On December 6, 2017 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported results from the positive, pivotal Phase III IMpower150 study of Tecentriq (atezolizumab) and Avastin (bevacizumab) plus chemotherapy (carboplatin and paclitaxel) in people with previously untreated advanced non-squamous non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche, DEC 6, 2017, View Source [SID1234522415]). The study showed that people who received Tecentriq and Avastin plus chemotherapy had a 38 percent reduced risk of their disease worsening or death (progression-free survival, PFS) compared with those who received Avastin plus chemotherapy (hazard ratio [HR]=0.62; p<0.0001 95 % CI: 0.52-0.74; median PFS = 8.3 vs. 6.8 months). Importantly, a doubling of the 12-month landmark PFS rate was observed with the combination of Tecentriq and Avastin plus chemotherapy (37 percent) compared to Avastin plus chemotherapy (18 percent). The rate of tumour shrinkage (overall response rate, ORR), a secondary endpoint in the study, was higher in people treated with Tecentriq and Avastin plus chemotherapy compared with Avastin plus chemotherapy (64 percent vs. 48 percent). The safety profile of the Tecentriq and Avastin plus chemotherapy combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination.

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The analysis of the co-primary PFS endpoint in IMpower150 was assessed in two populations: all randomised people without an ALK* or EGFR** genetic mutation (intention-to-treat wild-type, ITT-WT) and in a subgroup of people who had a specific biomarker (T-effector "Teff" gene signature expression Teff WT). IMpower150 met its PFS co-primary endpoint per study protocol for both populations assessed. In the Teff-WT population, the combination of Tecentriq and Avastin plus chemotherapy reduced the risk of disease worsening or death by 49 percent compared to Avastin plus chemotherapy (HR=0.51; p<0.0001 95% CI: 0.38-0.68; median PFS = 11.3 vs 6.8 months).
"This Tecentriq study is the first positive Phase III combination trial that showed a cancer immunotherapy reduced the risk of the disease getting worse when used as an initial treatment in a broad group of people with advanced non-squamous NSCLC," Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "The IMpower150 study represents an important advance in lung cancer treatment, and we will submit these results to regulatory authorities around the world to potentially bring a new standard of care to people living with this disease as soon as possible."

The late-breaking IMpower150 data will be presented at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Immuno Oncology Congress (Abstract #LBA1_PR) on Thursday, 7 December 6.15 pm. Central European Time (CET) and are also part of the official press programme. Early results from the co-primary endpoint of overall survival (OS) are encouraging. While they are not yet fully mature, these preliminary OS results will be presented at the ESMO (Free ESMO Whitepaper) IO congress. The next analysis of survival is expected in the first half of 2018.

About the IMpower150 study
IMpower150 is a multicentre, open-label, randomised, controlled Phase III study evaluating the efficacy and safety of Tecentriq in combination with chemotherapy (carboplatin and paclitaxel) with or without Avastin in people with stage IV or recurrent metastatic non-squamous NSCLC who had not been treated with chemotherapy for their advanced disease. It enrolled 1,202 people of which those with ALK and EGFR mutations were excluded from the primary ITT analysis. People were randomised (1:1:1) to receive:

Tecentriq plus carboplatin and paclitaxel (Arm A), or
Tecentriq and Avastin plus carboplatin and paclitaxel (Arm B), or
Avastin plus carboplatin and paclitaxel (Arm C, control arm).
During the treatment-induction phase, people in Arm A received Tecentriq administered intravenously at 1200 mg in combination with intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. Following the induction phase, people received maintenance treatment with Tecentriq (1200 mg every 3 weeks) until loss of clinical benefit or disease progression.

Due to pre-specified statistical testing hierarchy, Arm A vs Arm C has not been formally tested yet. IMpower150 was designed to formally compare Tecentriq plus chemotherapy (Arm A) versus Avastin plus chemotherapy (Arm C), only if Tecentriq and Avastin plus chemotherapy (Arm B) is shown to improve OS in the ITT-WT population compared to Avastin plus chemotherapy (Arm C). These OS results are expected in the first half of 2018.

People in Arm B received induction treatment with Tecentriq (1200 mg) and Avastin administered intravenously at 15 mg/kg in combination with intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. People then received maintenance treatment with the Tecentriq Avastin regimen until disease progression (Avastin) or loss of clinical benefit/disease progression (Tecentriq).

