On June 2, 2019 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported detailed results from the Phase III POLO trial at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago, US (Abs #LBA4) (Press release, AstraZeneca, JUN 2, 2019, View Source [SID1234536743]). Results are today also published in The New England Journal of Medicine (NEJM).

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The POLO trial tested Lynparza (olaparib) tablets as 1st-line maintenance monotherapy for patients with germline BRCA-mutated (gBRCAm) metastatic adenocarcinoma of the pancreas (pancreatic cancer) whose disease had not progressed following standard-of-care platinum-based 1st-line chemotherapy.

Results from the trial showed a statistically-significant and clinically-meaningful improvement in progression-free survival (PFS) for Lynparza vs. placebo, improving the time without disease progression by a median of 7.4 months for patients treated with Lynparza vs. 3.8 months for those on placebo (HR 0.53 [95% CI, 0.35-0.82], p=0.004). More than twice as many patients showed no disease progression both at one year (34% on Lynparza vs. 15% on placebo) and two years (22% vs. 10%, respectively).

José Baselga, Executive Vice President, Oncology R&D, said: "These unprecedented results raise new hope for patients that have seen little progress over a long period of time. From as early as six months after initiation, more than twice as many patients taking Lynparza lived without progression of their disease compared to those on placebo and we are now working with regulatory authorities to bring Lynparza to patients as quickly as possible."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "We are encouraged by the results of the POLO trial which showed a considerable reduction in risk of disease progression or death with Lynparza for germline BRCA-mutated metastatic pancreatic cancer patients who did not progress on chemotherapy. Currently less than 3% of metastatic pancreatic cancer patients survive more than five years after diagnosis. The results of this trial reinforce MSD and AstraZeneca’s commitment to develop innovative treatments for cancers with few options."

Hedy L. Kindler, MD, co-principal investigator of the POLO trial and Professor of Medicine, University of Chicago Medicine, said: "Despite efforts to identify therapies, targeted or combination treatments to improve patient outcomes, pancreatic cancer remains an area of high unmet need. The results of the POLO trial may open the door to a new era of personalised, biomarker-led care in metastatic pancreatic cancer and reinforces the importance of knowing BRCA status at diagnosis."

Kaplan-Meier estimates of PFS by blinded, independent central review

From The New England Journal of Medicine, Golan T, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer, Jun 2 [Epub ahead of print] Copyright © 2019 Massachusetts Medical Society. Reprinted with permission from the Massachusetts Medical Society.

The safety and tolerability profile of Lynparza in the POLO trial was in line with that observed in prior clinical trials. The most common adverse events (AEs) ≥20% were fatigue/asthenia (60%), nausea (45%), abdominal pain (29%), diarrhoea (29%), anaemia (28%), decreased appetite (25%) and constipation (23%). The most common ≥ grade 3 AEs were anaemia (11%), fatigue/asthenia (5%), decreased appetite (3%), abdominal pain (2%), vomiting (1%) and arthralgia (1%). AEs led to dose interruption in 16% of patients on Lynparza while 5% of patients discontinued treatment.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for multiple indications in advanced ovarian cancer and metastatic breast cancer and has been used in over 20,000 patients worldwide.

About POLO

POLO is a Phase III randomised, double-blinded, placebo-controlled, multicentre trial of Lynparza tablets (300mg twice daily) as maintenance monotherapy vs. placebo. The trial randomised 154 patients with gBRCAm metastatic pancreatic cancer whose disease had not progressed on 1st-line platinum-based chemotherapy. Patients were randomised (3:2) to receive Lynparza or placebo until disease progression. The primary endpoint was PFS and key secondary endpoints included overall survival, time to second disease progression, overall response rate, disease control rate and health-related quality of life.

