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 [SID1234539887]).

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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 Merck (NYSE: MRK), known as MSD outside the United States and Canada, reported detailed positive results from the Phase 3 PAOLA-1 trial showing LYNPARZA added to bevacizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) in women with newly-diagnosed advanced ovarian cancer who had a complete or partial response to first-line treatment with platinum-based chemotherapy and bevacizumab (Press release, Merck & Co, SEP 28, 2019, View Source [SID1234539882]).

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The trial compared LYNPARZA when added to standard-of-care (SoC) bevacizumab versus bevacizumab alone in women in the first-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% and improved PFS to a median of 22.1 months versus 16.6 months for those treated with bevacizumab alone (HR 0.59 [95% CI, 0.49-0.72], p<0.0001).

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 versus 18.3 months for bevacizumab alone (HR 0.63 [95% CI, 0.51-0.77], p<0.0001).

The safety and tolerability profile of LYNPARZA and bevacizumab were consistent with those known from previous trials for each medicine.

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

Dr. José Baselga, executive vice president, Oncology R&D, AstraZeneca, said, "This trial was designed to reflect everyday clinical practice and used a global standard-of-care treatment with LYNPARZA. We are working with regulatory authorities to bring LYNPARZA to these patients as quickly as possible."

Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, "PAOLA-1 is the second positive Phase 3 trial involving LYNPARZA in the first-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 Merck’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, Department of Medical Oncology at the Clinical Science Institute of the Léon Bérard Centre and President of the GINECO (Groupe d’Investigateurs National des Etudes des Cancers Ovariens et du sein) group, said, "The goal of first-line, including maintenance treatment for women with newly-diagnosed advanced ovarian cancer, is to delay relapse. Unfortunately, the risk of relapse 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 first-line maintenance setting."

The trial also included exploratory sub-group analyses including BRCA-mutated (BRCAm) and broader homologous recombination deficiency (HRD) populations. In the BRCAm-positive sub-group, LYNPARZA added to SoC bevacizumab vs. bevacizumab alone resulted in median PFS of 37.2 months versus 21.7 months (HR 0.31 [95% CI, 0.20-0.47]) and 18.9 months versus 16 months in the non-BRCAm sub-group (HR 0.71 [95% CI, 0.58-0.88]). For the HRD-positive sub-group, median PFS for LYNPARZA added to bevacizumab was 37.2 months versus 17.7 months with bevacizumab alone (HR 0.33 [95% CI, 0.25-0.45]). In the HRD-positive, non-BRCAm sub-group, there was a median PFS of 28.1 months with LYNPARZA added to bevacizumab versus 16.6 months on bevacizumab alone (HR 0.43 [95% CI, 0.28-0.66]). The HRD-negative/unknown sub-group results showed a median PFS of 16.9 months for LYNPARZA added to bevacizumab vs. 16 months for bevacizumab alone (HR 0.92 [95% CI, 0.72-1.17]).

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)

37.2i.

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)

37.2i.

17.7

0.33 (0.25-0.45)

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

28.1i.

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

The most common adverse events (AEs) ≥20% for LYNPARZA plus bevacizumab compared to bevacizumab alone were nausea (53% vs. 22%), fatigue (53% vs. 32%), hypertension (46% vs. 60%), anemia (41% vs. 10%), lymphopenia (24% vs. 10%), vomiting (22% vs. 11%) and arthralgia (22% vs. 24%). Overall Grade 3 or above (AEs) were 57% for LYNPARZA added to bevacizumab and 51% for bevacizumab alone. Grade 3 or above AEs were hypertension (19% vs. 30%), anemia (17% vs. 0.4%), lymphopenia (7% vs. 1%), fatigue (5% vs. 2%), neutropenia (6% vs 3%), nausea (2% vs. 1%), diarrhea (2% each), leukopenia (2% vs. 1%), vomiting (2% each) and abdominal pain (1% vs. 2% AEs led to dose interruption in 54% of patients on LYNPARZA plus bevacizumab vs. 24% on bevacizumab alone, while 20% of patients on LYNPARZA plus bevacizumab discontinued treatment vs. 6% on bevacizumab alone.

LYNPARZA, which is being jointly developed and commercialized by Merck and AstraZeneca, 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 U.S. as first-line maintenance treatment in BRCAm advanced ovarian cancer following response to platinum-based chemotherapy. It is also approved in 38 countries, including the U.S., countries in the EU, and Japan, for germline BRCAm HER2-negative metastatic breast cancer previously treated with chemotherapy; in the EU this includes locally advanced breast cancer. LYNPARZA has been used to treat over 25,000 patients worldwide.