People in Arm C received induction treatment with Avastin administered intravenously at 15 mg/kg plus intravenous infusion of carboplatin and paclitaxel on Day 1 of a 3-week treatment cycle for 4 or 6 cycles. This was followed by maintenance treatment with Avastin alone until disease progression.

The co-primary endpoints were PFS, as determined by the investigator using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST v1.1), and OS.

A summary of the IMpower150 Arm B vs Arm C PFS and ORR results are included below; additional data, including preliminary OS results and Arm A vs Arm C PFS will be presented as part of the Late-Breaking Abstract presentation.

The safety profile of Tecentriq and Avastin plus chemotherapy combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified with the combination. Serious adverse events related to treatment were observed in 25.4 percent of people who received Tecentriq and Avastin plus chemotherapy compared to 19.3 percent of those who received Avastin plus chemotherapy.

About NSCLC
Despite recent advances in the treatment of NSCLC, there is still a need for new treatment options. Lung cancer is the leading cause of cancer death globally1. Each year 1.59 million people die as a result of the disease; this translates into more than 4,350 deaths worldwide every day.2 Lung cancer can be broadly divided into two major types: NSCLC and small cell lung cancer. NSCLC is the most prevalent type, accounting for around 85% of all cases.2
About Tecentriq (atezolizumab)

Tecentriq is a monoclonal antibody designed to bind with a protein called PD-L1 expressed on tumour cells and tumour-infiltrating immune cells, blocking its interactions with both PD-1 and B7.1 receptors. By inhibiting PD-L1, Tecentriq may enable the activation of T cells. Tecentriq has the potential to be used as a foundational combination partner with cancer immunotherapies, targeted medicines and various chemotherapies across a broad range of cancers.

Currently, Roche has eight Phase III lung cancer studies underway, evaluating Tecentriq alone or in combination with other medicines.

Tecentriq is already approved in the European Union, United States and more than 50 countries for people with previously treated metastatic NSCLC and for people with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin chemotherapy, or who have had disease progression during or following platinum-containing therapy.

About the Tecentriq (atezolizumab) and Avastin (bevacizumab) combination

There is a strong scientific rationale to support the use of Tecentriq plus Avastin in combination. The Tecentriq and Avastin regimen may enhance the potential of the immune system to combat a broad range of cancers, including first-line advanced NSCLC. Avastin, in addition to its established anti-angiogenic effects, may further enhance Tecentriq’s ability to restore anti-cancer immunity, by inhibiting VEGF-related immunosuppression, promoting T-cell tumour infiltration and enabling priming and activation of T-cell responses against tumour antigens.

About Roche in cancer immunotherapy

For more than 50 years, Roche has been developing medicines with the goal to redefine treatment in oncology. Today, we’re investing more than ever in our effort to bring innovative treatment options that help a person’s own immune system fight cancer.

By applying our seminal research in immune tumour profiling within the framework of the Roche-devised cancer immunity cycle, we are accelerating and expanding the transformative benefits with Tecentriq to a greater number of people living with cancer. Our cancer immunotherapy development programme takes a comprehensive approach in pursuing the goal of restoring cancer immunity to improve outcomes for patients.

On December 6, 2017 Transgene (Paris:TNG) (Euronext Paris: TNG), a company that designs and develops viral-based immunotherapies, and BioInvent International AB (OMXS: BINV), focused on the discovery and development of novel and first-in-class immuno-regulatory antibodies to treat cancer and reported that they have entered a collaboration to co-develop next generation oncolytic virus (OV) candidates encoding an anti-CTLA-4 antibody sequence – potentially with additional transgenes – capable of treating multiple solid tumors (Press release, Transgene, DEC 6, 2017, View Source [SID1234522412]).

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Under the terms of the agreement Transgene will contribute both its OV design and engineering expertise as well as its proprietary engineered Vaccinia virus, derived from its Invir.IOTM platform. These oncolytic viruses are designed to directly and selectively destroy cancer cells by the intracellular replication of the virus in the cancer cell (oncolysis). Oncolysis is important as it induces an immune response against tumors (immunogenic lysis). In addition, the replication of the virus allows the expression of the genes carried by the oncolytic viral genome including therapeutic "weapons" that have been specifically designed to attack the tumor.