About pancreatic cancer

Pancreatic cancer is the 12th most common cancer worldwide,1 with 458,918 new cases in 2018 alone.1 With the worst survival rate of all the most common cancers,2 it is the 4th leading cause of cancer death,3 and less than 3% of patients with metastatic disease survive more than five years after diagnosis.4 Early diagnosis of pancreatic cancer is difficult, as often there are no symptoms until it is too late.5 Around 80% of patients are diagnosed at the metastatic stage.6

There are two types of pancreatic cancer. Exocrine tumours, of which the most common type is pancreatic ductal adenocarcinoma (PDAC),7 start in the exocrine cells, where enzymes help to digest food. Neuroendocrine tumours start in neuroendocrine cells, which produce hormones, such as insulin,6 that control different functions of the body.

About BRCA mutations

Breast cancer susceptibility genes 1/2 (BRCA1 and BRCA2) are human genes that produce proteins responsible for repairing damaged DNA and play an important role maintaining the genetic stability of cells. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly, and cells become unstable. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

About Lynparza

Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2. Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. Lynparza is being tested in a range of PARP-dependent tumour types with defects and dependencies in the DDR.

Lynparza is currently approved in over 60 countries, including those in the EU, for the maintenance treatment of platinum-sensitive relapsed ovarian cancer regardless of BRCA status. It is approved in the US, Canada and Brazil as 1st-line maintenance treatment of BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in nearly 40 countries, including the US and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU this includes locally advanced breast cancer. Regulatory reviews are underway in other jurisdictions for both ovarian cancer and breast cancer.

Lynparza has the broadest and most advanced clinical trial development programme of any PARP inhibitor, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the United States and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and potential new medicine selumetinib, a MEK inhibitor, for multiple cancer types. Working together, the companies will develop Lynparza and selumetinib in combination with other potential new medicines and as monotherapies. Independently, the companies will develop Lynparza and selumetinib in combination with their respective PD-L1 and PD-1 medicines.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On June 2, 2019 AstraZeneca has reported three-year overall survival (OS) results from the Phase III PACIFIC trial of Imfinzi (durvalumab) in unresectable, Stage III non-small cell lung cancer (NSCLC) during the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago (Press release, AstraZeneca, JUN 2, 2019, View Source [SID1234536744]).

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These latest results show a durable and sustained OS benefit in patients with unresectable, Stage III NSCLC who had not progressed following concurrent chemoradiation therapy (CRT), a previous standard-of-care (SoC) treatment. The OS rate was 57% at three years for patients receiving Imfinzi vs. 43.5% for placebo following concurrent CRT. Median OS was not yet reached with the Imfinzi arm vs. 29.1 months for placebo.

Dave Fredrickson, Executive Vice President, Oncology Business Unit said: "These findings for Imfinzi are another example of our focus on bringing long-term survival benefits to patients who still have a chance of being cured. These three-year survival results further establish the PACIFIC regimen as the standard of care for these patients, and we are optimistic this survival trend will continue as we move towards the five-year landmark in this curative-intent setting."

Results build on the primary two-year OS analysis that was published in The New England Journal of Medicine in September 2018 and demonstrated a significant OS benefit for treatment with Imfinzi vs. placebo after CRT, regardless of PD-L1 expression. The primary analysis showed Imfinzi reduced the risk of death by 32% (HR 0.68, [99.73% CI, 0.47-0.997], p=0.0025).

With the additional year of follow up, the latest results for Imfinzi showed consistent and durable efficacy, maintaining a 31% reduction in the risk of death vs. placebo after CRT (HR 0.69, [95% CI 0.55-0.86]).

Jhanelle Gray, MD, Director of Clinical Research in the Thoracic Oncology Department at Moffitt Cancer Center in Tampa, Florida, and an investigator in the PACIFIC trial, said: "In the past, patients with unresectable, Stage III non-small cell lung cancer faced five-year survival rates of only 15% to 30%. It is remarkable to see that more than half of patients treated with the PACIFIC regimen remain alive at three years, an important milestone that raises the bar for treatments in this curative-intent setting."

