response (pCR) after treatment with neoadjuvant therapy. This exploratory subgroup is similar to the patient population in the Phase III KATHERINE trial of Kadcyla. The data presented demonstrated that in this subgroup, after two years of follow-up, invasive disease-free survival (iDFS) was 89.9% in the patients treated with neratinib compared with 85.2% in those receiving placebo (hazard ratio = 0.64; 95% CI: (0.30, 1.29)). Longer term follow up demonstrated that at five years, invasive disease-free survival (iDFS) was 85.0% in the patients treated with neratinib compared with 77.6% in those receiving placebo (hazard ratio = 0.60; 95% CI: (0.33, 1.07)).

The profile and frequency of treatment-emergent adverse events in this subgroup of patients with hormone receptor positive disease and who are less than one year from the completion of prior adjuvant trastuzumab was similar compared with the overall safety population. The most common grade 3 treatment-emergent adverse events in this subgroup were diarrhea (neratinib, 39% vs placebo, 1%), nausea (1% vs <1%), and fatigue (2% vs <1%); rates in the overall safety population were diarrhea (neratinib, 40% [included one grade 4 event] vs placebo, 2%), nausea (2% vs <1%), and fatigue (2% vs <1%).

"Reducing the risk of disease recurrence remains a need for patients, despite advances in the treatment of early stage HER2-positive breast cancer," said Professor Michael Gnant, Department of Surgery, Medical University of Vienna, Austria. "This analysis shows that we may be able to provide this type of improvement with neratinib to further reduce this risk of recurrence."

Puma Biotechnology CEO and President Alan H. Auerbach added, "We are encouraged by the data in this patient population and we are committed to continuing to expand NERLYNX accessibility to patients worldwide. We expect NERLYNX to be commercially available in Europe in 2019, beginning with our launch in Germany during the first half of 2019 and followed by additional countries throughout Europe in the second half of 2019."

On December 6, 2018 Chugai Pharmaceutical Co., Ltd. (TOKYO: 4519) reported that humanized anti-PD-L1 monoclonal antibody TECENTRIQ Intravenous Infusion 1200 mg [generic name: atezolizumab (genetical recombination)], and ROS1/TRK inhibitor entrectinib which is under development, received orphan drug designation by the Ministry of Health, Labour and Welfare for the treatment of small cell lung cancer (SCLC) and NTRK fusion-positive locally advanced or metastatic solid tumors, respectively (Press release, Chugai, DEC 6, 2018, View Source [SID1234531936]).

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"SCLC is an aggressive disease with poor prognosis and high unmet medical needs. TECENTRIQ became the first immune checkpoint inhibitor whose efficacy against the disease has been confirmed in the first-line setting, thus it is expected to become a new therapeutic option to treat cancer," said Dr. Yasushi Ito, Chugai’s Executive Vice President, Co-Head of Project & Lifecycle Management Unit. "Entrectinib, moreover, demonstrates efficacy against solid tumors having NTRK fusion gene, regardless of their site of origin. We are aiming to realize a new personalized medicine by combining it with next generation sequencing."

Seven clinical studies of TECENTRIQ are currently underway in patients with lung cancer including a global phase I/III clinical study targeting SCLC (IMpower133 study), and 12 studies are being carried out in patients with other types of cancer in Japan. For entrectinib, a global phase II study (The STARTRK-2 study) is being conducted in Japan.

Roche’s Tecentriq in combination with chemotherapy helped people live significantly longer as an initial treatment for people with extensive-stage small cell lung cancer IMpower 133 study (Roche media release dated September 25, 2018)

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Roche’s investigational personalised medicine entrectinib shrank tumours in people with NTRK fusion-positive solid tumours (Roche media release dated October 21, 2018)

View Source

About small cell lung cancer

In Japan, 114,550 people (77,617 men and 36,933 women; 2014 predicted values) are estimated to be afflicted with lung cancer each year. 73,838 people in Japan (52,430 men and 21,408 women; 2016 predicted values) die as a result of the disease. Lung cancer is the leading cause of cancer death. Lung cancer can be broadly divided into small cell lung cancer (SCLC) and non-small cell lung cancer according to the tissue type, with SCLC accounting for approximately 10 to 15% of all lung cancer cases. SCLC has a high tumor-proliferative capacity, and characteristically causes a wide range of metastases rapidly after tumor diagnosis.

