Category: Healthcare

Based on a subgroup analysis, improvement in event-free survival (EFS) with the KEYTRUDA-based regimen was consistent across all PD-L1 expression subgroups, histology and stage

 

Exploratory subgroup analysis showed a reduction in EFS events with the KEYTRUDA perioperative regimen for patients with or without pathological complete response (pCR) compared with the chemotherapy-placebo regimen

 

KEYNOTE-671 is the eighth positive pivotal study evaluating a KEYTRUDA-based regimen in earlier stages of cancer and the seventh positive pivotal study in lung cancer

 

RAHWAY, N.J. — (BUSINESS WIRE) — Merck (NYSE: MRK), known as MSD outside of the United States and Canada, today announced positive results from the pivotal Phase 3 KEYNOTE-671 trial evaluating KEYTRUDA, Merck’s anti-PD-1 therapy, as a perioperative treatment regimen, which includes treatment before surgery (neoadjuvant) and after surgery (adjuvant), for patients with resectable stage II, IIIA or IIIB non-small cell lung cancer (NSCLC). After a median follow-up of 25.2 months, neoadjuvant KEYTRUDA plus chemotherapy followed by resection and adjuvant single-agent KEYTRUDA significantly improved EFS, reducing the risk of disease recurrence, progression or death by 42% (HR=0.58 [95% CI, 0.46-0.72]; p<0.00001) for patients with resectable stage II, IIIA or IIIB NSCLC versus neoadjuvant placebo plus chemotherapy followed by adjuvant placebo. For patients who received the KEYTRUDA-based regimen, median EFS was not reached (95% CI, 34.1-NR) versus 17 months (95% CI, 14.3-22) for patients who received chemotherapy alone.

The trial is continuing to allow for additional follow-up of overall survival (OS), the other dual primary endpoint. A favorable trend in OS was observed for the KEYTRUDA regimen versus pre-operative chemotherapy (HR 0.73 [95% CI, 0.54-0.99]; p=0.02124); with only 177 events, these OS data are not mature and did not reach statistical significance at the time of this interim analysis. The safety profile of the KEYTRUDA regimen was consistent with the safety profile in earlier stages and metastatic NSCLC, with no new safety concerns identified. These results are being presented today during a clinical science symposium, The Promise of Neoadjuvant Immunotherapy Across Solid Tumors, at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA100) and are also being simultaneously published in the New England Journal of Medicine.

 

In a subgroup analysis, improvement in EFS with the KEYTRUDA regimen was consistent across PD-L1 expression subgroups, histology and stage. Treatment with the KEYTRUDA-based regimen reduced the risk of EFS events regardless of PD-L1 expression versus the chemotherapy-placebo regimen (tumor proportion score [TPS] ≥50% [n=266] HR=0.42 [95% CI, 0.28-0.65]; TPS 1-49% [n=242] HR=0.51 [95% CI, 0.34-0.75]; TPS <1% [n=289] HR=0.77 [95% CI, 0.55-1.07]). The KEYTRUDA-based regimen also improved EFS compared with the chemotherapy-placebo regimen regardless of histology (nonsquamous [n=453] HR=0.58 [95% CI, 0.43-0.78]; squamous [n=344] HR=0.57 [95% CI, 0.41-0.77]) and stage (stage II [n=239] HR=0.65 [95% CI, 0.42-1.01]; stage IIIA [n=442] HR=0.54 [95% CI, 0.41-0.72]; stage IIIB [n=116] HR=0.52 [95% CI, 0.31-0.88]).

 

While achieving pCR is a predictor of better outcomes, an exploratory subgroup analysis showed the reduction in EFS events with the KEYTRUDA perioperative regimen was observed for patients with or without pCR (with pCR: HR=0.33 [95% CI, 0.09-1.22]; without pCR: HR=0.69 [95% CI, 0.55-0.86]).

 

“Historically, more than half of people with earlier stages of non-small cell lung cancer that has been surgically removed will experience recurrence,” said Dr. Heather Wakelee, thoracic medical oncologist and professor of medicine at Stanford Medicine, president of the International Association for the Study of Lung Cancer and principal investigator for KEYNOTE-671. “Results showed that a pembrolizumab-based regimen before and after surgery significantly reduced the risk of recurrence, progression or death by 42 percent versus pre-operative chemotherapy, regardless of PD-L1 expression and with or without a pathological complete response. These event-free survival data are very encouraging and support the potential of this perioperative approach for patients with resectable stage II, IIIA or IIIB non-small cell lung cancer.”