BioInvent will provide its cancer biology and antibody expertise to the collaboration as well as anti-CTLA-4 monoclonal antibody coding sequences, generated through its proprietary n-CoDeR/FIRST platforms, which will be encoded from in Transgene’s Invir.IOTM viral vectors. The local expression of such therapeutic payloads in the cancer cell is expected to augment the anti-cancer effects of viral oncolysis, by efficiently modulating the tumor micro-environment and increasing the immunocompetency of the tumor.

Encoding BioInvent’s anti-CTLA-4 antibody sequence in Transgene’s latest improved Vaccinia virus, promises to optimize the efficacy of this potent checkpoint inhibitor, while reducing the side effects seen when it is given systemically. There is also the potential for this novel OV product to be significantly more effective than the combination of these single agents. Transgene has generated preclinical proof-of-concept data showing that an oncolytic Vaccinia virus encoded with a checkpoint inhibitor demonstrated better overall survival than the corresponding combination as separate single agents.

The collaboration’s research and development costs, as well as the revenues and royalties from candidates generated by the collaboration, will be shared 50:50.

Philippe Archinard, PhD, Chairman and CEO of Transgene, said: "We look forward to starting this first, exciting collaboration with BioInvent. We believe that the next generation of multi-functional OVs derived from our Invir.IOTM platform, armed with highly targeted immune modulators such as those engineered by BioInvent, will provide patients with better clinical outcomes. Based on the compelling preclinical data we have generated, we expect the resulting OVs to deliver a significant improvement in overall survival, with an enhanced safety profile when compared to administering an OV and checkpoint inhibitor separately."

Commenting on the agreement, Michael Oredsson, CEO of BioInvent, said: "We are very pleased to announce this first collaboration with Transgene which will allow us to leverage our cancer antibody biology and immuno-oncology expertise. We are looking forward to working with Transgene to generate the next generation OVs capable of expressing immune modulatory antibodies in the tumor, thus enhancing their efficacy and improving their safety profile. We are confident that such next generation oncolytic viruses have the potential to significantly improve treatment of solid tumors."

On December 6, 2017 Puma Biotechnology, Inc. (Nasdaq: PBYI), a biopharmaceutical company, reported that it will present updated interim results from a Phase II clinical trial of Puma’s drug neratinib at the 2017 San Antonio Breast Cancer Symposium (SABCS) that is currently taking place in San Antonio, Texas (Press release, Puma Biotechnology, DEC 6, 2017, View Source [SID1234522411]). The presentation entitled, "Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2-positive early stage breast cancer: the CONTROL trial," will be presented at a poster session on December 7 at 5:00 p.m. CST. A full copy of the poster is available on the Puma Biotechnology website.

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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.

The main adverse event seen to date in clinical trials of neratinib is diarrhea and, more specifically, grade 3 diarrhea. In the Phase III ExteNET trial of neratinib as extended adjuvant treatment of HER2-positive early stage breast cancer that has previously been treated with adjuvant Herceptin, 95.4% of the patients experienced all grade diarrhea and 39.8% of the patients experienced grade 3 or higher diarrhea (there was one event of grade 4 diarrhea). The CONTROL trial is an international, open-label, Phase II study investigating the use of loperamide prophylaxis with or without other agents in the reduction of neratinib-associated diarrhea that has a primary endpoint of the incidence of grade 3 diarrhea.

In the CONTROL trial, patients with HER2-positive early stage breast cancer who had completed trastuzumab-based adjuvant therapy received neratinib daily for a period of one year. The trial initially tested high dose loperamide prophylaxis given for the first 2 cycles (56 days) of treatment (12 mg on days 1-14, 8 mg on days 15-56 and as needed thereafter). The CONTROL trial was then expanded to include two additional cohorts. One cohort received the combination of loperamide and budesonide and the other cohort received the combination of loperamide plus colestipol. Budesonide is a locally acting corticosteroid that the Company believes targets the inflammation identified in a preclinical model of neratinib-induced diarrhea and colestipol is a bile acid sequestrant that the Company believes targets potential bile acid malabsorption that could result from such inflammation.

The interim analysis of the trial presented in the poster included a total of 137 patients who received neratinib plus loperamide prophylaxis, 64 patients who received neratinib plus loperamide prophylaxis for 2 cycles and budesonide for 1 cycle, and 120 patients who received neratinib plus loperamide prophylaxis for 1 cycle and colestipol for 1 cycle.

