On September 28, 2019 AstraZeneca reported detailed overall survival (OS) results from the Phase III FLAURA trial of Tagrisso (osimertinib) in the 1st-line treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, SEP 28, 2019, View Source [SID1234539870]).

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Results showed a statistically significant and clinically meaningful improvement in OS, a key secondary endpoint for Tagrisso versus gefitinib or erlotinib, both of which were previous standard-of-care (SoC) treatments in this setting (HR 0.799 [95% CI, 0.641-0.997], p=0.0462).

Tagrisso delivered a median OS of 38.6 months versus 31.8 months for the comparator arm. At three years, 28% of patients in the Tagrisso arm and 9% of patients in the comparator arm remained on 1st-line study treatment. Tagrisso also showed a statistically significant and clinically meaningful 52% reduction in the risk of central nervous system (CNS) disease progression, increasing the time patients with CNS metastases lived without CNS disease progression or death (HR 0.48 [95% CI, 0.26-0.86], p=0.014).1

The results were presented at the Presidential Symposium of the ESMO (Free ESMO Whitepaper) (European Society for Medical Oncology) 2019 Congress in Barcelona, Spain (Abstract #LBA5_PR).

José Baselga, Executive Vice President, Oncology R&D said: "Tagrisso has set a new benchmark in EGFR-mutated non-small cell lung cancer by demonstrating a median overall survival of more than three years. We have not before seen survival benefits of this magnitude in any global Phase III trial with any such therapy. The ground-breaking data reaffirm the benefit of using Tagrisso first and further support its use as the 1st-line standard of care in this setting."

Dr Suresh S. Ramalingam, Principal Investigator of the FLAURA trial from Winship Cancer Institute of Emory University, Atlanta, US, said: "The results of the FLAURA trial provide further evidence to support the role of osimertinib as the preferred 1st-line therapy option for patients with EGFR-mutated non-small cell lung cancer. It is highly noteworthy that 28% of patients are still being treated with 1st-line osimertinib at three years versus 9% on either gefitinib or erlotinib."

Summary of FLAURA results

Tagrisso

(n=279)

EGFR-tyrosine kinase inhibitors (TKI)

(gefitinib or erlotinib)

(n=277)

Progression-free survival (PFS) (primary endpoint)i

Median in months

(95% CI)

18.9

(15.2, 21.4)

10.2 months

(9.6, 11.1)

Hazard ratio

(95% CI)

0.46

(0.37, 0.57)

p-value

p < 0.0001

OS (secondary endpoint)i

Hazard ratio

(95% CI)

0.799

(0.641-0.997)

p-value

p = 0.0462ii

Median in months

(95% CI)

38.6

(34.5-41.8)

31.8

(26.6-36.0)

Survival at 12 months

(95% CI)

89.1%

(84.8-92.2)

82.5%

(77.4-86.6)

Survival at 24 months

(95% CI)

74.2%

(68.6-79.0)

58.9%

(52.7-64.6)

Survival at 36 months

(95% CI)

53.7%

(47.5-59.5)

44.1%

(38.0-50.1)

CNS PFS (secondary endpoint)i,1

Hazard ratio

(95% CI)

0.48

(0.26-0.86)

p-value

p = 0.014

Median in months

(95% CI)

Not reached

(16.5-NC)iii

13.9

(8.3-NC)iii

Time to first subsequent therapy or death (TFST) (exploratory endpoint)i

Hazard ratio

(95% CI)

0.48

(0.39-0.58)

Number (%) of patients with events

69.5%

87.4%

Median in months

(95% CI)

25.5

(22.0, 29.1)

13.7

(12.3, 15.7)

Time to second subsequent therapy or death (TSST) (exploratory endpoint)i

Hazard ratio

(95% CI)

0.69

(0.56-0.84)

Number (%) of patients with events

64.5%

73.3%

Median in months

(95% CI)

31.1

(28.8, 35.9)

23.4

(20.0, 25.6)