 

“These compelling new results build on previous studies of KEYTRUDA in earlier stages of disease across certain types of cancer, including non-small cell lung cancer,” said Dr. Marjorie Green, senior vice president and head of late-stage oncology, global clinical development, Merck Research Laboratories. “KEYNOTE-671 demonstrated statistically significant and clinically meaningful improvements in event-free survival for patients with stage II, IIIA or IIIB non-small cell lung cancer treated with the KEYTRUDA perioperative regimen compared with chemotherapy and surgery alone. We are working with the FDA and other global authorities to bring this new option to patients as quickly as possible.”

 

“These results are meaningful for the community of thoracic surgeons given the need for additional treatment options that can improve event-free survival for patients with resectable stage II, IIIA or IIIB non-small cell lung cancer,” said Dr. Jonathan Spicer, associate professor of surgery, McGill University, attending surgeon, division of thoracic and upper gastrointestinal surgery, Montreal General Hospital, McGill University Health Centre and KEYNOTE-671 investigator. “Notably, the results showed that the KEYTRUDA-based perioperative regimen did not impact the opportunity for a complete resection and improvements were seen regardless of if they achieved a pathological complete response or not.”

 

Merck previously announced that, based on these results, the U.S. Food and Drug Administration (FDA) has accepted a new supplemental Biologics License Application (sBLA) for KEYTRUDA for the treatment of patients with resectable stage II, IIIA, or IIIB (T3-4N2) NSCLC in combination with platinum-containing chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment. The FDA has set a Prescription Drug User Fee Act, or target action, date of Oct. 16, 2023.

 

 

In addition to KEYNOTE-671, seven other pivotal trials evaluating a KEYTRUDA-based regimen in patients with earlier stages of cancer met their primary endpoint(s). These trials included: KEYNOTE-057 in Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer; KEYNOTE-629 in cutaneous squamous cell carcinoma; KEYNOTE-716 in stage IIB and IIC melanoma; KEYNOTE-054 in stage III melanoma; KEYNOTE-091 in stage IB, II or IIIA NSCLC; KEYNOTE-564 in renal cell carcinoma; and KEYNOTE-522 in triple-negative breast cancer.

 

The seven positive pivotal studies in lung cancer include: KEYNOTE-189, KEYNOTE-407, KEYNOTE-042, KEYNOTE-024, KEYNOTE-010, KEYNOTE-091 and KEYNOTE-671.

 

Merck has an extensive clinical development program in lung cancer and is advancing multiple registration-enabling studies, with research directed at earlier stages of disease and novel combinations. Key studies in earlier stages of NSCLC and small cell lung cancer (SCLC) include KEYNOTE-671, KEYNOTE-091, KEYNOTE-867, KEYLYNK-012, KEYVIBE-006 and KEYLYNK-013.

 

As announced, data spanning more than 25 different types of cancer are being presented from Merck’s broad oncology portfolio and investigational pipeline at the 2023 ASCO Annual Meeting. A compendium of Merck’s presentations and posters is available here.

 

Study design and additional data from KEYNOTE-671

KEYNOTE-671 is a randomized, double-blind Phase 3 trial (ClinicalTrials.gov, NCT03425643) evaluating neoadjuvant KEYTRUDA plus chemotherapy, followed by resection and adjuvant KEYTRUDA as a single agent, versus placebo plus neoadjuvant chemotherapy, followed by resection and adjuvant placebo, in patients with resectable stage II, IIIA or IIIB (T3-4N2) NSCLC. The trial’s dual primary endpoints are EFS and OS. Key secondary endpoints include pCR and major pathological response (mPR). The study enrolled 797 patients who were randomly assigned (1:1) to receive either:

 

• KEYTRUDA (200 mg intravenously [IV] every three weeks [Q3W] for up to four cycles) plus chemotherapy (cisplatin [75 mg/m², IV; given on Day 1 of each cycle] and either gemcitabine [1000 mg/m², IV; given on Days 1 and 8 of each cycle or pemetrexed [500 mg/m², IV; given on Day 1 of each cycle]) as neoadjuvant therapy prior to surgery, followed by KEYTRUDA (200 mg IV Q3W for up to 13 cycles) as adjuvant therapy post-surgery (n=397) for up to 13 cycles, or;
• Placebo (saline IV Q3W for up to four cycles) plus chemotherapy (cisplatin [75 mg/m², IV; given on Day 1 of each cycle] and either gemcitabine [1000 mg/m², IV; given on Days 1 and 8 of each cycle] or pemetrexed [500 mg/m², IV; given on Day 1 of each cycle]) as neoadjuvant therapy prior to surgery, followed by placebo (saline IV Q3W for up to 13 cycles) as adjuvant therapy post-surgery (n=400) for up to 13 cycles.