About NTRK fusion gene positive cancer

NTRK fusion gene is an abnormal gene that can be formed by fusing the NTRK genes (NTRK1, NTRK2, NTRK3 encode TRKA, TRKB, TRKC protein, respectively) and other genes (ETV6, LMNA, TPM3, etc.) as a result of chromosomal translocation. The TRK fusion kinase made from NTRK fusion gene is thought to promote cancer cell proliferation. There is very rare expression of NTRK fusion but in various adult and pediatric solid tumors, including appendiceal cancer, breast cancer, cholangiocarcinoma, colorectal cancer, gastrointestinal stromal tumor (GIST), infantile fibrosarcoma, lung cancer, mammary analogue secretory carcinoma of the salivary gland, melanoma, pancreatic cancer, thyroid cancer, and various sarcomas.

About orphan drugs

Based on Pharmaceuticals and Medical Devices Law, orphan drugs are designated by the Minister of Health, Labour and Welfare and granted priority review. The designation criteria are as follows: The number of patients who may use the drug is less than 50,000 in Japan; The drug is indicated for the treatment of serious diseases and there is a significant medical value such as no alternative appropriate drug or treatment, or high efficacy or safety expected compared to existing products; there is a theoretical rationale for using the product for the targeted disease and the development plan is reasonable.

Sources

National Cancer Center Japan, Cancer Information Services "Cancer Registration and Statistics," from: View Source Accessed December 2018.
Govindan R, Page N, Morgensztern D, Read W, Tierney R, Vlahiotis A, et al. Changing epidemiology of small cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006 Oct 1; 24: 4539-44.
Japanese Society of Medical Oncology, editor. New Clinical Oncology. 4th ed., Nankodo
Eilas DA. Small cell lung cancer: state-of-the-art therapy in 1996. Chest. 1997 Oct.; 112: 251S-258S.
Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018 Oct 17. doi: 10.1038/s41571-018-0113-0. [Epub ahead of print]

On December 6, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, is reported that updated results from a Phase II clinical trial of Puma’s drug neratinib at the 2018 San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 6, 2018, View Source [SID1234531920]). The presentation entitled, "The impact of neratinib with or without anti-diarrheal prophylaxis on health-related quality of life in HER2-positive early stage breast cancer: Analyses from the ExteNET and CONTROL trials." is being presented by Dr. Suzette Delaloge, Institut Gustave Roussy, Paris, France, at a poster session on December 6 from 7:00 – 9:00 a.m. CST. A full copy of the poster is available on the Puma Biotechnology website at www.pumabiotechnology.com.

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Neratinib was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets. NERLYNX was granted marketing authorization in September 2018 by the European Commission for extended adjuvant treatment of adult patients with early stage hormone receptor positive HER2-overexpressed/amplified breast cancer and who are less than one year from the completion of prior adjuvant trastuzumab based therapy

Diarrhea is the main side effect of neratinib. In ExteNET, where antidiarrheal prophylaxis was not mandated by the study protocol, grade 1/2 diarrhea was reported in 55% and 34% of patients in the neratinib and placebo groups, respectively, and grade 3 diarrhea occurred in 40% and 2%, respectively. Because neratinib-induced diarrhea occurs early in the course of treatment, a structured high dose regimen of loperamide prophylaxis given for one or two cycles has been introduced to better manage this side effect. The Phase II CONTROL study, conducted in the exact same setting as ExteNET, investigated the effectiveness of anti-diarrheal prophylaxis with loperamide alone or in combination with budesonide or colestipol in the prevention of neratinib-associated diarrhea.

Both ExteNET and CONTROL assessed patient-reported outcomes using the Functional Assessment of Cancer Therapy for Breast Cancer (FACT-B), a validated instrument for the assessment of health-related quality of life (HRQoL) in breast cancer. Total scores of FACT-B range from 0-144, with higher scores indicating better HRQoL. A change of 7-8 points in the FACT-B total score is considered clinically meaningful. Preliminary HRQoL findings from the CONTROL study were presented in 2017 and are posted on Puma’s website at www.pumabiotechnology.com/pr20171206.html. The poster presented at SABCS reports more detailed and mature HRQoL data from CONTROL, and compares it to the HRQoL findings from the ExteNET study.

In ExteNET, 17% of patients in the neratinib group and less than 1% of patients in the placebo group discontinued treatment because of diarrhea. In CONTROL, 20% of patients in the loperamide cohort, 11% in the budesonide plus loperamide cohort, and 4% in the colestipol plus loperamide cohort discontinued treatment due to diarrhea.

