On September 14, 2024 Johnson & Johnson (NYSE:JNJ) reported new data from the Phase 1b/2 OrigAMI-1 study, which showed RYBREVANT (amivantamab-vmjw) combined with chemotherapy (mFOLFOX6 [FOLFOX] or FOLFIRI) demonstrated promising rapid and durable antitumor activity in patients with RAS/BRAF wild-type (WT) metastatic colorectal cancer (mCRC) who have not previously received anti-epidermal growth factor receptor (EGFR) therapy (Press release, Johnson & Johnson, SEP 14, 2024, View Source [SID1234646574]). These data were presented in a mini-oral presentation at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2024 Congress.1

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"OrigAMI-1 is the first study to show RYBREVANT plus chemotherapy may provide clinically meaningful benefits to patients with metastatic colorectal cancer who have not received any EGFR-targeted treatments as their first or second line of therapy," said Filippo Pietrantonio, M.D., medical oncologist at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and presenting author.* "Notably, we saw 21 percent of patients proceed to curative intent surgery, showing the promise of RYBREVANT in patients in this setting."

In the study, patients receiving RYBREVANT plus chemotherapy were either in their first (26 percent) or second line (74 percent) of treatment for mCRC and had not been treated with specific anti-EGFR therapies. Patients receiving FOLFOX were oxaliplatin-naïve and patients receiving FOLFIRI were irinotecan-naïve. Response was assessed by the investigator per RECIST v1.1.** Forty-three patients were treated with RYBREVANT along with either FOLFOX (20 patients) or FOLFIRI (23 patients). The median follow-up period was 7.3 months for RYBREVANT plus FOLFOX and RYBREVANT plus FOLFIRI.1

Patients treated with RYBREVANT plus chemotherapy achieved an overall response rate (ORR) of 49 percent (95 percent confidence interval [CI], 33-65), median duration of response of 7.4 months (95 percent CI, 5.6-not estimable [NE]) and median progression-free survival of 7.5 months (95 percent CI, 7.4‒NE). Disease control was observed in 88 percent of patients (95 percent CI, 75-96). Clinically meaningful intrahepatic antitumor activity was observed among patients with liver metastases treated with RYBREVANT plus chemotherapy, demonstrating a significant reduction in liver tumors (ORR of 53 percent, disease control rate of 93 percent). Notably, nine (21 percent) patients were able to proceed to curative-intent surgery due to strong antitumor activity.1

The safety profile of RYBREVANT plus FOLFOX/FOLFIRI was manageable and consistent with each of the individual components, without any additive toxicity. No new safety signals were observed. The most frequent treatment-emergent adverse events were neutropenia, rash, stomatitis, infusion-related reactions (IRRs) and diarrhea. All IRRs were Grade 1 or 2 and there were no Grade 3 or higher IRR events reported. Treatment-related discontinuations of RYBREVANT were 10 percent for RYBREVANT plus FOLFOX and nine percent for RYBREVANT plus FOLFIRI.1

"Confirmation that RYBREVANT has activity beyond lung cancer, given its unique multi-targeted approach in inhibiting EGFR and MET, is a potentially important step forward for patients with EGFR inhibitor-naïve metastatic colorectal cancer," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "Colorectal cancer is the third most common cancer globally, representing about 10 percent of all cancer cases and the second leading cause of cancer-related deaths. Our commitment to advancing cancer care drives us to evaluate every possibility to improve patient outcomes, and these findings highlight the potential of RYBREVANT to help even more patients with cancer."

Pivotal Phase 3 registration trials evaluating RYBREVANT-based regimens as first- and second-line treatment in colorectal cancer are planned.