 

As previously announced, KEYNOTE-671 met the dual primary endpoint of EFS at the first interim analysis. At two years, 62.4% of patients treated with the KEYTRUDA regimen were alive and did not experience an EFS event compared to 40.6% of patients treated with the chemotherapy-placebo regimen.

 

The KEYTRUDA-based perioperative treatment regimen also demonstrated statistically significant and clinically meaningful improvements in key secondary endpoints of pCR and mPR. In the study, 18.1% of patients treated with the KEYTRUDA plus chemotherapy regimen achieved pCR versus 4% of patients treated with pre-operative chemotherapy (difference: 14.2% (95% CI: 10.1-18.7); p<0.00001). Additionally, treatment with the KEYTRUDA plus chemotherapy regimen resulted in a 30.2% mPR rate, meaning 10% or less or their tumor cells remained after receiving perioperative treatment, versus 11% with chemotherapy alone (difference: 19.2% [95% CI: 13.9-24.7]; p<0.00001).

 

Among patients treated with pre-operative KEYTRUDA plus chemotherapy, 80.6% underwent definitive surgery compared to 75.5% who received chemotherapy alone. Of these patients, 92% and 84% had a complete resection (R0 resection), respectively.

 

Treatment-related adverse events (TRAEs) occurred in 96.7% of patients receiving the KEYTRUDA regimen (n=396) and 95% of patients receiving the chemotherapy-placebo regimen (n=399); Grade 3-5 TRAEs occurred in 44.9% versus 37.3%, respectively. Treatment-related adverse events led to discontinuation of all study treatment in 12.6% of patients treated with the KEYTRUDA regimen and 5.3% treated with the chemotherapy-placebo regimen. Treatment-related adverse events led to death in 1.0% of patients receiving the KEYTRUDA regimen (n=4) and 0.8% of patients receiving the chemotherapy-placebo regimen (n=3). No new safety concerns were identified.

 

Immune-mediated adverse events (AEs) and infusion reactions of any grade occurred in 25.3% of patients receiving the KEYTRUDA regimen and 10.5% of patients receiving the chemotherapy-placebo regimen. Grade 3-5 immune-mediated AEs and infusion reactions occurred in 5.8% versus 1.5%, respectively. The most common of these events (occurring in ≥10% of patients) was hypothyroidism (11.1%) in patients receiving the KEYTRUDA regimen. Immune-mediated AEs and infusion reactions led to death in 0.3% of patients receiving the KEYTRUDA regimen (n=1) and no patients receiving the chemotherapy-placebo regimen. Immune-mediated AEs and infusion reactions that led to discontinuation of all study treatment occurred in 5.1% of patients receiving the KEYTRUDA regimen and 0.8% of patients receiving the chemotherapy-placebo regimen.

 

About lung cancer

Lung cancer is the leading cause of cancer death worldwide. In 2020 alone, there were more than 2.2 million new cases and 1.8 million deaths from lung cancer globally. Non-small cell lung cancer is the most common type of lung cancer, accounting for about 81% of all cases. In the U.S., the overall five-year survival rate for patients diagnosed with lung cancer is 25%, which is a 21% improvement over the last five years. Improved survival rates are due, in part, to reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, screening, early detection and improving treatment rates remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. Only 5.8% of people in the U.S. who are eligible were screened for lung cancer in 2021.

 

About Merck’s research in lung cancer

Merck is advancing research aimed at transforming the way lung cancer is treated, with a goal of improving outcomes for patients affected by this deadly disease. Through nearly 200 clinical trials evaluating more than 36,000 patients around the world, Merck is at the forefront of lung cancer research. In NSCLC, KEYTRUDA has five approved U.S. indications (see indications below) and is approved for advanced disease in more than 95 countries. Among Merck’s research efforts are trials focused on evaluating KEYTRUDA in earlier stages of lung cancer as well as identifying new combinations and coformulations with KEYTRUDA.

 

About Merck’s early-stage cancer clinical program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

 

About KEYTRUDA^® (pembrolizumab) injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

 

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

 

Selected KEYTRUDA^® (pembrolizumab) Indications in the U.S.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) ≥1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

• stage III where patients are not candidates for surgical resection or definitive chemoradiation, or
• metastatic.