The results of the trial showed that the incidence of grade 3 diarrhea for the 137 patients who received the loperamide prophylaxis was 30.7%. For the 137 patients who received the loperamide prophylaxis, the median number of grade 3 diarrhea episodes per patient was 1 and the median cumulative duration of grade 3 diarrhea was 3 days. For the 137 patients who received loperamide prophylaxis, 20.4% discontinued neratinib due to diarrhea.

For the 64 patients who received the combination of loperamide plus budesonide, the results of the trial showed that the incidence of grade 3 diarrhea was 26.6%. The median number of grade 3 diarrhea episodes per patient was 1 and the median cumulative duration of grade 3 diarrhea was 2 days. For the 64 patients who received loperamide plus budesonide prophylaxis, 10.9% discontinued neratinib due to diarrhea.

For the 120 patients who received the combination of loperamide plus colestipol, the results of the trial showed that the incidence of grade 3 diarrhea was 10.8%. The median number of grade 3 diarrhea episodes per patient was 1 and the median cumulative duration of grade 3 diarrhea was 3 days. For the 120 patients who received loperamide plus colestipol prophylaxis, 1.7% discontinued neratinib due to diarrhea. Further information is provided in Table 1 below:

Table 1: Characteristics of Treatment-Emergent Diarrhea

Study CONTROL ExteNET
Loperamide + Loperamide + Loperamide
Loperamide budesonide colestipol prn
(n=137) (n=64) (n=120) (n=1408)
Diarrhea, %
Any grade 79.6 86.0 66.7 95.4
Grade 1 24.8 25.0 30.0 22.9
Grade 2 24.1 34.4 25.8 32.5
Grade 3a 30.7 26.6 10.8 39.8
Grade 4 0 0 0 0.1

Median cumulative duration, days
Any grade 14.0 24.0 16.0 59.0
Grade ≥2 5.0 6.0 3.5 10.0
Grade ≥3a 3.0 2.0 3.0 5.0

Median diarrhea episodes/patient
Any grade 2.0 9.0 2.5 8.0
Grade ≥2 2.0 3.0 1.0 3.0
Grade ≥3a 1.0 1.0 1.0 2.0

Action taken, %
Dose hold 15.3 18.8 9.2 33.9
Dose reduction 7.3 3.1 4.2 26.4
Discontinuation 20.4 10.9 1.7 16.8
Hospitalization 1.5 0 0 1.4

Duration of neratinib treatment, months
Median 11.5 11.9 3.7 11.6

a No grade 4 events in the CONTROL study; one grade 4 event in the ExteNET study.

Hope S. Rugo, MD, USCF Helen Diller Family Comprehensive Cancer Center, San Francisco, California, said, "We are pleased to see the maturation of the data supporting observations of a reduction in incidence, severity and duration of neratinib-associated diarrhea with loperamide prophylaxis, loperamide plus budesonide prophylaxis or the loperamide plus colestipol prophylaxis. Along with the continued reduction in the incidence and severity of grade 3 diarrhea with neratinib, diarrhea appears to be acute, self-limiting and manageable. The addition of budesonide or colestipol to loperamide prophylaxis appears to greatly improve the tolerability of neratinib and we look forward to the completion of the colestipol cohort."

Alan H. Auerbach, Chief Executive Officer and President of Puma Biotechnology, said, "We are pleased to see the reductions in the incidence of severe neratinib-related diarrhea in the CONTROL trial when using the loperamide, loperamide plus budesonide or loperamide plus colestipol regimens. The severe diarrhea appears to become more acute, whereby it does not typically recur after the first month. We are also very encouraged by the improvements in tolerability that have been seen to date in the budesonide and the colestipol cohorts. This is a marked improvement in tolerability over what was seen in the ExteNET trial and we look forward to continuing to monitor this in the loperamide plus colestipol cohort."

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, 2017 Pfizer Inc. (NYSE:PFE) reported updated progression-free survival (PFS) results from the Phase 3 PALOMA-2 trial reinforcing the clinical benefit of IBRANCE (palbociclib) combined with letrozole (Press release, Pfizer, DEC 6, 2017, View Source [SID1234522409]). The data, which will be presented at the 2017 San Antonio Breast Cancer Symposium (SABCS) on December 8 [abstract #P5-21-03], demonstrate that the combination of IBRANCE plus letrozole reduced the risk of disease progression by 44 percent and improved median PFS by more than one year compared to letrozole plus placebo (27.6 months [95% CI: 22.4, 30.3] vs 14.5 months [95% CI: 12.3, 17.1]) when used as the initial treatment for postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative (ER+, HER2-) metastatic breast cancer (HR=0.56 [95% CI: 0.46, 0.69]). This updated, post-hoc analysis included a median follow-up of more than three years, which is the longest to date of any Phase 3 study of a CDK 4/6 inhibitor.