Patients remaining on initial study treatment

12 months

69.5%

47.3%

24 months

42.3%

16.2%

36 months

28.0%

9.4%

I The data cut-off date was 25 June 2019 (OS, TFST, TSST) and 12 June 2017 (PFS, CNS PFS)

ii Criteria for statistical significance at the final analysis of OS was a p-value of less than 0.0495 (determined by O’Brien- Fleming approach)

iii NC=Not Calculable

In the FLAURA trial, the safety and tolerability of Tagrisso was consistent with its established profile. Tagrisso was generally well tolerated, with Grade 3 or higher adverse events (AEs) occurring in 42% of patients taking Tagrisso versus 47% in the comparator arm. The most common AEs in patients treated with Tagrisso were diarrhoea (60%), rash (59%), nail toxicity (39%), dry skin (38%), stomatitis (29%), fatigue (21%) and decreased appetite (20%). Despite almost twice the length of therapy, fewer patients experienced a grade 3 or higher AE (42% vs. 47%) or discontinued due to AEs (15% vs. 18%).

The FLAURA trial met its primary endpoint in July 2017, showing a statistically significant and clinically meaningful improvement in PFS, increasing the time patients lived without disease progression or death from any cause.

Tagrisso is currently approved in 78 countries, including the US, Japan, China and the EU, for 1st-line EGFR-mutated (EGFRm) metastatic NSCLC.

About lung cancer

Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths, more than breast, prostate and colorectal cancers combined.2 Lung cancer is broadly split into NSCLC and small cell lung cancer (SCLC), with 80-85% classified as NSCLC.3 Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.4-6 These patients are particularly sensitive to treatment with EGFR-TKIs which block the cell-signalling pathways that drive the growth of tumour cells. Approximately 25% of patients with EGFRm NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis.7 The presence of brain metastases often reduces median survival to less than eight months.8

About Tagrisso

Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI designed to inhibit both EGFR-sensitising and EGFR T790M-resistance mutations, with clinical activity against CNS metastases. Tagrisso 40mg and 80mg once-daily oral tablets have now received approval in more than 75 countries, including the US, Japan, China and the EU, for 1st-line EGFRm advanced NSCLC, and in more than 85 countries, including the US, Japan, China and the EU, for 2nd-line use in patients with EGFR T790M mutation-positive advanced NSCLC. Tagrisso is also being developed in the adjuvant setting (ADAURA trial), in the locally-advanced unresectable setting (LAURA), in combination with chemotherapy (FLAURA2) in the metastatic setting, and with potential new medicines to address resistance to EGFR-TKIs (SAVANNAH, ORCHARD).

About FLAURA

The FLAURA trial assessed the efficacy and safety of Tagrisso 80mg orally once daily versus comparator EGFR-TKIs (either gefitinib [250mg orally, once daily] or erlotinib [150mg orally, once daily]) in previously-untreated patients with locally-advanced or metastatic EGFRm NSCLC. The trial was double-blinded and randomised, with 556 patients across 29 countries.

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, and ongoing Phase III trials ADAURA, LAURA and FLAURA2 as well as the Phase II combination trials SAVANNAH and ORCHARD.4-6

Our extensive late-stage Immuno-Oncology programme focuses on lung cancer patients without a targetable genetic mutation which represents approximately three-quarters of all patients with lung cancer.9 Imfinzi (durvalumab), an anti-PDL1 antibody, is in development for patients with advanced disease (Phase III trials POSEIDON, PEARL, and CASPIAN) and for patients in earlier stages of disease including potentially-curative settings (Phase III trials AEGEAN, PACIFIC-2, ADRIATIC, ADJUVANT BR.31, PACIFIC-4, and PACIFIC-5) both as monotherapy and in combination with tremelimumab and/or chemotherapy.

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, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investments that accelerate the delivery of our strategy, as illustrated by the 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 September 28, 2019 AstraZeneca and MSD Inc., Kenilworth, N.J., US (MSD: known as Merck & Co., Inc. inside the US and Canada) reported detailed positive results from the Phase III PAOLA-1 trial, showing Lynparza (olaparib) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in women with newly-diagnosed advanced ovarian cancer (Press release, AstraZeneca, SEP 28, 2019, View Source [SID1234539869]).

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The trial compared Lynparza when added to standard-of-care (SoC) bevacizumab vs. bevacizumab alone in women in the 1st-line maintenance setting, irrespective of their genetic biomarker status or outcome from previous surgery. Investigator-assessed results showed Lynparza added to bevacizumab reduced the risk of disease progression or death by 41% (equal to a hazard ratio of 0.59) and improved PFS to a median of 22.1 months vs. 16.6 months for those treated with bevacizumab alone. At two years since trial initiation, 46% of women treated with Lynparza added to bevacizumab showed no disease progression vs. 28% of women receiving bevacizumab alone.