 

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

 

KEYTRUDA, as a single agent, is indicated as adjuvant treatment following resection and platinum-based chemotherapy for adult patients with stage IB (T2a ≥4 cm), II, or IIIA NSCLC.

 

See additional selected indications for KEYTRUDA in the U.S. after the Selected Important Safety Information

 

Selected Important Safety Information for KEYTRUDA

 

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

 

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

 

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

 

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

 

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

 

Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.

 

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

 

Hepatotoxicity and Immune-Mediated Hepatitis

 

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

 

KEYTRUDA With Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

 

Immune-Mediated Endocrinopathies

 

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.

Contacts

Media:

Julie Cunningham

(617) 519-6264

Nikki Sullivan

(718) 644-0730

Investor:

Peter Dannenbaum

(732) 594-1579

Damini Chokshi

(732) 594-1577

Read full story here

• DESTINY-PanTumor02 late-breaking interim data and DESTINY-CRC02 primary results further support potential of ENHERTU across multiple HER2 expressing cancers
• TROPION-Lung02 updated results continue to demonstrate promising clinical activity of datopotamab deruxtecan-based combinations in patients with non-small cell lung cancer
• Investor meeting to discuss ASCO presentations and oncology development updates

 

BASKING RIDGE, N.J. — (BUSINESS WIRE) — Daiichi Sankyo (TSE: 4568) will present new clinical research across its oncology portfolio at the 2023 American Society of Clinical Oncology Scientific Program (#ASCO23) and the European Hematology Association Congress (#EHA23).

 

Presentations at ASCO showcasing the company’s leadership in developing multiple innovative medicines for patients with cancer will include the DESTINY-PanTumor02 late-breaking (LBA #3000) and DESTINY-CRC02 oral presentations (#3501) evaluating ENHERTU^® (trastuzumab deruxtecan) across multiple HER2 expressing cancers. Data from DESTINY-PanTumor02 will be featured in an ASCO press briefing.

 

Additional data from Daiichi Sankyo’s DXd antibody drug conjugate (ADC) portfolio at ASCO include oral presentations featuring TROPION-Lung02 updated results of datopotamab deruxtecan (Dato-DXd)-based combinations in patients with advanced or metastatic non-small cell lung cancer (NSCLC) and the first results from BRE-354, a collaborative trial with Sarah Cannon Research Institute, evaluating patritumab deruxtecan (HER3-DXd) in patients with metastatic breast cancer.

 

Two analyses from the QuANTUM-First trial evaluating the addition of quizartinib to standard induction and consolidation chemotherapy followed by continuation monotherapy for the treatment of patients with newly diagnosed FLT3-ITD positive acute myeloid leukemia (AML) will be highlighted at EHA.

 

“Our data at ASCO and EHA represent another step forward in realizing our vision to create new standards of care for patients with cancer. Data from our ENHERTU clinical development program will be presented at ASCO showcasing how this medicine potentially may change the way HER2 targetable solid tumors are treated beyond breast, gastric and lung cancer,” said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. “New datopotamab deruxtecan-based combination data from our TROPION-Lung02 trial will be reported at ASCO along with analyses from our QuANTUM-First trial of quizartinib in newly diagnosed acute myeloid leukemia at EHA.”

 

ENHERTU Redefining HER2 Targetable Cancers

Data from an interim analysis of the DESTINY-PanTumor02 phase 2 trial evaluating ENHERTU in patients with pre-treated metastatic HER2 expressing solid tumors, including biliary tract, bladder, cervical, endometrial, ovarian, pancreatic and other rare cancers will be presented as a late-breaking presentation and included in an ASCO press briefing on Sunday, June 4.

 

In topline results from DESTINY-PanTumor02, ENHERTU demonstrated clinically meaningful and durable responses across many of these HER2 expressing cancers, potentially redefining how these tumors may be treated. The safety profile observed in the DESTINY-PanTumor02 trial was consistent with that seen in other trials of ENHERTU with no new safety signals identified.

 

Other ENHERTU data being presented include two oral presentations featuring the primary results from the DESTINY-CRC02 phase 2 trial evaluating ENHERTU in patients with previously treated HER2 overexpressing metastatic colorectal cancer and age-specific pooled analysis of ENHERTU from three global breast cancer trials (DESTINY-Breast01, DESTINY-Breast02 and DESTINY-Breast03).