The poster presentation demonstrates that in both studies decreases in FACT-B total scores seen in early months were followed by recovery towards baseline levels. Decreases in FACT-B total scores observed did not cross a clinically meaningful threshold at any time point.

In the ExteNET study, a transient decrease in FACT-B total score was observed with neratinib at month 1 (mean change from baseline, –4.6 points) followed by recovery towards baseline. Decreases were also evident in the placebo group, with mean changes from baseline ranging from –3.5 to –1.7 points during study treatment. After month 3, mean changes from baseline were similar in neratinib and placebo arms. None of these changes reached clinically meaningful thresholds (7–8 points) at any time point.

The presentation also shows that in the CONTROL study, FACT-B total scores decreased from baseline in all cohorts; mean changes from baseline ranged from –6.0 to –1.5 points over the course of study treatment. In the cohorts that had completed follow-up (loperamide, budesonide plus loperamide), the largest decreases in FACT-B total scores were evident during months 1 and 3 followed by recovery towards baseline levels. None of these changes reached clinically meaningful thresholds (7–8 points) at any time point.

An evaluation of each of the FACT-B subscales (n=5) were evaluated and this analysis suggested that physical well-being (PWB) was the only subscale where the clinically important difference (CID) threshold was crossed in both trials. In the ExteNET study, in the neratinib arm, FACT-B PWB decreased at month 1 before improving at later visits. The mean change from baseline at month 1 with neratinib was –2.9 points and was greater than clinically meaningful thresholds (2‒3 points); changes at later time-points were all less than the clinically meaningful threshold.

In the CONTROL study, decreases in FACT-B PWB were observed in all CONTROL cohorts throughout study treatment, with largest changes from baseline observed at month 1. In the loperamide alone and colestipol plus loperamide cohorts, changes reached clinically meaningful thresholds (2‒3 points) at 4 out of 5 study visits, whereas in the budesonide plus loperamide cohort, changes crossed the CID threshold during months 1 and 3 only.

Suzette Delaloge, MD, Institut Gustave Roussy, Paris, France, said, "Diarrhea is the main side effect of neratinib and can be bothersome in some patients. Although this is not a direct comparison, the confrontation of Extenet and Control data teach us how to prevent grade 3 diarrhea and how to allow better quality of life, together with better adherence of patients to this therapy."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased with the HRQoL data from ExteNET and CONTROL. We look forward to additional data from the CONTROL trial, which may continue to improve HRQoL and adherence to treatment."

About HER2-Positive Breast Cancer

Approximately 20% to 25% of breast cancer tumors over-express the HER2 protein. HER2-positive breast cancer is often more aggressive than other types of breast cancer, increasing the risk of disease progression and death. Although research has shown that trastuzumab can reduce the risk of early stage HER2-positive breast cancer returning after surgery, up to 25% of patients treated with trastuzumab experience recurrence.

IMPORTANT SAFETY INFORMATION

NERLYNX (neratinib) tablets, for oral use

INDICATIONS AND USAGE: NERLYNX is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early-stage HER2 overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.

CONTRAINDICATIONS: None

WARNINGS AND PRECAUTIONS:

Diarrhea: Aggressively manage diarrhea occurring despite recommended prophylaxis with additional antidiarrheals, fluids, and electrolytes as clinically indicated. Withhold NERLYNX in patients experiencing severe and/or persistent diarrhea. Permanently discontinue NERLYNX in patients experiencing Grade 4 diarrhea or Grade ≥ 2 diarrhea that occurs after maximal dose reduction.
Hepatotoxicity: Monitor liver function tests monthly for the first 3 months of treatment, then every 3 months while on treatment and as clinically indicated. Withhold NERLYNX in patients experiencing Grade 3 liver abnormalities and permanently discontinue NERLYNX in patients experiencing Grade 4 liver abnormalities.
Embryo-Fetal Toxicity: NERLYNX can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception.
ADVERSE REACTIONS: The most common adverse reactions (≥ 5%) were diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, AST or ALT increase, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased and urinary tract infection.