About the OrigAMI-1 Study

OrigAMI-1 (NCT05379595) is an open-label Phase 1b/2 study assessing the efficacy and safety of RYBREVANT plus mFOLFOX6 or FOLFIRI in anti-EGFR-naïve RAS/BRAF WT mCRC. Eligible patients were WT for KRAS, NRAS or BRAF genes based on circulating tumor DNA testing. Additionally, patients were required to have no amplification of the ERBB2/HER2 gene. In the RYBREVANT and chemotherapy cohorts, patients were either treatment-naïve or had received at least one prior line in the metastatic setting (no EGFR inhibitor treatment). The primary endpoint of the combination cohorts was to characterize the safety and confirm the dose of RYBREVANT plus mFOLFOX6 or FOLFIRI. Response was assessed by the investigator per RECIST v1.1.2

About RYBREVANT

RYBREVANT (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, is approved in the U.S., Europe, and in other markets around the world as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.3

RYBREVANT is approved in the U.S., Europe, and in markets around the world in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test.

RYBREVANT is approved in the U.S. in combination with LAZCLUZE (lazertinib) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, as detected by an FDA-approved test. A marketing authorization application (MAA) and type II extension of indication application were submitted to the European Medicines Agency (EMA) seeking approval of LAZCLUZE in combination with RYBREVANT based on the MARIPOSA study.

In November 2023, Johnson & Johnson submitted a supplemental Biologics License Application (sBLA) to the U.S. FDA for RYBREVANT in combination with chemotherapy for the treatment of patients with EGFR-mutated NSCLC who progressed on or after osimertinib based on the MARIPOSA-2 study. This indication was approved in Europe in August 2024.

In June 2024, Johnson & Johnson submitted a BLA to the U.S. FDA for the subcutaneous formulation of RYBREVANT in combination with LAZCLUZE for all currently approved or submitted indications of intravenous (IV) RYBREVANT in certain patients with NSCLC. A submission for the extension of the RYBREVANT marketing authorization (line extension) was also submitted to the EMA seeking approval for this indication.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC§ prefer next-generation sequencing–based strategies over polymerase chain reaction–based approaches for the detection of EGFR exon 20 insertion variants. The NCCN Guidelines include:

Amivantamab-vmjw (RYBREVANT) plus lazertinib (LAZCLUZE) as a Category 1 recommendation for first-line therapy in patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations.4 †‡
Amivantamab-vmjw (RYBREVANT) plus chemotherapy as a Category 1 recommendation for patients with locally advanced or metastatic NCSLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.4 †‡
Amivantamab-vmjw (RYBREVANT) plus carboplatin and pemetrexed as a Category 1 recommendation for first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a Category 2A recommendation for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.4 †‡
Amivantamab-vmjw (RYBREVANT) as a Category 2A recommendation for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.4 †‡
In addition to the Phase 1b/2 OrigAMI-1 study, RYBREVANT is being studied in multiple clinical trials, including:

The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT in combination with LAZCLUZE versus osimertinib and versus LAZCLUZE alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations.5
The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT (with or without LAZCLUZE) carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib.6
The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.7
The Phase 3 PALOMA-3 (NCT05388669) study assessing LAZCLUZE with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.8
The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.9
The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab subcutaneous delivery.10
The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT in patients with advanced NSCLC.11
The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT in combination with LAZCLUZE and LAZCLUZE as a monotherapy in patients with advanced NSCLC with EGFR mutations.12
The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT and capmatinib combination therapy in locally advanced or metastatic NSCLC.13
The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT and cetrelimab combination therapy in locally advanced or metastatic NSCLC.14
The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT in combination with LAZCLUZE in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.15
The Phase 1/2 swalloWTail (NCT06532032) study assessing RYBREVANT and docetaxel combination therapy in patients with metastatic NSCLC.16
The Phase 1b/2 OrigAMI-4 (NCT06385080) study assessing RYBREVANT monotherapy and in addition to standard-of-care therapeutic agents in patients with recurrent/metastatic head and neck squamous cell carcinoma.17
For more information, visit: View Source

About Colorectal Cancer

Colorectal cancer is the third most common cancer worldwide, accounting for approximately 10 percent of all cancer cases and is the second leading cause of cancer-related deaths worldwide.18 While it predominantly affects older individuals, recent research suggests that colorectal cancer is now being diagnosed in adults under the age of 50 at record rates.19