 

Datopotamab Deruxtecan-Based Combinations Continuing to Show Promise in NSCLC

Updated results from the TROPION-Lung02 phase 1b trial evaluating datopotamab deruxtecan in combination with pembrolizumab with or without platinum-based chemotherapy in patients with previously untreated or pretreated advanced or metastatic NSCLC without actionable genomic alterations will be featured in an ASCO oral presentation.

 

Trials-in-progress presentations also will be featured including the TROPION-Lung04 phase 1b trial evaluating datopotamab deruxtecan in various immunotherapy combinations with or without carboplatin in patients with advanced or metastatic NSCLC, and the TROPION-PanTumor03 phase 2 trial evaluating datopotamab deruxtecan monotherapy as well as combination therapy with other anticancer treatments (immunotherapy, PARP inhibitor, VEGF inhibitor or chemotherapy) in patients with advanced/metastatic endometrial, gastric, ovarian, colorectal and castration-resistant prostate cancer.

 

Daiichi Sankyo will hold a hybrid investor meeting/conference call for investors on Monday, June 5, 2023 from 7:30 to 9:00 pm CDT / Tuesday, June 6, 2023 from 9:30 to 11:00 am JST. Executives from Daiichi Sankyo will provide an overview of the ASCO research data and address questions.

 

Highlights of data from Daiichi Sankyo’s DXd ADC portfolio at 2023 ASCO include:

Presentation Title		Author	Abstract #	Presentation
ENHERTU (trastuzumab deruxtecan; T-DXd)
Pan-Tumor	Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients with HER2 expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results	F. Meric-Bernstam	LBA 3000	Oral Presentation Monday, June 5 8:00 – 11:00 am CDT
GI	Trastuzumab deruxtecan (T-DXd) in patients with HER2 overexpressing/amplified (HER2+) metastatic colorectal cancer: primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study	K. Raghav	3501	Oral Presentation Sunday, June 4 8:00 – 11:00 am CDT
Breast	An age-specific pooled analysis of trastuzumab deruxtecan (T-DXd) in patients with HER2 positive metastatic breast cancer from DESTINY-Breast01, 02, and 03	I. Krop	1006	Oral Presentation Monday, June 5 11:30 am – 2:30 pm CDT
	Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice in patients with HER2 low, hormone receptor-positive unresectable and/or metastatic breast cancer: exploratory biomarker analysis of DESTINY-Breast04	S. Modi	1020	Poster Presentation Sunday, June 4 11:30 am – 1:00 pm CDT
	Interim real-world treatment patterns in patients with HER2+ unresectable or metastatic breast cancer: interim results from HER2 REAL Asia cohort	S. Lee	1047	Poster Presentation Sunday, June 4 8:00 – 11:00 am CDT
Lung	Analytical and clinical validation of Oncomine Dx Target (ODxT) test and local testing for identifying patients with HER2 (ERBB2) mutant non-small cell lung cancer for treatment with trastuzumab deruxtecan (T-DXd) in DESTINY-Lung01/02 (DL-01/02)	B. Li	9033	Poster Presentation Sunday, June 4 8:00 – 11:00 am CDT
Datopotamab Deruxtecan (Dato-DXd)
Lung	TROPION-Lung02: datopotamab deruxtecan (Dato-DXd) plus pembrolizumab with or without platinum chemotherapy in advanced non-small cell lung cancer	Y. Goto	9004	Oral Presentation Tuesday, June 6 9:45 am – 12:45 pm CDT
	TROPION-Lung04: phase 1b, multicenter study of datopotamab deruxtecan (Dato-DXd) in combination with immunotherapy ± carboplatin in advanced/metastatic non-small cell lung cancer	H. Borghaei	TPS3158	Poster Presentation Saturday, June 3 8:00 – 11:00 am CDT
Pan-Tumor	TROPION-PanTumor03: phase 2, multicenter study of datopotamab deruxtecan (Dato-DXd) as monotherapy and in combination with anticancer agents in patients with advanced/metastatic solid tumors	Y. Janjigian	TPS3153	Poster Presentation Saturday, June 3 8:00 – 11:00 am CDT
Patritumab Deruxtecan (HER3-DXd)
Breast	A phase 2 study of HER3-DXd in patients with metastatic breast cancer	E. Hamilton	1004		Oral Presentation Monday, June 5 11:30 am – 2:30 pm CDT

Quizartinib Analyses in Newly Diagnosed FLT3-ITD Positive AML

Two analyses of data from the QuANTUM-First phase 3 trial of quizartinib in combination with standard induction and consolidation chemotherapy and as continuation monotherapy in patients with newly diagnosed FLT3-ITD positive AML will be presented at EHA. An oral presentation will feature data reporting the impact of hematopoietic stem cell transplantation (HSCT) following first complete remission followed by up to three years of quizartinib monotherapy. An analysis of FLT3-ITD-specific measurable residual disease (MRD) and how it

impacted patient outcomes in QuANTUM-First will be reported in a poster presentation. The primary manuscript of the QuANTUM-First trial was recently published online in The Lancet along with approval received in Japan today for use in this AML patient population.