LYNPARZA is the only PARP inhibitor with positive Phase 3 trials in four different cancer types.

About PAOLA-1

PAOLA-1 is a double-blind Phase 3 trial evaluating the efficacy and safety of LYNPARZA added to SoC bevacizumab vs. bevacizumab alone, as a first-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 first-line treatment with platinum-based chemotherapy and bevacizumab. The intent-to-treat* population refers to all patients randomized in the trial.

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).

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in <1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy, and some also had a history of more than one primary malignancy or of bone marrow dysplasia.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females

Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males

Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%), and dyspepsia (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

ADVERSE REACTIONS—Advanced gBRCAm ovarian cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—gBRCAm, HER2-negative metastatic breast cancer

Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in >25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

DRUG INTERACTIONS

Anticancer Agents: Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid concomitant use of strong or moderate CYP3A inhibitors. If a strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid concomitant use of strong or moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, there is a potential for decreased efficacy of LYNPARZA.

USE IN SPECIFIC POPULATIONS

Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No adjustment to the starting dose is necessary in patients with mild renal impairment (CLcr=51-80 mL/min), but patients should be monitored closely for toxicity. In patients with moderate renal impairment (CLcr=31-50 mL/min), reduce the dose to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

INDICATIONS

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCAm Advanced Ovarian Cancer

For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients with gBRCAm advanced epithelial ovarian, fallopian tube or primary peritoneal cancer for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer

For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Advanced gBRCAm ovarian cancer

For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

gBRCAm, HER2-negative metastatic breast cancer

In patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please click here for complete Prescribing Information, including Patient Information (Medication Guide).

About LYNPARZA (olaparib)

LYNPARZA is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. 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 tumor types with defects and dependencies in the DDR.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad and advanced clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.

About Ovarian Cancer

Ovarian cancer the eighth most common cause of death from cancer in women worldwide, with a five-year survival rate of approximately 19%. In 2018, there were nearly 300,000 new cases diagnosed and around 185,000 deaths.

About Homologous Recombination Deficiency (HRD)

Homologous recombination deficiencies (HRDs), including BRCA, cause genomic instability which can be detected using assays such as the Myriad My Choice HRD test. BRCA mutations are just one of many homologous recombination repair deficiencies which are found in up to half of newly diagnosed advanced ovarian cancer patients.

About GINECO

GINECO (Groupe d’Investigateurs Nationaux pour l’Étude 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 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 Merck 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-commercialize 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.

Merck’s Focus on Cancer

Our goal is to translate breakthrough science into innovative oncology medicines to help people with cancer worldwide. At Merck, the potential to bring new hope to people with cancer drives our purpose and supporting accessibility to our cancer medicines is our commitment. As part of our focus on cancer, Merck is committed to exploring the potential of immuno-oncology with one of the largest development programs in the industry across more than 30 tumor types. We also continue to strengthen our portfolio through strategic acquisitions and are prioritizing the development of several promising oncology candidates with the potential to improve the treatment of advanced cancers. For more information about our oncology clinical trials, visit www.merck.com/clinicaltrials.

On September 28, 2019 GlaxoSmithKline plc (LSE/NYSE: GSK) reported GSK3359609, an inducible T cell co-stimulatory (ICOS) agonist antibody designed to selectively enhance T cell function, showed promising anti-tumour activity in combination with pembrolizumab in PD-1/L1 naive patients with head and neck squamous cell carcinoma (HNSCC) (Press release, GlaxoSmithKline, SEP 28, 2019, View Source [SID1234539879]). Findings from the INDUCE-1 study also suggested GSK3359609 has single agent activity in patients with PD-1/L1 experienced HNSCC.

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The safety and tolerability profile of GSK3359609 was consistent with the results reported in the dose escalation phase of INDUCE-1. The data were presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2019 in Barcelona, Spain.