The sensitivity analysis of blinded independent central review (BICR) of PFS was consistent, showing a similar improvement with a median of 26.1 months for Lynparza added to bevacizumab vs. 18.3 months for bevacizumab alone. The safety and tolerability profile of Lynparza and bevacizumab were consistent with those known from previous trials for each medicine, and with no detriment to quality of life.

The results were presented during the Presidential Symposium of the 2019 European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) congress in Barcelona, Spain (Abstract #LBA2_PR).

The trial also included exploratory sub-group analyses including BRCA-mutated (BRCAm) and broader homologous recombination deficiency (HRD) populations, which showed treatment with Lynparza added to bevacizumab demonstrated greater benefit vs. bevacizumab alone. In the BRCAm-positive sub-group, Lynparza added to bevacizumab reduced the risk of disease progression or death by 69% (equal to a hazard ratio of 0.31). In the broader HRD-positive sub-group, which represents approximately half of women with newly-diagnosed advanced ovarian cancer and includes BRCAm, Lynparza added to bevacizumab reduced the risk of disease progression or death by 67% (equal to a hazard ratio of 0.33).

José Baselga, Executive Vice President, Oncology R&D, said: "This trial was designed to reflect everyday clinical practice using a global standard-of-care treatment with Lynparza. The results showed at two years nearly half of women with advanced ovarian cancer were progression-free with Lynparza added to bevacizumab as a 1st-line maintenance treatment, regardless of their biomarker status or surgical outcome. We are working with regulatory authorities to bring Lynparza to these patients as quickly as possible."

Roy Baynes, Senior Vice President and Head of Global Clinical Development, Chief Medical Officer, MSD Research Laboratories, said: "PAOLA-1 is the second positive Phase III trial involving Lynparza in the 1st-line maintenance setting for advanced ovarian cancer. Following the positive SOLO-1 trial, we are encouraged by the PAOLA-1 results which reaffirm AstraZeneca and MSD’s ongoing commitment to explore potential treatment options for more women with ovarian cancer."

Isabelle Ray-Coquard, principal investigator of the PAOLA-1 trial and medical oncologist, Centre Léon Bérard and President of the GINECO group, said: "The goal of 1st-line, including maintenance, treatment for women with newly-diagnosed advanced ovarian cancer is to delay relapse. Unfortunately, the risk of relapsing is high, as two out of three women relapse within three years of initial diagnosis. In PAOLA-1, the results of Lynparza added to bevacizumab were significant and have the potential to change clinical practice in how women with advanced ovarian cancer are treated in the 1st-line maintenance setting."

Summary of PFS in overall population

Median in months

Hazard Ratio

(95% CI)

Lynparza +

bevacizumab

bevacizumab alone

PFS (investigator assessed)

(n=806)

22.1

16.6

0.59 (0.49-0.72)

p<0.0001

PFS (BICR)

26.1

18.3

0.63 (0.51-0.77)

p<0.0001

Summary of PFS in exploratory subgroup analyses

Median in months

Hazard Ratio

(95% CI)

Lynparza +

bevacizumab

bevacizumab alone

PFS by BRCAm status

BRCAm (n=237)

37.2 i

21.7

0.31 (0.20-0.47)

Non-BRCAm (n=569)

18.9

16.0

0.71 (0.58-0.88)

PFS by HRD status

HRD-positive (n=387)

37.2 i

17.7

0.33 (0.25-0.45)

HRD-positive, non-BRCAm (n=152)

28.1 i

16.6

0.43 (0.28-0.66)

HRD-negative/unknown (n=419)

16.9

16.0

0.92 (0.72-1.17)

i The median PFS estimate is immature at this time (below 50% maturity) and will evolve with additional follow up

Overall Grade 3 or above adverse events (AEs) were 57% for Lynparza added to bevacizumab and 51% for bevacizumab alone. The most common AEs ≥20% were nausea (53%), fatigue (53%), hypertension (46%), anaemia (41%), lymphopenia (24%), vomiting (22%) and arthralgia (22%). Grade 3 or above AEs were hypertension (19%), anaemia (17%), lymphopenia (7%), neutropenia (6%), fatigue (5%), nausea (2%), diarrhoea (2%), leukopenia (2%) vomiting (1%) and abdominal pain (1%). AEs led to dose interruption in 54% of patients on Lynparza while 20% of patients discontinued treatment.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for the treatment of advanced ovarian cancer and metastatic breast cancer and has been used to treat over 25,000 patients worldwide. It is the only PARP inhibitor with positive Phase III trials in four different cancer types (ovarian, breast, pancreatic and prostate).