The safety and tolerability profile for Imfinzi was consistent with the results reported at the time of the previous OS analysis. Among patients receiving Imfinzi, the most common adverse events (AE) (greater than or equal to 20% of patients) vs. placebo were cough (35.2% vs. 25.2%), fatigue (24.0% vs. 20.5%), dyspnoea (22.3% vs. 23.9%) and radiation pneumonitis (20.2% vs. 15.8%). 30.5% of patients experienced a grade 3 or 4 AE with Imfinzi vs. 26.1% with placebo, and 15.4% of patients discontinued treatment due to AEs with Imfinzi vs. 9.8% of patients on placebo.

Building on PACIFIC

AstraZeneca has several ongoing trials focused on testing Imfinzi in earlier stages of NSCLC (Stages I-III) in potentially-curative settings. The Phase III PACIFIC-2 trial design, presented today at the ASCO (Free ASCO Whitepaper) Annual Meeting, is evaluating Imfinzi given concurrently with CRT in patients with unresectable, Stage III NSCLC. In the Phase II PACIFIC-6 trial, Imfinzi is being tested in the same population following sequential chemotherapy and radiation therapy.

Additional trials assess Imfinzi in the neoadjuvant setting (prior to other treatments) in Stage II and III NSCLC patients (AEGEAN) and in the adjuvant setting (following the primary treatment) in Stage I to III (BR.31). The Phase III PACIFIC-4 trial is testing Imfinzi in unresected Stage I and II NSCLC patients following definitive stereotactic body radiation therapy (SBRT).

AstraZeneca is also testing novel combinations with Imfinzi in two Phase II platform trials in both unresectable, Stage III disease (COAST) and in resectable Stage I-III disease starting before surgery (NeoCOAST), to help find solutions for NSCLC patients not benefiting from currently-available therapies.

Immuno-Oncology trials in early-stage non-small cell lung cancer (NSCLC)

Trial name

Phase

Population

Trial arms

Stages I-III

PACIFIC-4

Phase III

Unresected, Stage I/II NSCLC

Imfinzi monotherapy vs. placebo following definitive SBRT

AEGEAN

Phase III

Resectable, Stage II and III NSCLC, neoadjuvant (incl. EGFR/ALK positive)1

SoC chemotherapy + Imfinzi vs. SoC chemotherapy + placebo followed by surgery

ADJUVANT BR.312

Phase III

Completely resected, Stage Ib-IIIa NSCLC (incl. EGFR/ALK positive)1

Placebo vs. Imfinzi monotherapy

NeoCOAST

Phase II

Resectable, Stage I-IIIA NSCLC

Imfinzi in combination with potential new medicines vs. Imfinzi monotherapy followed by surgery

COAST

Phase II

Unresectable, Stage III NSCLC following concurrent CRT

Imfinzi in combination with potential new medicines vs. Imfinzi monotherapy

Stage III

PACIFIC-2

Phase III

Unresected, Stage III NSCLC

Concurrent CRT + placebo vs. concurrent CRT + Imfinzi

PACIFIC-5

Phase III

Unresected, Stage III NSCLC (ex US global trial, China focus)

Placebo following concurrent CRT vs. Imfinzi following concurrent CRT

PACIFIC-6

Phase II

Unresectable, Stage III NSCLC

Imfinzi following sequential CRT

1. EGFR = epidermal growth factor receptor, ALK = anaplastic lymphoma kinase
2. BR.31 is an externally-sponsored research study led by the Canadian Cancer Trials Group (CCTG)

Imfinzi is approved for the treatment of unresectable, Stage III non-small cell lung cancer in more than 45 countries, including the US, EU and Japan, based on the Phase III PACIFIC trial. Since the first approval in February 2018, more than 20,000 patients in this setting have been treated with Imfinzi.

About PACIFIC

The PACIFIC trial is a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial of Imfinzi as treatment in ‘all-comer’ patients (i.e. regardless of PD-L1 status) with unresectable, Stage III (locally-advanced) NSCLC whose disease has not progressed following platinum-based chemotherapy and radiation therapy (CRT).

The trial is being conducted in 235 centres across 26 countries involving 713 patients. The primary endpoints of the trial are progression-free survival (PFS) and OS, and secondary endpoints include landmark PFS and OS, objective response rate, and duration of response.