Dr. Axel Hoos, Senior Vice President and Head Oncology R&D, said: "Immunotherapies such as GSK3359609 are a critical part of our oncology pipeline and we are encouraged by the INDUCE-1 data demonstrating the potential of this agent to enhance anti-tumour activity beyond what PD-1 blockade alone has demonstrated. The clinical responses observed are encouraging and, based on precedent with CTLA-4 or PD-1, we aim to demonstrate the main effect of our ICOS agonist to be on improving survival for patients, which requires further study. Based on these results, we are initiating the INDUCE-3 registrational trial to investigate the potential survival benefit of GSK3359609 with pembrolizumab in first-line recurrent/metastatic HNSCC for patients who are PD-L1 positive."

The data presented stem from the expansion phase of INDUCE-1, a first-in-human, open-label study investigating GSK3359609 as a monotherapy and in combination with other regimens. Patients in the study had recurrent or metastatic HNSCC and had received up to five prior lines of therapy in the advanced setting. Patients in the monotherapy cohort had previously been treated with PD-1/L1 therapy and received 1 mg/kg GSK3359609. Patients in the combination cohort were naive to PD-1/L1 therapy and received 0.3 mg/kg GSK3359609 and 200 mg pembrolizumab. Patients in both cohorts were evaluated until disease progression or unacceptable toxicity, for up to two years.

In the 34 evaluable patients who received the combination therapy, the overall response rate was 24% (n=8; 95% CI: 11, 58.7). Responses in the combination cohort were durable with all responding patients maintaining benefit for 6 months or longer (median not reached; 95% CI: 4.2 months, NR); the median progression-free survival (PFS) was 5.6 months (95% CI: 2.4, 7.4). Of the 21 patients with known PD-L1 expression data, the majority of responders and patients with stable disease had PD-L1 score below 20. Of the 16 evaluable patients who received monotherapy, the overall response rate was 6% (n=1; 95% CI: 0.2, 30.2).

The INDUCE-1 study was conducted pursuant to an agreement between GSK and Merck & Co, Inc., Kenilworth, N.J., U.S.A. (known as MSD outside the U.S. and Canada). GSK is continuing its relationship with MSD to support the INDUCE-3 phase II/III combination trial to be initiated by the end of 2019.

HNSCC is a cancer that develops from squamous cells in the mucous membranes of the mouth, nose and throat, and is the seventh most common cancer worldwide with approximately 600,000 new cases diagnosed each year.[i] Although HNSCC occurs more frequently in men in their 50s or 60s, the incidence is increasing among younger individuals.[ii] HNSCC tumours are highly immunogenic and have an elevated expression of immune checkpoint modulators, including ICOS and PD-1.[iii]

GSK3359609 Clinical Development Programme
The clinical development programme for GSK3359609 looks to investigate the anti-tumour potential of targeting the ICOS receptor through an agonist antibody alone and in combination with other immune checkpoint therapies for the treatment of a range of tumour types.

GSK3359609 is not currently approved for use anywhere in the world.

GSK in Oncology
GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, cell therapy, cancer epigenetics and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, antibody drug conjugates and cells, either alone or in combination.

On September 28, 2019 GlaxoSmithKline plc (LSE/NYSE: GSK) reported results from PRIMA (ENGOT-OV26/GOG-3012), the Phase 3 randomised, double-blind, placebo-controlled study of Zejula (niraparib) as a maintenance therapy in women with first-line ovarian cancer following a response to platinum-based chemotherapy (Press release, GlaxoSmithKline, SEP 28, 2019, View Source [SID1234539878]). Niraparib treatment resulted in a 38% reduction in the risk of disease progression or death in the overall population (PFS, HR 0.62; 95% CI, 0.50–0.75; p<0.001).

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These results were driven by a clinically meaningful reduction in risk of progression in women with:

BRCA mutation tumours (risk reduction of 60%, HR 0.40 (95% CI, 0.27–0.62) p<0.001).
HR-deficient BRCA wild type tumours (risk reduction of 50%, HR 0.50 (95% CI, 0.30–0.83), p=0.006).
HR-proficient tumours (risk reduction of 32%, HR 0.68 (95% CI, 0.49–0.94), p=0.020).
The PRIMA study enrolled patients with a response to their first-line treatment with platinum-based chemotherapy including those with high risk of disease progression, a population with high unmet need and previously under-represented in first-line ovarian cancer studies.

Dr. Hal Barron, Chief Scientific Officer and President R&D, GSK said: "Ovarian cancer is the eighth most commonly occurring cancer in women worldwide and women with this devastating disease have a five-year survival rate of less than 50%. PRIMA is a landmark study as we believe these data have the potential to fundamentally change how women with ovarian cancer are treated."