About PAOLA-1

PAOLA-1 is a double-blind Phase III trial testing the efficacy and safety of Lynparza added to SoC bevacizumab vs. bevacizumab alone, as a 1st-line maintenance treatment for newly-diagnosed advanced FIGO Stage III-IV high grade serous or endometroid ovarian, fallopian tube, or peritoneal cancer patients who had a complete or partial response to 1st-line treatment with platinum-based chemotherapy and bevacizumab.

PAOLA-1 is an ENGOT (European Network of Gynaecological Oncological Trial groups) trial, sponsored by ARCAGY Research (Association de Recherche sur les CAncers dont GYnécologiques) on behalf of GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein). ARCAGY-GINECO is an academic group specialising in clinical and translational research in patients’ cancers and a member of the GCIG (Gynecologic Cancer InterGroup).

About ovarian cancer

Ovarian cancer is the eighth most common cause of death from cancer in women worldwide. In 2018, there were nearly 300,000 new cases diagnosed and around 185,000 deaths.1 Most women are diagnosed with advanced (Stage III or IV) ovarian cancer and have a five-year survival rate of approximately 30%.2 For newly-diagnosed advanced ovarian cancer, the primary aim of treatment is to delay progression of the disease for as long as possible and maintain the patient’s quality of life with the intent of achieving complete remission or cure.3,4,5,6

About homologous recombination deficiency

Homologous recombination deficiencies (HRDs) encompass a wide range of genetic abnormalities, including BRCA mutations, that can be detected using tests. As the BRCA gene drives DNA repair via homologous recombination, mutation of this gene leads to HR deficiency thereby interfering with normal cell DNA repair mechanisms. BRCA mutations are just one of many HRDs which are found in up to half of all newly diagnosed advanced ovarian cancer patients and confer sensitivity to PARP inhibitors including Lynparza.

About Lynparza

Lynparza 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, 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 pathway.

Lynparza is currently approved in 64 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, the EU, Japan and several other countries as 1st-line maintenance treatment of BRCA-mutated advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 43 countries, including the US and Japan, for germline BRCA-mutated, 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 ovarian, breast and pancreatic cancers.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, is approved for the treatment of advanced ovarian cancer and metastatic breast cancer and has been used to treat over 25,000 patients worldwide. 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 GINECO

GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein) is the French Cooperative Group in Oncology labelled by INCA (Institut National du Cancer, or French NCI) developing and conducting gynaecological and metastatic breast cancer clinical trials at the national and international level. Founded in 1993, the GINECO group is a member of international consortia such as ENGOT and GCIG.

About ENGOT

ENGOT (European Network for Gynaecological Oncological Trial groups) is a research network of the European Society of Gynaecological Oncology (ESGO). Founded in 2007, ENGOT includes 21 cooperative groups from 25 European countries.

About GCIG

The GCIG (Gynecological Cancer InterGroup) aims to promote and facilitate high quality clinical trials in order to improve outcomes for women with gynaecological cancer. Founded in 1998, GCIG includes 23 cooperative groups from 28 countries worldwide.

About the AstraZeneca and MSD strategic oncology collaboration

In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US 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, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the 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 September 28, 2019 Seattle Genetics, Inc. (Nasdaq: SGEN) and Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") reported initial results from the phase 1 clinical trial EV-103. Forty-five patients were evaluated for safety with the combination of the investigational agent enfortumab vedotin and the immune therapy pembrolizumab in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for treatment with cisplatin-based chemotherapy (Press release, Astellas, SEP 28, 2019, View Source [SID1234539868]). The study met outcome measures for safety and exhibited encouraging clinical activity for this platinum-free combination in a first-line setting. The data will be presented during an oral session today at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 Congress in Barcelona, Spain (Abstract #901O).