Left-sided colorectal cancer, which represents approximately 65 percent of cases, often has distinct characteristics that influence treatment strategies. Around half of colorectal cancer patients have mutations in the RAS genes, with KRAS being the most common mutation. While tumors with normal RAS and BRAF genes generally respond better to EGFR inhibitors, those with RAS and BRAF mutations – particularly on the left side – are associated with poorer outcomes.20

IMPORTANT SAFETY INFORMATION3,21

WARNINGS AND PRECAUTIONS

Infusion-Related Reactions

RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. The median time to IRR onset is approximately 1 hour.

RYBREVANT with LAZCLUZE

RYBREVANT in combination with LAZCLUZE can cause infusion-related reactions. In MARIPOSA (n=421), IRRs occurred in 63% of patients treated with RYBREVANT in combination with LAZCLUZE, including Grade 3 in 5% and Grade 4 in 1% of patients. The incidence of infusion modifications due to IRR was 54% of patients, and IRRs leading to dose reduction of RYBREVANT occurred in 0.7% of patients. Infusion-related reactions leading to permanent discontinuation of RYBREVANT occurred in 4.5% of patients receiving RYBREVANT in combination with LAZCLUZE.

RYBREVANT with Carboplatin and Pemetrexed

In PAPILLON (n=151), infusion-related reactions occurred in 42% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (1.3%) adverse reactions. The incidence of infusion modifications due to IRR was 40%, and 0.7% of patients permanently discontinued RYBREVANT.

RYBREVANT as a Single Agent

In CHRYSALIS (n=302), IRR occurred in 66% of patients treated with RYBREVANT. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT due to IRR.

Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended. Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. Monitor patients for signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity.

Interstitial Lung Disease/Pneumonitis

RYBREVANT can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.

RYBREVANT with LAZCLUZE

In MARIPOSA, ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT in combination with LAZCLUZE, including Grade 3 in 1.0% and Grade 4 in 0.2% of patients. There was one fatal case (0.2%) of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT and LAZCLUZE due to ILD/pneumonitis.

RYBREVANT with Carboplatin and Pemetrexed

In PAPILLON, Grade 3 ILD/pneumonitis occurred in 2.6% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, all patients required permanent discontinuation.

RYBREVANT as a Single Agent

In CHRYSALIS, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). For patients receiving RYBREVANT in combination with LAZCLUZE, immediately withhold both drugs in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. For patients receiving RYBREVANT as a single agent or in combination with carboplatin and pemetrexed, immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT and LAZCLUZE

RYBREVANT in combination with LAZCLUZE can cause serious and fatal venous thromboembolic (VTEs) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of therapy.

In MARIPOSA, VTEs occurred in 36% of patients receiving RYBREVANT in combination with LAZCLUZE, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT, and 7% of patients had VTE leading to dose interruptions of LAZCLUZE; 1% of patients had VTE leading to dose reductions of RYBREVANT, and 0.5% of patients had VTE leading to dose reductions of LAZCLUZE; 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT, and 1.9% of patients had VTE leading to permanent discontinuation of LAZCLUZE. The median time to onset of VTEs was 84 days (range: 6 to 777).

Administer prophylactic anticoagulation for the first four months of treatment. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.

Withhold RYBREVANT and LAZCLUZE based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT and LAZCLUZE at the same dose level at the discretion of the healthcare provider. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT and continue treatment with LAZCLUZE at the same dose level at the discretion of the healthcare provider.

Dermatologic Adverse Reactions

RYBREVANT can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin.

RYBREVANT with LAZCLUZE

In MARIPOSA, rash occurred in 86% of patients treated with RYBREVANT in combination with LAZCLUZE, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions occurred in 37% of patients for RYBREVANT and 30% for LAZCLUZE, rash leading to dose reductions occurred in 23% of patients for RYBREVANT and 19% for LAZCLUZE, and rash leading to permanent discontinuation occurred in 5% of patients for RYBREVANT and 1.7% for LAZCLUZE.