About Stage III NSCLC

Stage III (locally-advanced) NSCLC is commonly divided into three sub-categories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally and the possibility of surgery.1 Stage III disease is different from Stage IV disease, when the cancer has spread (metastasised) to distant organs, as Stage III is currently treated with curative intent.1,2

Stage III NSCLC represents approximately one-third of NSCLC incidence and was estimated to affect nearly 200,000 patients in the top-eight countries (China, France, Germany, Italy, Japan, Spain, UK, US) in 2015.3,4 The majority of Stage III NSCLC patients are diagnosed with unresectable tumours.5 No new treatments beyond chemoradiation therapy, followed by active surveillance to monitor for progression, have been available to patients for decades.6-9

About Imfinzi

Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is approved for unresectable, Stage III NSCLC in more than 45 countries including the US, in the EU, and Japan based on the Phase III PACIFIC trial. Imfinzi is also approved for previously-treated patients with advanced bladder cancer in the US, Canada, Brazil, Australia, Israel, India, United Arab Emirates, Qatar, Macau and Hong Kong.

As part of a broad development programme, Imfinzi is also being tested as a monotherapy and in combination with tremelimumab, an anti-CTLA4 monoclonal antibody and potential new medicine, as a treatment for patients with NSCLC, small cell lung cancer, bladder cancer, head and neck cancer, liver cancer, cervical cancer, biliary tract cancer and other solid tumours.
About AstraZeneca in lung cancer

AstraZeneca has a comprehensive portfolio of approved and potential new medicines in late-stage clinical development for the treatment of different forms of lung cancer spanning several stages of disease, lines of therapy and modes of action. We aim to address the unmet needs of patients with EGFR-mutated tumours as a genetic driver of disease, which occur in 10-15% of NSCLC patients in the US and EU and 30-40% of NSCLC patients in Asia, with our approved medicines Iressa (gefitinib) and Tagrisso (osimertinib), and ongoing Phase III trials FLAURA, ADAURA and LAURA as well as the Phase II exploratory combination trials SAVANNAH and ORCHARD.10-12

Our extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a known genetic mutation which represents up to 50% of all patients with lung cancer. Imfinzi (durvalumab), an anti-PDL1 antibody, is in development as monotherapy (Phase III trials ADJUVANT BR.31, PACIFIC-4, PACIFIC-5, and PEARL) and in combination with tremelimumab and/or chemotherapy (AEGEAN, PACIFIC-2, NEPTUNE, POSEIDON, ADRIATIC and CASPIAN Phase III trials).

About AstraZeneca’s approach to Immuno-Oncology (IO)

IO is a therapeutic approach designed to stimulate the body’s immune system to attack tumours. Our IO portfolio is anchored by immunotherapies that have been designed to overcome anti-tumour immune suppression. We believe that IO-based therapies offer the potential for life-changing cancer treatments for the clear majority of patients.

We are pursuing a comprehensive clinical-trial programme that includes Imfinzi (anti-PDL1) as monotherapy and in combination with tremelimumab (anti-CTLA4) in multiple tumour types, stages of disease, and lines of therapy, using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient. In addition, the ability to combine our IO portfolio with small, targeted molecules from across our Oncology pipeline, and from our research partners, may provide new treatment options across a broad range of tumours.

About AstraZeneca in Oncology

AstraZeneca has a deep-rooted heritage in Oncology and offers a quickly-growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advance Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and one day eliminate cancer as a cause of death.

On June 2, 2019 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 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) 2019 Annual Meeting in Chicago. The presentation entitled, "Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial," will be presented at a poster session on June 2 at 8:00 a.m. CT. 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, prophylactic use of anti-diarrheal medications was not mandatory. In the trial, 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 median cumulative duration of grade 3 diarrhea in the ExteNET trial was 5 days and 16.8% of patients who received neratinib in the ExteNET trial discontinued the drug due to diarrhea.