In an interim analysis of overall survival (OS), niraparib also demonstrated an encouraging trend toward improvement in OS relative to placebo. A pre-planned interim analysis of OS numerically favoured niraparib in the overall population (HR 0.70; 95% CI 0.44-1.11). In the HR-deficient subgroup, 91% of women on niraparib were alive at 24 months vs. 85% for placebo (HR=0.61; 95% CI, 0.27-1.40). These data are not yet mature, and the significance is not fully known. The OS interim analysis also showed 81% of women receiving niraparib in the HR-proficient subgroup were alive at 24 months vs. 59% of women receiving placebo (HR=0.51; 95% CI, 0.27-0.97).

Dr. Antonio Gonzalez, co-director, department of medical oncology, Clinica Universidad de Navarra, and Primary Investigator for PRIMA said: "The PRIMA study demonstrated the importance of maintenance therapy and the benefit that niraparib provided to women with ovarian cancer. I believe that niraparib monotherapy after surgery and platinum-based chemotherapy could be an important new treatment option for patients."

Niraparib is not currently approved in the first-line ovarian cancer maintenance setting. GSK will share these data with the relevant health authorities and is on track to file by the end of the year.

The safety profile demonstrated in PRIMA did not differ from the established safety profile. The most common grade 3 or higher adverse events with niraparib included anaemia (31%), thrombocytopenia (29%), and neutropenia (13%). Implementation of an individualised dosing regimen based on body weight and/or platelet count reduced the incidence of haematological treatment-emergent adverse events. No new safety signals were identified. Validated patient reported outcomes indicate quality of life was similar between the niraparib and placebo treatment arms.

Niraparib is marketed in the United States and Europe under the trade name Zejula.

About PRIMA
PRIMA is a double-blind, randomised Phase 3 study designed to evaluate niraparib versus placebo in first-line Stage III or IV ovarian cancer patients. The study assessed the efficacy of niraparib as maintenance treatment, as measured by progression free survival. Patients with a response to first-line platinum chemotherapy were randomised 2:1 to niraparib or placebo. The trial was amended to include an individualised niraparib starting dose of 200 mg once-daily in patients with baseline weight <77kg and/or platelet count <150K/μL and 300 mg in all other patients.

About Zejula (niraparib)
Niraparib is indicated as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.

Niraparib is an oral, once-daily PARP inhibitor that is currently being evaluated in three pivotal trials. GSK is building a robust niraparib franchise by assessing activity across multiple tumour types and by evaluating several potential combinations of niraparib with other therapeutics. The ongoing development programme for niraparib includes a Phase 3 trial as first-line monotherapy maintenance treatment in patients with first-line ovarian cancer (the PRIMA trial), a Phase 3 study as a first-line triplet maintenance treatment in ovarian cancer (FIRST), a Phase 3 trial for the treatment of patients with germline BRCA-mutated, metastatic breast cancer (the BRAVO trial), and a Phase 2 study of niraparib combined with bevacizumab maintenance treatment in advanced ovarian cancer (OVARIO).

Several combination studies are also underway, including trials of niraparib plus pembrolizumab in metastatic, triple-negative breast cancer and advanced, platinum-resistant ovarian cancer (the TOPACIO trial). Janssen Biotech has licensed rights to develop and commercialise niraparib specifically for patients with prostate cancer worldwide, except in Japan.

Important Safety Information for ZEJULA
Myelodysplastic Syndrome/Acute Myeloid Leukaemia (MDS/AML), including some fatal cases, was reported in 1.4% of patients receiving ZEJULA vs 1.1% of patients receiving placebo in Trial 1 (NOVA), and 0.9% of patients treated with ZEJULA in all clinical studies. The duration of ZEJULA treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received prior chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Haematologic adverse reactions (thrombocytopenia, anaemia and neutropenia) have been reported in patients receiving ZEJULA. Grade ≥3 thrombocytopenia, anaemia and neutropenia were reported in 29%, 25%, and 20% of patients receiving ZEJULA, respectively. Discontinuation due to thrombocytopenia, anaemia, and neutropenia occurred, in 3%, 1%, and 2% of patients, respectively. Do not start ZEJULA until patients have recovered from haematological toxicity caused by prior chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically thereafter. If haematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a haematologist for further investigations.