The updated data are consistent with results from the primary analysis for PALOMA-2, which showed a median PFS for women treated with IBRANCE plus letrozole of 24.8 months (95% CI: 22.1, NE) compared with 14.5 months (95% CI: 12.9, 17.1) for women treated with letrozole plus placebo (HR=0.58 [95% CI: 0.46,0.72], p<0.0001). Consistent with findings from the primary analysis, the updated data demonstrate that clinical benefit was observed across all patient subgroups receiving the combination of IBRANCE and letrozole. Overall survival data were not yet mature at the time of this updated PFS analysis.

"There currently is no cure for metastatic breast cancer, so prolonging progression-free survival and delaying the need for additional anticancer therapies are critical factors in treating these patients," said Hope Rugo, MD, lead author and professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. "The updated findings from PALOMA-2 provide additional evidence to support the use of palbociclib with an aromatase inhibitor as a standard of care in the first-line setting for postmenopausal patients with hormone receptor-positive (HR+), HER2- metastatic breast cancer across all patient subgroups."

At SABCS, 10 additional Pfizer-sponsored abstracts will be presented evaluating IBRANCE, several of which explore further analysis of PALOMA-2 along with three real-world studies of patients treated with IBRANCE in clinical practice. These real-world data include patients who have received IBRANCE in combination with endocrine therapy in various settings and across age groups, including young women (aged 50 years and under, which functioned as a surrogate for premenopausal status in the analysis).

"The real-world data to be presented at SABCS underscore the transformational impact IBRANCE has made on the treatment of HR+, HER2- metastatic breast cancer, and provide important insights into the way in which IBRANCE is being used in clinical practice," said Mace Rothenberg, MD, chief development officer, Oncology, Pfizer Global Product Development. "The rapid adoption of IBRANCE in young women is particularly notable because premenopausal women with metastatic breast cancer historically have had fewer approved treatment options available to them than postmenopausal women. The PALOMA-3 trial of IBRANCE was the first Phase 3 trial of a CDK 4/6 inhibitor to include premenopausal women and establish its efficacy in this patient population."

The safety profile of IBRANCE in the PALOMA-2 updated analysis is consistent with previous reports and will be presented at SABCS. In the primary analysis, the most common adverse reactions (≥20%) of any grade reported in the PALOMA-2 study of IBRANCE plus letrozole vs placebo plus letrozole included neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%) and anemia (24% vs 9%).1

IBRANCE was the first CDK 4/6 inhibitor approved by any regulatory authority, and now is approved in more than 75 countries. These global approvals are based on data from the PALOMA program, including PALOMA-2 as well as the Phase 3 PALOMA-3 trial, which evaluated IBRANCE in combination with fulvestrant in pre-, peri- and postmenopausal women with HR+, HER2- metastatic breast cancer whose disease progressed on or after prior endocrine therapy. Pre- and peri-menopausal women enrolled in PALOMA-3 received the LHRH agonist goserelin.

To date, IBRANCE has been prescribed to more than 90,000 patients worldwide.

The full prescribing information for IBRANCE can be found at www.pfizer.com.

About PALOMA-2

PALOMA-2 is a randomized (2:1), multicenter, multinational, double-blind Phase 3 study designed to assess the PFS of IBRANCE (125 mg orally once daily for three out of four weeks in repeated cycles) in combination with letrozole (2.5 mg once daily continuously) versus letrozole plus placebo as a first-line treatment for postmenopausal women with ER+, HER2- metastatic breast cancer. PALOMA-2 evaluated a total of 666 women from 186 global sites in 17 countries.

Results from PALOMA-2 after a median 23-month follow-up were previously published in The New England Journal of Medicine in November 2016.

About IBRANCE (palbociclib) 125 mg capsules

IBRANCE is an oral inhibitor of CDKs 4 and 6,1 which are key regulators of the cell cycle that trigger cellular progression.2,3 In the U.S., IBRANCE is indicated for the treatment of HR+, HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women, or fulvestrant in women with disease progression following endocrine therapy.