To report SUSPECTED ADVERSE REACTIONS, contact Puma Biotechnology, Inc. at 1-844-NERLYNX (1-844-637-5969) and www.NERLYNX.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

DRUG INTERACTIONS:

Gastric acid reducing agents: Avoid concomitant use with proton pump inhibitors (PPI) and H2-receptor antagonists. Separate NERLYNX by 3 hours after antacid dosing.
Strong or moderate CYP3A4 inhibitors: Avoid concomitant use.
Strong or moderate CYP3A4 inducers: Avoid concomitant use.
P-glycoprotein (P-gp) substrates: Monitor for adverse reactions of narrow therapeutic agents that are P-gp substrates when used concomitantly with NERLYNX.
USE IN SPECIFIC POPULATIONS:

Lactation: Advise women not to breastfeed.
Please see Full Prescribing Information for additional safety information.

The recommended dose of NERLYNX is 240 mg (six 40 mg tablets) given orally once daily with food, continuously for one year. Antidiarrheal prophylaxis should be initiated with the first dose of NERLYNX and continued during the first 2 months (56 days) of treatment and as needed thereafter.

To help ensure patients have access to NERLYNX, Puma has implemented the Puma Patient Lynx support program to assist patients and healthcare providers with reimbursement support and referrals to resources that can help with financial assistance. More information on the Puma Patient Lynx program can be found at www.NERLYNX.com or 1-855-816-5421.

On December 6, 2018 MorphoSys AG (FSE: MOR; Prime Standard Segment; MDAX & TecDAX; Nasdaq: MOR) reported its data from the ongoing single-arm phase 2 clinical trial known as L-MIND in an oral presentation at the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2018 in San Diego, USA (Press release, MorphoSys, DEC 6, 2018, View Source [SID1234531937]). L-MIND is designed to investigate the antibody MOR208 in combination with lenalidomide in patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). MOR208 is an investigational humanized Fc-enhanced monoclonal antibody directed against CD19 and is currently in clinical development in blood cancer indications.

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The L-MIND study enrolled patients with r/r DLBCL, who are ineligible for HDC and ASCT, after up to three prior lines of therapy, with at least one prior therapy including an anti-CD20 targeting therapy, such as rituximab. The updated interim data reported today (cut-off date June 5, 2018) included all 81 patients enrolled in the L-MIND trial, with a median observation time of 12 months. Efficacy results in this update are based on assessment by the investigators for all 81 patients. Patients enrolled had a median age of 72 years and had received a median of two prior treatment lines.

The data showed a response in 47 out of 81 patients (overall response rate, or ORR, 58%), with complete responses (CR) in 27 (33%) and partial responses (PR) in 20 (25%) patients. The median progression-free survival (mPFS) was 16.2 months (95% confidence interval (CI) 6.3 months – not reached). Responses were durable with the median duration of response (DoR) not reached (95% CI: NR – NR) and 70% of responding patients were without progression at 12 months (12-month DoR rate: 70%, Kaplan-Meier estimate). A significant proportion of patients (37/81; 46%) were still on study treatment, with 19 having been treated for over 12 months. Median overall survival (OS) was not reached (95% CI: 18.6 months – NR); the 12-month OS rate was 73% (95% CI: 63% – 85%).

Efficacy parameters, such as response rates and median PFS showed comparable results in most patient subgroups of interest, including low/low-intermediate versus intermediate-high/high IPI score, rituximab refractory versus not refractory and primary refractory versus not refractory, amongst others.

No unexpected toxicities were observed for the treatment combination and no infusion-related reactions (IRRs) were reported for MOR208. The most frequent treatment-emergent adverse events (TEAEs) with a toxicity grading of 3 or higher were neutropenia in 35 (43%), thrombocytopenia in 14 (17%), and anemia in 7 (9%) patients each. Treatment-related serious adverse events (SAEs) occurred in 16 (19.8%) patients, the majority of which were infections or neutropenic fever. 41 (50.6%) patients required dose reduction with lenalidomide, 58 patients (72%) could stay on a daily lenalidomide dose of 20 mg or higher.

The results reported today confirm data from earlier interim analyses reported from this trial in March 2018, when 68 patients had been eligible for investigators’ efficacy assessment at the Dec 12, 2017 cut-off date.

"Patients with relapsed or refractory DLBCL who, after having failed initial therapies, are ineligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT), need more treatment options," commented Dr. Malte Peters, Chief Development Officer of MorphoSys AG. "We are encouraged by our most recent clinical data from the ongoing L-MIND trial. These support our plan to develop MOR208 in combination with lenalidomide, based on our current FDA breakthrough therapy designation, as a potential chemo-free treatment option for this patient population."