Hypertension and hypertensive crisis have been reported in patients receiving ZEJULA. Grade 3-4 hypertension occurred in 9% of patients receiving ZEJULA vs 2% of patients receiving placebo in Trial 1, with discontinuation occurring in <1% of patients. Monitor blood pressure and heart rate monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Manage hypertension with antihypertensive medications and adjustment of the ZEJULA dose, if necessary.

Based on its mechanism of action, ZEJULA can cause foetal harm. Advise females of reproductive potential of the potential risk to a foetus and to use effective contraception during treatment and for 6 months after receiving their final dose. Because of the potential for serious adverse reactions from ZEJULA in breastfed infants, advise lactating women to not breastfeed during treatment with ZEJULA and for 1 month after receiving the final dose.

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥10% of patients included: thrombocytopenia (61%), anaemia (50%), neutropenia (30%), leukopenia (17%), palpitations (10%), nausea (74%), constipation (40%), vomiting (34%), abdominal pain/distention (33%), mucositis/stomatitis (20%), diarrhoea (20%), dyspepsia (18%), dry mouth (10%), fatigue/asthenia (57%), decreased appetite (25%), urinary tract infection (13%), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation (10%), myalgia (19%), back pain (18%), arthralgia (13%), headache (26%), dizziness (18%), dysgeusia (10%), insomnia (27%), anxiety (11%), nasopharyngitis (23%), dyspnoea (20%), cough (16%), rash (21%) and hypertension (20%).

Common lab abnormalities (Grades 1-4) in ≥25% of patients included: decrease in haemoglobin (85%), decrease in platelet count (72%), decrease in white blood cell count (66%), decrease in absolute neutrophil count (53%), increase in AST (36%) and increase in ALT (28%).

About Ovarian Cancer
Approximately 300,000 women are diagnosed with ovarian cancer each year. Ovarian cancer is the eighth most frequent cause of cancer death among women. Despite high response rates to platinum-based chemotherapy in the second-line advanced treatment setting, approximately 85% of patients will experience recurrence within two years. Late-line treatment options for patients with ovarian cancer are few, with the proportion of patients achieving an overall response typically less than 10% when treated with chemotherapy.

GSK in Oncology
GSK is focused on maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, cell therapy, cancer epigenetics and synthetic lethality. Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, antibody drug conjugates and cells, either alone or in combination.

On September 28, 2019 Roche (SIX: RO, ROG; OTCQX: RHHBY) reported that it will present new data at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2019 congress, the results of a number of studies in patients receiving Alecensa (alectinib) for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) (Press release, Hoffmann-La Roche, SEP 28, 2019, View Source [SID1234539877]).

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"The data presented at ESMO (Free ESMO Whitepaper) this year further demonstrate the well-established benefits of Alecensa, and confirm its use as the standard of care for newly diagnosed advanced or metastatic ALK-positive lung cancer patients," said Sandra Horning, MD, Roche’s Chief Medical Officer and Head of Global Product Development. "The positive results from our real-world data study further support the benefits we have seen from our Phase III clinical studies."

Real-world data results in patients with ALK-positive NSCLC
Insights utilising real-world data from the Flatiron Health database will be presented at the congress on Saturday 28 September (Abstract #1546P, 12:00 CEST). These data further support the benefits of Alecensa in the real-world setting, where real-world progression free survival (rwPFS), time to treatment discontinuation (TTD – used as a surrogate for real-world treatment duration) and overall survival (OS) were demonstrated to be longest in Alecensa treated patients with previously untreated ALK-positive NSCLC. The results also show that despite the established benefit of individual ALK inhibitors (ALKi) as first-line therapies and the inclusion of ALKi in many clinical guidelines, as recently as 2017 and 2018 more than 25% of patients with ALK-positive NSCLC received a non-ALKi as first-line therapy. Data were available for 620 patients with ALK-positive advanced NSCLC.

1L, first-line therapy; ALKi, ALK inhibitor; rwPFS, real-world progression-free survival; TTD, time to treatment discontinuation; OS, overall survival; NR, not reached (median survival estimate could not be calculated). 6 & 12-month probability is the event-free survival probability for the following events: progression, treatment discontinuation and death at 6 months and at 12 months, respectively.