RYBREVANT with Carboplatin and Pemetrexed

In PAPILLON, rash occurred in 89% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (19%) adverse reactions. Rash leading to dose reductions occurred in 19% of patients, and 2% permanently discontinued RYBREVANT and 1.3% discontinued pemetrexed.

RYBREVANT as a Single Agent

In CHRYSALIS, rash occurred in 74% of patients treated with RYBREVANT as a single agent, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients.

Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT as a single agent.

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT or LAZCLUZE in combination with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.

When initiating RYBREVANT treatment with or without LAZCLUZE, administer alcohol-free emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g. use of oral antibiotics) to reduce the risk of dermatologic reactions. If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. For patients receiving RYBREVANT in combination with LAZCLUZE, withhold, dose reduce or permanently discontinue both drugs based on severity. For patients receiving RYBREVANT as a single agent or in combination with carboplatin and pemetrexed, withhold, dose reduce or permanently discontinue RYBREVANT based on severity.

Ocular Toxicity

RYBREVANT can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.

RYBREVANT with LAZCLUZE

In MARIPOSA, ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with LAZCLUZE, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT and continue LAZCLUZE based on severity.

RYBREVANT with Carboplatin and Pemetrexed

In PAPILLON, ocular toxicity including blepharitis, dry eye, conjunctival redness, blurred vision, and eye pruritus occurred in 9%. All events were Grade 1-2.

RYBREVANT as a Single Agent

In CHRYSALIS, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2.

Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT and LAZCLUZE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus.

Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT.

Advise females of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LAZCLUZE and for 3 weeks after the last dose.

Adverse Reactions

RYBREVANT with LAZCLUZE

For the 421 patients in the MARIPOSA clinical trial who received RYBREVANT in combination with LAZCLUZE, the most common adverse reactions (≥20%) were rash (86%), nail toxicity (71%), infusion-related reactions (RYBREVANT, 63%), musculoskeletal pain (47%), stomatitis (43%), edema (43%), VTE (36%), paresthesia (35%), fatigue (32%), diarrhea (31%), constipation (29%), COVID-19 (26%), hemorrhage (25%), dry skin (25%), decreased appetite (24%), pruritus (24%), nausea (21%), and ocular toxicity (16%). The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased albumin (8%), decreased sodium (7%), increased ALT (7%), decreased potassium (5%), decreased hemoglobin (3.8%), increased AST (3.8%), increased GGT (2.6%), and increased magnesium (2.6%).

Serious adverse reactions occurred in 49% of patients who received RYBREVANT in combination with LAZCLUZE. Serious adverse reactions occurring in ≥2% of patients included VTE (11%), pneumonia (4%), ILD/pneumonitis and rash (2.9% each), COVID-19 (2.4%), and pleural effusion and infusion-related reaction (RYBREVANT) (2.1% each). Fatal adverse reactions occurred in 7% of patients who received RYBREVANT in combination with LAZCLUZE due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction, and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD/pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each).

RYBREVANT with Carboplatin and Pemetrexed

For the 151 patients in the PAPILLON clinical trial who received RYBREVANT in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (90%), nail toxicity (62%), stomatitis (43%), infusion-related reaction (42%), fatigue (42%), edema (40%), constipation (40%), decreased appetite (36%), nausea (36%), COVID-19 (24%), diarrhea (21%), and vomiting (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin (7%), increased alanine aminotransferase (4%), increased gamma-glutamyl transferase (4%), decreased sodium (7%), decreased potassium (11%), decreased magnesium (2%), and decreases in white blood cells (17%), hemoglobin (11%), neutrophils (36%), platelets (10%), and lymphocytes (11%).

Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥2% of patients included rash, pneumonia, ILD, pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified.

RYBREVANT as a Single Agent

For the 129 patients in the CHRYSALIS clinical trial who received RYBREVANT as a single agent, the most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%).

Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death.

LAZCLUZE Drug Interactions

Avoid concomitant use of LAZCLUZE with strong and moderate CYP3A4 inducers. Consider an alternate concomitant medication with no potential to induce CYP3A4.