The CONTROL trial is an international, open-label, Phase II study investigating the use of antidiarrheal prophylaxis or dose escalation 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 four additional cohorts. One cohort received the combination of loperamide and budesonide, the second cohort received the combination of loperamide plus colestipol, the third cohort received colestipol plus loperamide as needed and the fourth cohort did not use any antidiarrheal drugs as mandatory prophylaxis but instead used a dose escalation during the first month of neratinib treatment. Budesonide is a locally acting corticosteroid that Puma believes targets the inflammation identified in a preclinical model of neratinib-induced diarrhea and colestipol is a bile acid sequestrant that Puma believes targets potential bile acid malabsorption that could result from such inflammation. The dose escalation involved treating with neratinib at 120 mg per day for the first week, 160 mg per week for the second week and 240 mg per week starting at week 3 and until the end of treatment.

The interim analysis of the CONTROL 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, 136 patients who received neratinib plus loperamide prophylaxis for 1 cycle and colestipol for 1 cycle, 104 patients who received colestipol for 1 cycle and loperamide as needed and 60 patients who received the dose escalation regimen of neratinib.

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% and that for the 137 patients in this cohort, 20.4% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 3 days.

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 28.1% and that for the 64 patients in this cohort, 10.9% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 2.5 days.

For the 136 patients who received the combination of loperamide plus colestipol, the results of the trial showed that the incidence of grade 3 diarrhea was 20.6% and that for the 136 patients in this cohort, 4.4% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 3.5 days.

For the 104 patients who received colestipol and loperamide as needed, the results of the trial showed that the incidence of grade 3 diarrhea was 31.7% and that for the 104 patients in this cohort, 6.7% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 3 days.

For the 60 patients who received no antidiarrheal drugs as mandatory prophylaxis and dose escalation of neratinib in the first month, the results of the trial showed that the incidence of grade 3 diarrhea was 11.7% and that for the 60 patients in this cohort, 3.3% discontinued neratinib due to diarrhea. The median cumulative duration of grade 3 diarrhea was 2 days.

Further information is provided in Table 1 below:

Table 1: Characteristics of Treatment-Emergent Diarrhea
Neratinib dose
Loperamide + Loperamide + Loperamide escalation +
Loperamide budesonide colestipol prn + colestipol loperamide prn
(n=137) (n=64) (n=136) (n=104) (n=60)
Diarrhea, %
Any grade 79.6 85.9 83.1 95.2 95.0
Grade 1 24.1 25.0 27.9 30.8 43.3
Grade 2 24.8 32.8 34.6 32.7 40.0
Grade 3 30.7 28.1 20.6 31.7 11.7

Diarrhea leading to discontinuation, %

20.4 10.9 4.4 6.7 3.3

Hospitalization (due to diarrhea), %

1.5 0 0 0 0

Discontinuation of study (any cause), %

44.6 20.3 28.7 26.0 13.6

Note: Each patient was counted only once in the highest grade category.
No Grade 4 events reported in the CONTROL study.
Carlos H. Barcenas, MD, MS, Assistant Professor in the Department of Breast Medical Oncology of The University of Texas MD Anderson Cancer Center, 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. We are pleased to see the initial results of the dose escalation regimen. Along with the continued reduction in the incidence and severity of grade 3 diarrhea with neratinib, diarrhea appears to be early onset, acute, self-limiting and manageable. Not only does the addition of budesonide or colestipol to loperamide prophylaxis appear to greatly improve the tolerability of neratinib, the dose escalation regimen appears as another promising option since there is no mandatory prophylaxis. We look forward to the completion of the dose escalation 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 antidiarrheal regimens and the dose escalation. The reduction in the discontinuations due to diarrhea are encouraging and appear to represent a marked improvement in tolerability over what was seen in the ExteNET trial."