IMPORTANT IBRANCE (palbociclib) SAFETY INFORMATION FROM THE U.S. PRESCRIBING INFORMATION

Neutropenia was the most frequently reported adverse reaction in PALOMA-2 (80%) and PALOMA-3 (83%). In PALOMA-2, Grade 3 (56%) or 4 (10%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. In PALOMA-3, Grade 3 (55%) or Grade 4 (11%) decreased neutrophil counts were reported in patients receiving IBRANCE plus fulvestrant. Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Inform patients to promptly report any fever.

Monitor complete blood count prior to starting IBRANCE, at the beginning of each cycle, on Day 15 of first 2 cycles and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females of reproductive potential to use effective contraception during IBRANCE treatment and for at least 3 weeks after the last dose. IBRANCE may impair fertility in males and has the potential to cause genotoxicity. Advise male patients with female partners of reproductive potential to use effective contraception during IBRANCE treatment and for 3 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy. Advise women not to breastfeed during IBRANCE treatment and for 3 weeks after the last dose because of the potential for serious adverse reactions in nursing infants.

The most common adverse reactions (≥10%) of any grade reported in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (80% vs 6%), infections (60% vs 42%), leukopenia (39% vs 2%), fatigue (37% vs 28%), nausea (35% vs 26%), alopecia (33% vs 16%), stomatitis (30% vs 14%), diarrhea (26% vs 19%), anemia (24% vs 9%), rash (18% vs 12%), asthenia (17% vs 12%), thrombocytopenia (16% vs 1%), vomiting (16% vs 17%), decreased appetite (15% vs 9%), dry skin (12% vs 6%), pyrexia (12% vs 9%), and dysgeusia (10% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were neutropenia (66% vs 2%), leukopenia (25% vs 0%), infections (7% vs 3%), and anemia (5% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-2 for IBRANCE plus letrozole vs placebo plus letrozole were decreased WBC (97% vs 25%), decreased neutrophils (95% vs 20%), anemia (78% vs 42%), decreased platelets (63% vs 14%), increased aspartate aminotransferase (52% vs 34%), and increased alanine aminotransferase (43% vs 30%).

The most common adverse reactions (≥10%) of any grade reported in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (83% vs 4%), leukopenia (53% vs 5%), infections (47% vs 31%), fatigue (41% vs 29%), nausea (34% vs 28%), anemia (30% vs 13%), stomatitis (28% vs 13%), diarrhea (24% vs 19%), thrombocytopenia (23% vs 0%), vomiting (19% vs 15%), alopecia (18% vs 6%), rash (17% vs 6%), decreased appetite (16% vs 8%), and pyrexia (13% vs 5%).

The most frequently reported Grade ≥3 adverse reactions (≥5%) in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were neutropenia (66% vs 1%) and leukopenia (31% vs 2%).

Lab abnormalities of any grade occurring in PALOMA-3 for IBRANCE plus fulvestrant vs placebo plus fulvestrant were decreased WBC (99% vs 26%), decreased neutrophils (96% vs 14%), anemia (78% vs 40%), decreased platelets (62% vs 10%), increased aspartate aminotransferase (43% vs 48%), and increased alanine aminotransferase (36% vs 34%).

Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure.

IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min).

On December 6, 2017 Novartis reported results from the Phase III MONALEESA-7 trial in premenopausal or perimenopausal women with hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced or metastatic breast cancer demonstrating Kisqali (ribociclib) in combination with an aromatase inhibitor or tamoxifen and goserelin as initial endocrine-based therapy significantly prolonged progression-free survival (PFS) compared to endocrine therapy and goserelin alone (Press release, Novartis, DEC 6, 2017, View Source [SID1234522407]). These data will be presented today as a late-breaker oral presentation at the 2017 San Antonio Breast Cancer Symposium (SABCS) (Abstract #S2-05).

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Kisqali in combination with tamoxifen or an aromatase inhibitor plus goserelin demonstrated a median PFS of 23.8 months (95% CI: 19.2 months-not reached) compared to 13.0 months (95% CI: 11.0-16.4 months) for tamoxifen or an aromatase inhibitor plus goserelin (HR=0.553; 95% CI: 0.441-0.694; p<0.0001)[1]. Premenopausal women treated with Kisqali combination therapy saw a response as early as eight weeks as demonstrated by separation of the PFS curves compared to endocrine therapy alone[1].