Monitor for adverse reactions associated with a CYP3A4 or BCRP substrate where minimal concentration changes may lead to serious adverse reactions, as recommended in the approved product labeling for the CYP3A4 or BCRP substrate.

Please read full Prescribing Information for RYBREVANT.

Please read full Prescribing Information for LAZCLUZE.

On September 9, 2024 Daiichi Sankyo reported the results from the DESTINY-Breast12 phase 3b/4 trial showed that ENHERTU (trastuzumab deruxtecan) demonstrated substantial overall and intracranial clinical activity in a large cohort of patients with HER2 positive metastatic breast cancer who have brain metastases and received no more than two prior lines of therapy in the metastatic setting (Press release, Daiichi Sankyo, SEP 13, 2024, View Source [SID1234646592]). Results will be presented today as a late-breaking proffered paper presentation (LBA18) at the European Society for Medical Oncology (#ESMO24) and simultaneously published in Nature Medicine.

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ENHERTU is a specifically engineered HER2 directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo (TSE: 4568) and being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca (LSE/STO/Nasdaq: AZN).

In the primary endpoint analysis of progression-free survival (PFS) assessed by independent central review in patients with brain metastases at baseline (n=263), ENHERTU achieved a 12-month PFS rate of 61.6% (95% confidence interval [CI]: 54.9-67.6). In an additional endpoint analysis in this patient population, ENHERTU demonstrated a central nervous system (CNS) 12-month PFS rate of 58.9% (95% CI: 51.9-65.3). Results were consistent in patients with stable and active brain metastases. Patients with stable brain metastases (n=157) had a 12-month PFS rate of 62.9% (95% CI: 54.0-70.5) and a 12-month CNS PFS rate of 57.8% (95% CI: 48.2-66.1). Patients with active brain metastases (n=106) had a 12-month PFS rate of 59.6% (95% CI: 49.0-68.7) and a 12-month CNS PFS rate of 60.1% (95% CI: 49.2-69.4).

In the primary endpoint analysis of confirmed objective response rate (ORR) assessed by independent central review in patients with no brain metastases at baseline (n=241), ENHERTU demonstrated an ORR of 62.7% (95% CI: 56.5-68.8) with 23 complete responses (CR) and 128 partial responses (PR).

An additional endpoint analysis of CNS ORR in patients with brain metastases at baseline showed ENHERTU demonstrated a CNS ORR of 62.3% (95% CI: 50.1-74.5; n=38/61) in patients with active brain metastases and 79.2% (95% CI: 70.2-88.3; n=61/77) in patients with stable brain metastases. A post-hoc analysis in patients with active brain metastases showed the CNS ORR was 82.6% (95% CI: 67.1-98.1; n=19/23) in untreated patients and 50.0% (95% CI: 34.1-65.9; n=19/38) in patients with treated/progressing brain metastases.

"Up to fifty percent of patients with HER2 positive metastatic breast cancer experience the spread of disease to the brain during the course of their illness, which significantly impacts quality of life and outcomes," said Nancy Lin, MD, Associate Chief, Division of Breast Oncology, Dana-Farber Cancer Institute, Boston, MA, U.S. and Principal Investigator for the trial. "These data help further characterize the clinical benefit and safety profile of ENHERTU in these patients, which will help guide treatment decisions."

The safety profile of ENHERTU in DESTINY-Breast12 was consistent with previous breast cancer clinical trials with no new safety concerns identified. The safety profile of DESTINY-Breast12 was generally consistent between the brain metastases and non-brain metastases cohorts. The most common grade 3 or higher adverse events occurring in 5% or more of patients in either cohort included neutropenia (16% in brain metastases and 18% in non-brain metastases), fatigue (9% in brain metastases and 10% in non-brain metastases), anemia (7% in brain metastases and 5% in non-brain metastases) and nausea (5% in brain metastases and 5% in non-brain metastases). Interstitial lung disease (ILD) or pneumonitis occurred in 16.0% of patients in the brain metastases cohort and 12.9% of patients in the non-brain metastases cohort as determined by the investigator. In the brain metastases cohort, there were 26 grade 1 events, eight grade 2 events, one grade 3 event, one grade 4 event and six grade 5 events as determined by the investigator. Five ILD or pneumonitis events in the brain metastases cohort were reported by the investigator as co-occurring with opportunistic infection (one grade 4 and four grade 5). In the non-brain metastases cohort, there were 22 grade 1 ILD events, six grade 2 events, zero grade 3 and 4 events, and three grade 5 events as determined by the investigator.