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, 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. When patients require gastric acid reducing agents, use an H2-receptor antagonist or antacid. Separate NERLYNX by at least 3 hours with antacids. Separate NERLYNX by at least 2 hours before or 10 hours after H2-receptor antagonists.
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 June 2, 2019 SOTIO, a biotechnology company owned by the PPF Group, reported new statistically and clinically significant results from its Phase I/II clinical trial evaluating DCVAC/LuCa, an active cellular immunotherapy product, in patients with stage IV non-small cell lung cancer (Press release, SOTIO, JUN 2, 2019, View Source [SID1234536778]). The final analysis of the data confirmed the promising clinical efficacy of DCVAC/LuCa. SLU01 clinical trial results were presented by the principal investigator Libor Havel, MD, from Thomayer University Hospital in Prague (Czech Republic) at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago today.

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SOTIO evaluated its proprietary product DCVAC/LuCa in an open label, randomized, multicenter Phase I/II trial in combination with carboplatin/paclitaxel in patients with advanced or metastatic non-small cell lung cancer. Patients that received DCVAC in combination with chemotherapy have a 46% lower risk of dying compared to those who received chemotherapy alone. Furthermore, the 3.7-month longer survival with the DCVAC/chemo combination is statistically and clinically significant. Treatment was very well tolerated and there were no serious adverse events solely related to DCVAC/LuCa.

"The final results of the SLU01 study confirmed our original hypothesis that adding DCVAC to the standard of care chemotherapy could prolong both overall survival and progression-free survival," commented Libor Havel, MD, Thomayer University Hospital in Prague (Czech Republic), principal investigator of SLU01 study. "I have seen that most of my patients receiving DCVAC have significantly improved their quality of life and I hope this can be confirmed in further clinical trials as well."

Radek Spisek, MD, PhD, Chief Executive Officer of SOTIO commented: "Lung cancer is one of the most insidious diseases with limited treatment options. We are encouraged by the results of the trial and will discuss the further clinical development of DCVAC/LuCa with our shareholders and key opinion leaders, with the goal being to provide patients with an effective treatment option in the future. Results of SLU01 follow the very promising results of DCVAC in patients with ovarian cancer, reported at ASCO (Free ASCO Whitepaper) 2018 and SGO 2019."

The abstract with final SLU01 clinical trial data is available online here: Abstract 9039. A copy of the poster can be found on SOTIO’s webpage.

SOTIO attends ASCO (Free ASCO Whitepaper) 2019 (May 31 to June 4, 2019) with its own exhibition booth (#5147) and presents its clinical development pipeline to the expert community.

About SLU01 clinical trial:

SLU01 is a randomized, open-label, three-arm, parallel group, multi-center Phase I/II clinical trial evaluating the safety and efficacy of DCVAC/LuCa added to standard first-line chemotherapy with carboplatin and paclitaxel +/- immune enhancers in patients with stage IV non-small cell lung carcinoma (NSCLC).

Webpage: www.sotio.com/news-publications/news

On June 2, 2019 Sanofi reported that Pivotal Phase 3 ICARIA-MM trial results demonstrated that isatuximab added to pomalidomide and dexamethasone (isatuximab combination therapy) showed statistically significant improvements compared to pomalidomide and dexamethasone (pom-dex) alone in patients with relapsed/refractory multiple myeloma (RRMM) (Press release, Sanofi, JUN 2, 2019, View Source [SID1234536763]).

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These findings were presented today at the 2019 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago. Isatuximab is an investigational monoclonal antibody that targets a specific epitope on the CD38 receptor of a plasma cell.

"Isatuximab in combination with pomalidomide and dexamethasone resulted in an impressive 40% reduction in the risk of progression or death compared to pomalidomide and dexamethasone alone," said Paul Richardson, MD, principal investigator and clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. "This outcome is noteworthy because this trial included a particularly difficult-to-treat, relapsed and refractory patient population that was, in my view, highly reflective of real-world practice."

Isatuximab combination therapy showed a statistically significant improvement in progression free survival (HR 0.596, 95% CI 0.44-0.81, p=0.001), and the median progression free survival was longer in the isatuximab combination therapy arm (11.53 months, 95% CI: 8.936 to 13.897) than pom-dex alone (6.47 months, 95% CI: 4.468 to 8.279).