Highlights of data from Daiichi Sankyo at 2023 EHA include:

Presentation Title		Author	Abstract #	Presentation
Quizartinib
AML	Impact of allogeneic hematopoietic cell transplantation in first complete remission plus FLT3 inhibition with quizartinib in acute myeloid leukemia with FLT3-ITD: results from QuANTUM-First	R. Schlenk	S137	Oral Presentation Sunday, June 11 12:00 – 12:15 pm CEST
	QuANTUM-First trial: FLT3-ITD-specific measurable residual disease (MRD) clearance is associated with improved overall survival	M. Levis	P483	Poster Presentation Friday, June 9 6:00 – 7:00 pm CEST

 

About the DXd ADC Portfolio of Daiichi Sankyo

The DXd ADC portfolio of Daiichi Sankyo currently consists of five ADCs in clinical development across multiple types of cancer. The company’s clinical trial stage DXd ADCs include ENHERTU, a HER2 directed ADC and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Two additional ADCs including ifinatamab deruxtecan (I-DXd; DS-7300), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd; DS-6000), a CDH6 directed ADC, are being developed through a strategic early-stage research collaboration with Sarah Cannon Research Institute.

 

Designed using Daiichi Sankyo’s proprietary DXd ADC technology to target and deliver a cytotoxic payload inside cancer cells that express a specific cell surface antigen, each ADC consists of a monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

 

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan and raludotatug deruxtecan are investigational medicines that have not been approved for any indication in any country. Safety and efficacy have not been established.

 

ENHERTU U.S. Important Safety Information

Indications

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

• Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either:– In the metastatic setting, or– In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy

• Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
• Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapyThis indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

• Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms. Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

 

Contraindications

None.

Warnings and Precautions

Interstitial Lung Disease / Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU. Median time to first onset was 5 months (range: 0.9 to 23).

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).

 

Neutropenia

Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 10⁹/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 10⁹/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 65% of patients. Sixteen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 664). Febrile neutropenia was reported in 1.1% of patients.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

 

Left Ventricular Dysfunction

Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

In patients with metastatic breast cancer and HER2-mutant NSCLC treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.6% of patients, of which 0.4% were Grade 3.

Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)

In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.

 

Embryo-Fetal Toxicity

ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.

 

Additional Dose Modifications

Thrombocytopenia

For Grade 3 thrombocytopenia (platelets <50 to 25 x 10⁹/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 10⁹/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.

Adverse Reactions

Metastatic Breast Cancer and HER2-Mutant NSCLC (5.4 mg/kg)

The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 984 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, and DESTINY-Lung02. Among these patients 65% were exposed for >6 months and 39% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (71%), decreased hemoglobin (66%), decreased neutrophil count (65%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (47%), increased aspartate aminotransferase (48%), vomiting (44%), increased alanine aminotransferase (42%), alopecia (39%), increased blood alkaline phosphatase (39%), constipation (34%), musculoskeletal pain (32%), decreased appetite (32%), hypokalemia (28%), diarrhea (28%), and respiratory infection (24%).

HER2-Positive Metastatic Breast Cancer

DESTINY-Breast03

The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg intravenously every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30).

Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each).

ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), hypokalemia (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), respiratory infection (22%), headache (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%).

HER2-Low Metastatic Breast Cancer

DESTINY-Breast04

The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU.

Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each).

ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and hypokalemia (25%).

Contacts

Global:
Jennifer Brennan

Daiichi Sankyo, Inc.

jbrennan2@dsi.com
+ 1 908 900 3183 (mobile)

Japan:
Koji Ogiwara

Daiichi Sankyo Co., Ltd.

ogiwara.koji.ay@daiichisankyo.co.jp
+81 3 6225 1126 (office)

Investor Relations Contact:
DaiichiSankyoIR@daiichisankyo.co.jp

Read full story here