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Enfortumab vedotin is a first-in-class antibody drug conjugate (ADC) that targets Nectin-4, a protein present on almost all urothelial tumor cells and associated with cancer formation.1

"Advanced urothelial cancer is an aggressive disease for which more options are needed, especially for patients who are ineligible for first-line treatment with cisplatin," said Dr. Christopher J. Hoimes, Director, Genitourinary Oncology, Case Comprehensive Cancer Center at University Hospitals Seidman Cancer Center, Cleveland, Ohio. "This study tests the combination of the investigational agent enfortumab vedotin with the PD-1 inhibitor pembrolizumab, in a biomarker unselected population. Initial results provide support for further development of enfortumab vedotin combinations in this and other settings of urothelial cancer."

Fifty-one percent of patients (23/45) had an adverse event greater than or equal to Grade 3. Among these events, an increase in lipase was the most frequent (13 percent; 6/45). Four patients (9 percent) discontinued treatment due to treatment-related adverse events, most commonly peripheral sensory neuropathy. There was one death deemed to be treatment-related by the investigator attributed to multiple organ dysfunction syndrome.

Treatment-related adverse events of clinical interest that were greater than or equal to Grade 3 were rash (11 percent; 5/45), hyperglycemia (7 percent; 3/45) and peripheral neuropathy (4 percent; 2/45); these rates were similar to those observed with enfortumab vedotin monotherapy.2 Eleven percent (5/45) of patients had treatment-related immune-mediated adverse events of clinical interest greater than or equal to Grade 3 that required the use of systemic steroids (one event each of pneumonitis, dermatitis bullous, hyperglycemia, tubulointerstitial nephritis, myasthenia gravis). None of the adverse events of clinical interest were Grade 5 events.

The data demonstrated the combination of enfortumab vedotin plus pembrolizumab shrank tumors in the majority of patients, resulting in a confirmed objective response rate (ORR) of 71 percent (32/45; 95% Confidence Interval (CI): 55.7, 83.6). The complete response (CR) rate was 13 percent (6/45). Fifty-eight percent (26/45) of patients had a partial response and 22 percent (10/45) had stable disease. Ninety-one percent of responses were observed at the first assessment.

"These data are encouraging and support further exploration of a potential platinum-free combination of pembrolizumab and the investigational agent enfortumab vedotin," said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.

"We are motivated by these results, and we will continue to study enfortumab vedotin alone and in combination with other agents in different stages of urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas.

Enfortumab vedotin is currently under review by the U.S. Food and Drug Administration (FDA) for the treatment of patients with locally advanced or metastatic urothelial cancer who have received a PD-1/L1 inhibitor and who have received a platinum-containing chemotherapy in a neoadjuvant/adjuvant, locally advanced or metastatic setting.

About the EV-103 Trial
EV-103 is an ongoing, multi-cohort, open-label, multicenter phase 1 trial of enfortumab vedotin alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive, locally advanced and first- and second-line metastatic urothelial cancer.

The dose escalation-cohort and expansion cohort A include locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. Patients were dosed in a 21-day cycle, receiving an intravenous (IV) infusion of enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At the time of this initial analysis, 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion cohort A) with locally advanced and/or metastatic urothelial cancer had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.

The primary outcome measure of the cohorts included in this analysis is safety. The analysis of these first cohorts included several of the study’s secondary objectives. Key secondary objectives related to efficacy include objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and overall survival (OS). DOR and OS were not mature at the time of analysis and will be included in a future analysis.

Additional cohorts in the EV-103 study will evaluate enfortumab vedotin:

with cisplatin or carboplatin in a first-line setting for metastatic disease;
in combination with pembrolizumab and carboplatin or cisplatin in first-line metastatic disease;
as a monotherapy or in combination with pembrolizumab in muscle invasive disease;
with pembrolizumab in second-line metastatic disease; and
with gemcitabine in first- or second-line metastatic disease.3
More information about enfortumab vedotin clinical trials can be found at clinicaltrials.gov.