Also of note, isatuximab combination therapy demonstrated a significantly greater overall response rate, compared to pom-dex alone (60% vs. 35%, p<0.0001). In additional analyses, isatuximab combination therapy compared to pom-dex alone showed a treatment benefit consistent across multiple subgroups, including patients 75 years and older, patients with renal insufficiency, and patients who were refractory to lenalidomide. The results presented above were based on an independent review committee assessment.

In addition, the following results favored isatuximab combination therapy:

Isatuximab combination therapy demonstrated significantly higher very good partial response (VGPR) rate compared to pom-dex (31.8% vs. 8.5%, respectively, p<0.0001) and a longer duration of response compared to pom-dex alone (median 13.27 months vs. 11.07 months, respectively). Among patients who achieved a response, isatuximab combination therapy demonstrated faster median time to first response compared to pom-dex alone (35 days vs. 58 days, respectively).
Time to next treatment was longer with isatuximab combination therapy compared to pom-dex alone (median not reached vs. 9.1 months, HR=0.538).
Data at the time of analysis showed a trend towards an overall survival benefit associated with isatuximab combination therapy. Final data on overall survival will be reported when available.

Adverse events (AEs) of Grade >=3 were observed in 86.8% of isatuximab combination therapy patients vs. 70.5% of pom-dex patients. Additionally, isatuximab combination therapy compared to pom-dex showed: 7.2% vs. 12.8% of patients discontinued due to AEs, respectively; 7.9% vs. 9.4% patients died due to AEs, respectively; infections of Grade >=3 were seen in 42.8% vs. 30.2% of patients, respectively; and Grade >=3 neutropenia was seen in 84.9% (febrile 11.8%) vs. 70.1% (febrile 2.0%) of patients, respectively. Infusion reactions were reported in 38.2% (2.6% grade 3-4) of isatuximab combination therapy patients.

First Positive Phase 3 Trial of a Monoclonal Antibody in Combination with Pom-Dex

ICARIA-MM is a pivotal Phase 3 randomized, open-label, multi-center trial evaluating isatuximab in combination with pom-dex versus pom-dex alone in patients with RRMM. The study enrolled 307 patients with RRMM across 96 centers spanning 24 countries. Overall, patients had received a median of three prior lines of anti-myeloma therapies, including at least two consecutive cycles of lenalidomide and a proteasome inhibitor given alone or in combination.

During the trial, isatuximab was administered through an intravenous infusion at a dose of 10mg/kg once weekly for four weeks, then every other week for 28-day cycles in combination with standard doses of pom-dex for the duration of treatment.

Topline results from ICARIA-MM were previously announced in February 2019.

Developing Isatuximab, a Monoclonal Antibody

Isatuximab is an investigational monoclonal antibody (mAb) targeting a specific epitope on the CD38 receptor. It is designed to trigger multiple, distinct mechanisms of action that are believed to directly promote programmed tumor cell death (apoptosis) and immunomodulatory activity. CD38 is highly and uniformly expressed on multiple myeloma cells and is a cell surface receptor target for antibody-based therapeutics in multiple myeloma and other malignancies. The clinical significance of these findings is under investigation.

Isatuximab is being developed by Sanofi and is currently being evaluated in multiple ongoing Phase 3 clinical trials in combination with currently available treatments across the multiple myeloma treatment continuum.

In the second quarter of 2019, the European Medicines Agency (EMA) accepted for review the Marketing Authorization Application and Sanofi filed a Biologics License Application with the U.S. Food and Drug Administration (FDA), both for use of isatuximab in combination with pom-dex for the treatment of certain patients with RRMM.

Isatuximab is also under investigation for the treatment of other hematologic malignancies and solid tumors. Isatuximab is an investigational agent and its safety and efficacy have not been evaluated by the U.S. FDA, the EMA, or any other regulatory authority.

Multiple Myeloma Leads to Significant Disease Burden

Multiple myeloma is the second most common hematologic malignancy[1], affecting more than 138,000[2] people worldwide. Multiple myeloma results in significant disease burden. Patients with multiple myeloma continue to relapse over time making it a difficult to treat and incurable malignancy.