"The strength of the MONALEESA-7 data is impressive and will give oncologists an important option if ribociclib is approved as treatment for this patient population as well as greater flexibility in the choice of endocrine therapy given with this agent," said Dr. Debu Tripathy, chair of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center. "Women who are premenopausal at the time of their breast cancer diagnosis tend to have more aggressive disease with poorer prognosis along with unique needs and experiences, so it is critical we determine which treatments will be most effective while also well tolerated."

MONALEESA-7 trial evaluated Kisqali in combination with tamoxifen and an aromatase inhibitor. This is the only Phase III study to evaluate a CDK4/6 inhibitor in combination with tamoxifen and establishes the safety and efficacy of Kisqali in this combination as first-line treatment for advanced breast cancer (median PFS of 22.1 vs 11.0 months; HR=0.585; 95% CI: 0.387-0.884)[1]. Kisqali in combination with an aromatase inhibitor demonstrated an additional 14 months progression-free survival over endocrine therapy alone (median PFS of 27.5 vs 13.8 months; HR=0.569; 95% CI: 0.436-0.743)[1].

Premenopausal women taking Kisqali benefited for a longer time until health-related quality of life (QoL) deterioration compared to those taking endocrine therapy alone[1]. Women taking Kisqali also had a clinically meaningful improvement in pain symptoms as early as eight weeks; this improvement was sustained[1].

No new safety signals were observed in the MONALEESA-7 trial; adverse events were generally consistent with those observed in MONALEESA-2, identified early and mostly managed through dose interruptions or reductions[1]. Combination treatment with Kisqali was well tolerated with a discontinuation rate due to adverse events of 3.6% compared to 3.0% in patients who received endocrine therapy alone[1]. The most common (>=5%) grade 3/4 adverse events in patients receiving Kisqali combination therapy compared to endocrine therapy alone were neutropenia (60.6% vs 3.6%) and leukopenia (14.3% vs 1.2%)[1].

"We are pleased to see Kisqali combination therapy provide strong efficacy and prolonged quality of life with pain reduction in younger women, and look forward to working with health authorities to bring a new treatment option to premenopausal or perimenopausal women," said Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development. "Research in premenopausal advanced breast cancer is extremely limited as these women traditionally have been excluded from clinical trials or reduced to a subgroup in trials designed for their postmenopausal counterparts. We designed the robust MONALEESA clinical trial program to be inclusive of all women and men with HR+/HER2- advanced breast cancer."

Premenopausal breast cancer is a biologically distinct and more aggressive disease than postmenopausal breast cancer, and it is the leading cause of cancer death in women 20-59 years old[3],[4].

Novartis plans to discuss MONALEESA-7 data with global health authorities worldwide.

About MONALEESA-7
MONALEESA-7 is a Phase III randomized, double-blind, placebo-controlled trial investigating the efficacy and safety of Kisqali in combination with tamoxifen or a non-steroidal aromatase inhibitor plus goserelin versus tamoxifen or an aromatase inhibitor plus goserelin, in premenopausal or perimenopausal women with HR+/HER2- advanced breast cancer who had not previously received endocrine therapy for advanced disease. More than 670 women ranging from 23-58 years in age were randomized in the MONALEESA-7 trial. The first patient assessment occurred at eight weeks; separation of the PFS curves at this time was not a pre-specified endpoint of the study.

About Kisqali (ribociclib)
Kisqali is a selective cyclin-dependent kinase inhibitor, a class of drugs that help slow the progression of cancer by inhibiting two proteins called cyclin-dependent kinase 4 and 6 (CDK4/6). These proteins, when over-activated, can enable cancer cells to grow and divide too quickly. Targeting CDK4/6 with enhanced precision may play a role in ensuring that cancer cells do not continue to replicate uncontrollably.

Kisqali was approved by the European Commission in August 2017, as initial endocrine-based therapy for postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer in combination with an aromatase inhibitor based on findings from the pivotal MONALEESA-2 trial. Kisqali is not currently approved for use in premenopausal patients.

Kisqali is approved for use in 44 countries around the world, including the United States and European Union member states. Kisqali was developed by the Novartis Institutes for BioMedical Research (NIBR) under a research collaboration with Astex Pharmaceuticals.

About the Kisqali Clinical Trial Program
With more than 2,000 patients, the MONALEESA program is the largest Phase III clinical program researching use of a CDK4/6 inhibitor in advanced breast cancer[1].