Details about the presentation on L-MIND data at ASH (Free ASH Whitepaper) 2018:

Abstract publication number: 227

Session name: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials"

Session date and time: Saturday, December 1, 2018, 4:00pm-5:30pm PST

Presentation time: 5:00pm PST

Room: Marriot Marquis San Diego Marina, Pacific Ballroom 20, San Diego, California.

MorphoSys will hold an investor & analyst event after the 60th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting 2018 on December 5, 2018, 10:00am EST (3:00pm GMT, 4:00pm CET) in New York. The presentation, a live webcast and a replay of the webcast will be made available at View Source

About DLBCL

Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of malignant lymphoma worldwide and accounts for approximately 30% of all non-Hodgkin lymphomas. Between 30% and 40% of all patients with DLBCL either fail to respond to or show a relapse to initial therapy. Patients who failed frontline therapy and are not eligible to high dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) are reported to have a poor outcome and require more therapeutic options.

About CD19 and MOR208

CD19 is broadly and homogeneously expressed across different B cell malignancies including DLBCL and CLL. CD19 has been reported to enhance B cell receptor (BCR) signaling, which is assumed important for B cell survival, making CD19 a potential target in B cell malignancies.

MOR208 is an investigational humanized Fc-engineered monoclonal antibody directed against CD19. Fc-modification of MOR208 is intended to lead to a significant potentiation of antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), thus aiming to improve a key mechanism of tumor cell killing. MOR208 has been observed in preclinical models to induce direct apoptosis by binding to CD19, which is assumed to be involved in B cell receptor (BCR) signaling.

MorphoSys is clinically investigating MOR208 as a therapeutic option in B cell malignancies in a number of ongoing combination trials. An open-label phase 2 combination trial (L-MIND study) is investigating the safety and efficacy of MOR208 in combination with lenalidomide in patients with relapsed/refractory DLBCL who are not eligible for high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT). Based on interim data from L-MIND, in October 2017 the U.S. FDA granted Breakthrough Therapy Designation for MOR208 plus lenalidomide in this patient population. The pivotal phase 2/3 B-MIND study is designed to investigate MOR208 in combination with the chemotherapeutic agent bendamustine in patients with relapsed/refractory DLBCL who are not eligible for high-

dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) in comparison to the combination of the anti-CD20 antibody rituximab plus bendamustine. In addition, MOR208 is currently being investigated in patients with relapsed/refractory CLL/SLL after discontinuation of a prior Bruton tyrosine kinase (BTK) inhibitor therapy (e.g. ibrutinib) in combination with idelalisib or venetoclax.

On December 6, 2018 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that results from an ongoing Phase II clinical trial of Puma’s drug neratinib are being presented at the 2018 San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 6, 2018, View Source [SID1234531921]). The presentation entitled, "Neratinib + fulvestrant for HER2-mutant, HR-positive, metastatic breast cancer: Updated results from the phase 2 SUMMIT trial," are being presented at a Spotlight Session by Lillian M. Smyth, M.D., Breast Medicine Service and Early Drug Development Service, Memorial Sloan Kettering Cancer Center, an investigator of the trial.

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Neratinib was approved by the U.S. Food and Drug Administration (FDA) in July 2017 for the extended adjuvant treatment of adult patients with early stage HER2-positive breast cancer following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX (neratinib) tablets. NERLYNX was granted marketing authorization by the European Commission for the extended adjuvant treatment of hormone receptor-positive HER2-positive early stage breast cancer in September 2018.

The Phase II SUMMIT basket trial is an open-label, multicenter, multinational study to evaluate the safety and efficacy of neratinib administered daily to patients who have solid tumors with activating HER2 or HER3 mutations. In the HER2-mutant, HR-positive breast cancer cohort, 47 patients received 240 mg of neratinib daily in combination with fulvestrant at the labeled dose. In this cohort, 43 patients (92%) had HER2-non-amplified disease, and patients had received a median of 3 prior lines of therapy in the metastatic setting (range 0-11 prior regimens) before entering the trial. All patients had been previously treated with an endocrine agent prior to entering the study, including 25 patients (53%) who had received prior fulvestrant. Further, 20 patients (43%) received prior cyclin-dependent kinase 4/6 (CDK4/6)-inhibitor therapy.