Final PFS and updated Phase III ALEX data
Final PFS and updated results from the pivotal Phase III ALEX study, to be presented on Sunday 29 September during a poster discussion (Abstract #1484PD, 16:30 CEST), confirm the superior efficacy and tolerability of Alecensa in comparison to crizotinib in patients with untreated ALK-positive NSCLC, reducing the risk of disease worsening or death by 57% (hazard ratio [HR]=0.43, 95% CI: 0.32–0.58). Mature data show that Alecensa provides a median investigator-assessed progression free survival (PFS) of nearly three years (34.8 months, 95% CI: 17.7-not reached [NR]) versus 10.9 months (95% CI: 9.1–12.9) in those who received crizotinib.

Alecensa also demonstrated superior efficacy compared to crizotinib regardless of the presence of central nervous system (CNS) metastases at baseline. For those with CNS metastases, the median investigator-assessed PFS was 25.4 months for Alecensa versus 7.4 months for crizotinib (HR=0.37, 95% CI: 0.23–0.58). In those without CNS metastases, it was 38.6 months versus 14.8 months respectively (HR=0.46, 95% CI: 0.31–0.68). Despite longer median treatment duration with Alecensa versus crizotinib (27.7 months versus 10.8 months), the safety profile for Alecensa remains favourable; fewer Alecensa-treated patients experienced Grade 3–5 adverse events (AEs) (48.7% versus 55.0% crizotinib).

BFAST
On Monday 30 September (08:30 – 10:00 CEST, Abstract LBA81), Roche will also present results from the first cohort of the Phase II/III Blood First Assay Screening Trial (BFAST). BFAST is the first prospective trial to use blood-based next generation sequencing (NGS) as the sole method of identifying and assigning NSCLC patients to targeted therapy based on actionable genetic alterations without the need for tissue biopsy. The study utilised FoundationOne Liquid, Foundation Medicine’s liquid (blood) biopsy assay to detect fusions in circulating tumour DNA (ctDNA) from a simple blood draw to identify ALK status and consequently eligibility for Alecensa.

About the ALEX Study
ALEX (NCT02075840/B028984) is a randomised, multicentre, open-label, Phase III study evaluating the efficacy and safety of Alecensa versus crizotinib in treatment-naïve patients with ALK-positive NSCLC whose tumours were characterised as ALK-positive by the VENTANA ALK (D5F3) CDx Assay, a companion immunohistochemistry (IHC) test developed by Roche Tissue Diagnostics. Patients were randomised (1:1) to receive either Alecensa or crizotinib. The primary endpoint of the ALEX study was PFS as assessed by the investigator, and secondary endpoints include: Independent Review Committee (IRC)-assessed PFS, time to CNS progression, objective response rate (ORR), duration of response (DOR) and OS. The multicentre study was conducted in 303 people across 161 sites in 31 countries. OS data continue to be considered immature.

About the real-world data Study
The real-world data study is a retrospective cohort study that utilised US electronic health record data from Flatiron Health, a nationwide database containing de-identified patient-level structured and unstructured data, curated via technology-enabled abstraction. Treatment patterns and outcomes, including real-world progression free survival (rwPFS) and overall survival (OS) were extracted for first- or second-line therapy. Time to treatment discontinuation (TTD) was used as a surrogate for real-world treatment duration accounting for treatment beyond progression. Time-to-event analyses were performed using Kaplan-Meier methods. Patients included were diagnosed with stage IIIB-IV ALK-positive NSCLC between 01 January 2011 and 30 September 2018. Data were available for 620 patients with ALK-positive advanced NSCLC. An ALKi was given to 420/620 (67.7%) patients as first-line therapy.

About Alecensa
Alecensa (RG7853/AF-802/RO5424802/CH5424802) is a highly selective, CNS active, oral medicine created at Chugai Kamakura Research Laboratories and is being developed for people with NSCLC whose tumours are identified as ALK-positive. ALK-positive NSCLC is often found in younger people who have a light or non-smoking history. It is almost always found in people with a specific type of NSCLC called adenocarcinoma. Alecensa is now approved in 83 countries as an initial (first-line) treatment for ALK-positive, metastatic NSCLC, including in the US, Europe, Japan and China.

About Roche in lung cancer
Lung cancer is a major area of focus and investment for Roche, and we are committed to developing new approaches, medicines and tests that can help people with this deadly disease. Our goal is to provide an effective treatment option for every person diagnosed with lung cancer. We currently have five approved medicines to treat certain kinds of lung cancer and more than ten medicines being developed to target the most common genetic drivers of lung cancer or to boost the immune system to combat the disease.