The MONALEESA-7 findings add to the body of evidence from MONALEESA-2 supporting the benefit of Kisqali plus hormone therapy in first-line treatment of HR+/HER2- advanced or metastatic breast cancer. Novartis is continuing to evaluate Kisqali in combination with multiple hormonal therapies across a broad range of patients, including in the adjuvant setting.

MONALEESA-2 is a Phase III global registration trial evaluating Kisqali in combination with letrozole compared to letrozole alone in postmenopausal women with HR+/HER2- advanced breast cancer who received no prior therapy for their advanced breast cancer.

MONALEESA-3 is a Phase III study evaluating Kisqali in combination with fulvestrant compared to fulvestrant alone in postmenopausal women or men with HR+/HER2- advanced breast cancer who have received no or a maximum of one prior endocrine therapy. MONALEESA-3 is fully enrolled.

CompLEEment-1 is an open-label, multicenter, Phase IIIb study evaluating the safety and efficacy of Kisqali plus letrozole in men and pre- or postmenopausal women with HR+/HER2- advanced breast cancer who have not received prior hormonal therapy for advanced disease. CompLEEment-1 is enrolling.

The safety and efficacy of Kisqali with endocrine therapy as adjuvant therapy in premenopausal and postmenopausal women who have not previously received treatment with a CDK4/6 inhibitor is also being evaluated in the EarLEE-1 study, which is enrolling.

More information about these studies can be found at www.ClinicalTrials.gov.

About Novartis in Advanced Breast Cancer
For more than 25 years, Novartis has been at the forefront of driving scientific advancements for breast cancer patients and improving clinical practice in collaboration with the global community. With one of the most diverse breast cancer pipelines and the largest number of breast cancer compounds in development, Novartis leads the industry in discovery of new therapies and combinations, especially in HR+ advanced breast cancer, the most common form of the disease.

Important Safety Information from the Kisqali EU SmPC
The most common ADRs and the most common grade 3/4 ADRs (reported at a frequency >=20% and >=2% respectively) for which the frequency for Kisqali plus letrozole exceeds the frequency for placebo plus letrozole were blood and lymphatic system disorders (including abnormally low neutrophil and white blood cell count), headache, back pain, nausea, fatigue, diarrhea, vomiting, constipation, hair loss and rash and abnormally low levels of neutrophils or white blood cells, abnormal liver function tests (increased alanine and aspartate aminotransferase), abnormally low lymphocyte count, low levels of phosphate, vomiting, nausea, fatigue and back pain, respectively. Low levels of neutrophils was the most commonly seen severe adverse event; fever in addition to a low neutrophil count was reported in 1.5% of patients.

Kisqali can cause serious side effects such as a significant decrease in neutrophil count, abnormal liver function tests and may have an effect on the electrical activity of the heart known as QT/QTc interval prolongation, which could lead to disturbances in heart rhythm. As a precaution, patients should have complete blood counts, liver function, and serum electrolyte levels measured prior to starting treatment as well as during treatment with Kisqali. Patients should also have their heart activity checked before and monitored during treatment.

The efficacy and safety of ribociclib have not been studied in patients with critical visceral disease.

The use of Kisqali with medicinal products known to prolong QTc interval or strong CYP3A4 inhibitors should be avoided as this may lead to prolongation of the QT/QTc interval. If treatment with a strong CYP3A4 inhibitor cannot be avoided, the Kisqali dose should be reduced. Concomitant administration with other medicines that could affect cardiac repolarization or prolong the QT/QTc interval should be taken into account prior to and during treatment with Kisqali. Patients taking sensitive CYP3A4 substrates with narrow therapeutic index should use caution because of the increased risk of adverse events that may occur if these medications are co-administered with Kisqali.

Kisqali contains soya lecithin and therefore it should not be taken by patients who are allergic to peanut or soya.

Animal studies suggest that Kisqali may cause fetal harm in pregnant women. Therefore, as a precaution, women of childbearing potential should use effective contraception while receiving Kisqali during treatment and up to 21 days after stopping treatment. Women should not breast feed for at least 21 days after the last dose of Kisqali. Kisqali may affect fertility in males.

Please see full Prescribing Information for Kisqali, available at www.kisqali.com.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "expect," "anticipate," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures; general economic and industry conditions, including the effects of the persistently weak economic and financial environment in many countries; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.