The efficacy summary of the breast cohort that received neratinib + fulvestrant is shown in Table 1 below. The interim efficacy results from the trial showed that for the 47 efficacy evaluable patients, 14 patients (30%) experienced an objective response, which included 4 patients with a complete response and 10 patients with partial responses, and 22 patients (47%) experienced clinical benefit (clinical benefit is defined as confirmed complete response or partial response or stable disease for at least 24 weeks). The median duration of response was 9.2 months and the median progression free survival was 5.4 months. Subgroup analysis demonstrated that patients who had received prior fulvestrant or CDK4/6 inhibitor targeted therapy prior to entering the trial also benefited from treatment of neratinib + fulvestrant. Of note, 6 patients (30%) with prior CDK4/6-inhibitor exposure demonstrated confirmed responses, with the duration of responses ranging from 4.5–14.8 months. Four patients were still on treatment at the time of data reporting.

Table 1: HER2-Mutant, HR-Positive Metastatic Breast Cancer
Phase II SUMMIT Trial Efficacy Summary

Neratinib + Fulvestrant
Subgroups
All Patients
(n=47)

Prior Fulvestrant
(n=25)

Prior CDK4/6 Inhibitor-Based
Therapy (n=20)

Efficacy Endpoint a :
Objective response (confirmed)b – n 14 4 6
CR 4 0 1
PR 10 4 5
Objective response rate (95% CI) 30 (17–45) 16 (5–36) 30 (12–54)
Medianc DOR, months (95% CI) 9.2 (5.5–16.6)
DOR for each responder 9.2; 9.3*; 14.8*; 16.6 4.5; 7.3; 9.2*; 9.3*; 11.2*; 14.8*

Clinical benefitd – n 22 9 8
CR or PR 14 4 6
SD 8 5 2
Clinical benefit rate (95% CI) 47 (32–62) 36 (18–58) 40 (19–64)

Medianc PFS (95% CI) time to event, months 5.4 (3.7–9.2) 3.7 (3.5–6.9) 4.1 (1.9–10.9)

Patients with RECIST v1.1 Measurable Disease
Subgroups
Efficacy Endpoint a : All Patients
(n = 39)

Prior Fulvestrant
(n = 21)

Prior CDK4/6 Inhibitor-Based
Therapy (n=15)

Objective response (confirmed)b – n 12 4 5
CR 2 0 0
PR 10 4 5
Objective response rate (95% CI) 31 (17–48) 19 (5–42) 33 (12–62)

Medianc DOR, months (95% CI) 9.0 (4.5–16.6)
DOR for each responder 9.2; 9.3*; 14.8*; 16.6 4.5; 7.3; 9.2*; 9.3*; 14.8*

Clinical benefitd – n 18 8 6
CR or PR 12 4 5
SD 6 4 1
Clinical benefit rate (95% CI) 46 (30–63) 38 (18–62) 40 (16–68)
Medianc PFS (95% CI) time to event, months 5.4 (3.5–10.3) NA NA
a

Response is based on investigator tumor assessments per RECIST v1.1 or modified PERCIST for patients with only PET-evaluable lesions.

Overall objective response (ORR) is defined as either a complete or partial response that is confirmed no less than 4-weeks after the criteria for response are initially met.

Kaplan-Meier analysis

Clinical benefit rate (CBR) is defined as confirmed CR or PR or stable disease (SD) for at least 24 weeks (within +/- 7 day visit window).

Patient still on treatment at time of data cut; DOR, duration of response; PFS, progression free survival; NA, not available

The safety profile observed in neratinib + fulvestrant-treated breast cancer patients in the SUMMIT study was consistent with that observed previously in metastatic patients with HER2 amplified tumors. With anti-diarrheal prophylaxis and management, diarrhea was not a treatment-limiting side effect in SUMMIT. The interim safety results of the study showed that the most frequently observed adverse event was diarrhea. For the 47 patients enrolled in the trial, 11 patients (23%) reported grade 3 diarrhea. The median duration of grade 3 diarrhea for those patients was 1.5 days. No patients permanently discontinued neratinib due to diarrhea.

Dr. Lillian Smyth said, "Somatic HER2 mutations represent a distinct class of oncogenic driver mutations that appear to be clinically actionable for metastatic breast cancers. The combination of neratinib plus fulvestrant therapy demonstrates encouraging clinical activity with durable responses in this heavily pretreated metastatic breast cancer patient population with HER2-mutated and hormone receptor-positive disease."

Alan H. Auerbach, CEO and President of Puma Biotechnology, added, "We are very pleased with the updated activity seen with neratinib in combination with fulvestrant in this cohort of patients with HER2-mutated breast cancer. We look forward to the further development of the combination of neratinib and fulvestrant in this patient population."