About Urothelial Cancer
Urothelial cancer is the most common type of bladder cancer (90 percent of cases).4 In 2018, more than 82,000 people were diagnosed with bladder cancer in the United States. Globally, approximately 549,000 people were diagnosed with bladder cancer last year, and there were approximately 200,000 deaths worldwide.5

The recommended first-line treatment for patients with advanced urothelial cancer is a cisplatin-based chemotherapy. For patients who are ineligible for cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens.6

About Enfortumab Vedotin
Enfortumab vedotin is an investigational antibody-drug conjugate (ADC) composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE, using Seattle Genetics’ proprietary linker technology. Enfortumab vedotin targets Nectin-4, a cell adhesion molecule that is expressed on many solid tumors, and that has been identified as an ADC target by Astellas.

The safety and efficacy of enfortumab vedotin are under investigation and have not been established. There is no guarantee that the agent will receive regulatory approval or become commercially available for the uses being investigated.

On September 27, 2019, Rigel Pharmaceuticals, Inc., a Delaware corporation (the "Company") reported that it entered into a Credit and Security Agreement, dated as of September 27, 2019 (the "Closing Date") by and among the Company, the lenders party thereto from time to time and MidCap Financial Trust, as administrative agent and collateral agent ("Agent") (the "Term Loan Credit Agreement"), which provides for a $60 million term loan facility (Filing, 8-K, Rigel, SEP 27, 2019, View Source [SID1234552181]). The Term Loan Credit Agreement provides for (i) on the Closing Date, $10.0 million aggregate principal amount of term loans, (ii) at the Company’s option, until December 31, 2020, an additional $10.0 million term loan facility, (iii) at the Company’s option, until March 31, 2021, an additional $20.0 million term loan facility subject to the satisfaction of certain conditions ("Tranche Three") and (iv) at the Company’s option, until March 31, 2022, an additional $20.0 million term loan facility subject to the satisfaction of certain conditions ("Tranche 4") (collectively, the "Term Loans"). The Company used the proceeds of the Term Loans for general corporate purposes

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The obligations under the Term Loan Credit Agreement are secured by a perfected security interest in all of the Company’s assets except for intellectual property and certain other customary excluded property pursuant to the terms of the Term Loan Credit Agreement.

The Term Loans are subject to an origination fee of 0.25% of each funded tranche of Term Loans. The Company will pay the Agent an annual administrative fee of 0.25% of the amount borrowed under the Term Loans, payable annually. The Term Loans may be prepaid in full or in part through September 27, 2020 with payment of a 2.5% prepayment premium, after which they may be prepaid in full or in part through September 27, 2021 with payment of a 1.5% prepayment premium, after which they may be prepaid in full or in part through September 27, 2022 with payment of a 1.0% prepayment premium, after which they may be prepaid in full or in part with no prepayment premium. An additional 2.5% of the amount of Terms Loans advanced by the lenders will be due upon prepayment or repayment of the Term Loans in full.

The interest rate applicable to the Term Loans is LIBOR plus 5.65%, subject to a LIBOR floor of 1.50%. Commencing October 1, 2019, the Company initially will make interest-only payments for 24 months, followed by 36 months of amortization payments. The interest-only period will be extended to 36 months and again to 48 months upon the satisfaction of certain conditions set forth in the Term Loan Credit Agreement. All unpaid principal and accrued interest is due and payable in full no later than September 1, 2024.

The Term Loan Credit Agreement requires that the Company (i) upon both of (x) the draw of Tranche 3 or Tranche 4 and (y) cash falling below 1.25x Term Loans outstanding, maintain U.S. Tavalisse Net Revenue (as defined in the Term Loan Credit Agreement) in amounts set forth in the Term Loan Credit Agreement and (ii) upon the draw of Tranche 3 or Tranche 4, maintain cash and cash equivalents of at least $10.0 million. The Term Loan Credit Agreement also contains customary representations and warranties and customary affirmative and negative covenants, including, among other things, restrictions on indebtedness, liens, investments, mergers, dispositions, prepayment of other indebtedness and dividends and other distributions.

Events of default under the Term Loan Credit Agreement include: (i) failure by the Company to timely make payments due under the Term Loan Credit Agreement; (ii) material misrepresentations or misstatements in any representation or warranty by the Company when made; (iii) failure by the Company or its subsidiaries to comply with the covenants under the Term Loan Credit Agreement and other related agreements; (iv) certain defaults under a specified amount of other indebtedness of the Company or its subsidiaries; (v) insolvency or bankruptcy-related events with respect to the Company or any of its subsidiaries; (vi) certain undischarged judgments against the Company or its subsidiaries; (vii) certain ERISA-related events with respect to the Company or its subsidiaries above a specified amount; (viii) certain security interests or liens under the loan documents ceasing to be, or being asserted by the Company not to be, in full force and effect; (ix) the institution of criminal proceedings against the Company; (x) an event of default under the guarantee of the obligations under the Term Loan Credit Agreement; (xi) the prepayment of any subordinated debt other than as specifically permitted by the terms of such subordination; (xii) the occurrence of a Material Adverse Change (as defined in the Term Loan Credit Agreement); (xiii) certain adverse actions by the FDA or DEA with respect to certain products or which could be reasonably expected to result in a Material Adverse Change (as defined in the Term Loan Credit Agreement); (xiv) a default or material breach under certain specified material contracts and (xv) any loan document ceasing to be, or any challenge or assertion by the Company that such loan document is not, in full force and effect. If one or more events of default occurs and continues beyond any applicable cure period, the Agent may, with the consent of the lenders holding a majority of the loans and commitments under the facilities, or will, at the request of such lenders, terminate the commitments of the lenders to make further loans and declare all of the obligations of the Company under the Term Loan Credit Agreement to be immediately due and payable.

On September 27, 2019 Three Upstate Medical University professors reported that it will present work at the world’s second-largest cancer conference starting this weekend in Spain (Press release, SUNY Upstate, SEP 27, 2019, View Source [SID1234551517]).

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Jeffrey Ross, MD, Jeffrey Bogart, MD, and Gennady Bratslavsky, MD, will attend the annual European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, Sept. 27 to Oct. 1 in Barcelona, Spain. About 30,000 cancer specialists gather at ESMO (Free ESMO Whitepaper) each fall. It is an opportunity for oncology experts from around the world to share their latest research and findings.

"Many breakthroughs in anti-cancer drug trials are now being presented at the ESMO (Free ESMO Whitepaper) meeting," said Ross, an assistant professor of pathology at Upstate and medical director of Foundation Medicine in Cambridge, Massachusetts. Ross, who has attended ESMO (Free ESMO Whitepaper) many times over the years, said he is involved in eight Upstate projects that will be either presented or addressed at ESMO (Free ESMO Whitepaper). His recent research into a particularly deadly type of cancer called Carcinoma of Unknown Primary (CUP) site, will be presented by a colleague at this year’s Congress and is being highlighted by the organization as a significant study.

CUP affects about one in 15 patients with cancer. CUP patients are diagnosed when the cancer has already spread and no primary tumor can be located. Only one in 10 CUP patients survive for one year.

Ross is first author on the study, which showed that about one in three patients with CUP may be a candidate for targeted treatment or immunotherapy based on DNA changes in the tumor. Ross said a colleague will present the study and he will be available to answer questions. This paper is a follow-up to one that was published in 2015, Ross said.

"That paper allowed pharma to initiate a $100 million clinical trial to enroll patients for treatment based on the genomic findings of their cancer," he said.

Bogart, interim director of the Upstate Cancer Center, will present on "interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on the experimental thoracic radiotherapy (TRT) arms of CALGB 30610 (Alliance.)" And Bratslavsky, chair of Upstate’s urology department, will present on malignant pheochromocytoma and malignant paraganglioma.

Bogart said his research is based on a 10-year study of more than 700 patients throughout the country – including many treated at Upstate. The study involved varying radiation treatment plans for patients with small cell lung cancer.

"The trial is completed and we will have to follow up with these patients over the next several years," Bogart said. "The final question is one we don’t have the answer to yet and that is the best way to give radiation, which will have a big impact for how patients are treated in the future."

Bogart and Ross said Upstate’s involvement at an international conference like ESMO (Free ESMO Whitepaper) helps to further establish Upstate as a leader in cancer research.

"It’s exciting for Upstate Cancer Center to be a significant source of new information for cancer patients and to be on the cutting edge of this kind of cancer genomics research," Ross said. "It’s hopefully going to make the breadth of cancer work done at Upstate more well known. We’re doing more than just treating cancer patients. We’re doing basic and clinical research trying to help patients not just in Syracuse but everywhere."