"Treating brain metastases in patients with breast cancer is challenging as there are few effective treatment options," said Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo. "Building on previous studies, these results show ENHERTU can provide strong overall and intracranial clinical activity and support its potential role in treating patients with active or stable brain metastases."

"The results from DESTINY-Breast12 show substantial clinical activity for patients whose disease has spread to the brain," said Sunil Verma, MD, Global Head, Oncology Franchise, AstraZeneca. "These data as well as the results in patients without brain metastases further build confidence in the clinical profile of ENHERTU for the second-line treatment of HER2 positive metastatic breast cancer."

Patients in the DESTINY-Breast12 trial received no more than two prior lines of therapy in the metastatic setting. Median duration of follow-up was 15.4 months (range 0.1-30.0) in the brain metastases cohort and 16.1 months (range 0.8-28.4) in the non-brain metastases cohort. A total of 213 patients (118 in the brain metastases cohort and 95 in the non-brain metastases cohort) remained on treatment as of the data cut-off of February 8, 2024.

Summary of DESTINY-Breast12 Primary Analysis Results

Efficacy Measure

Baseline Brain Metastases

(Cohort 2)

No Baseline Brain Metastases (Cohort 1)

Overall Population

(n=263)

Stable Brain Metastases

(n=157)i

Active Brain Metastases

(n=106)ii

Overall Population

(n=241)iii

12-month PFS Rate (%)iv

(95% CI)

61.6%

(54.9-67.6)

62.9%

(54.0-70.5)

59.6%

(49.0-68.7)

—

12-month CNS PFS Rate (%)v

(95% CI)

58.9%

(51.9-65.3)

57.8%

(48.2-66.1)

60.1%

(49.2-69.4)

—

12 month OS Rate (%)

(95% CI)

90.3%

(85.9-93.4)

—

—

90.6%

(86.0-93.8)

Confirmed ORR (%)vi, vii

(95% CI)

51.7%

(45.7-57.8)

49.7%

(41.9-57.5)

54.7%

(45.2-64.2)

62.7%

(56.5-68.8)

CR % (n)

4.2% (11)

—

—

9.5% (23)

PR % (n)

47.5% (125)

—

—

53.1% (128)viii

Confirmed CNS ORR (%) (n)

(95% CI)ix

71.7% (138)

(64.2-79.3)

79.2% (77)

(70.2-88.3)

62.3% (61)

(50.1-74.5)

—

CI, confidence interval; CNS, central nervous system; CR, complete response; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PR, partial response

i Stable brain metastases (previously treated)

ii Active brain metastases (untreated or previously treated / progressing [not requiring immediate local therapy])

iii Includes 26 patients with no measurable disease at baseline

iv Primary endpoint for baseline brain metastases was median PFS with 42.2% data maturity at time of data cut-off (February 8, 2024); post-hoc analysis showed median PFS of 17.3 months (95% CI: 13.7-22.1)

v Patients who had systemic progression, but no CNS progression, were censored at the time of the progression assessment; the analysis did not account for systemic progression as a competing event

vi Primary endpoint for no baseline brain metastases cohort (cohort 1)

vii ORR is (CR + PR)

viii One patient with no measurable disease at baseline was assigned PR by ICR

ix Analysis of CNS ORR was in patients with measurable CNS disease at baseline

About DESTINY-Breast12
DESTINY-Breast12 is an open-label, multicenter, phase 3b/4 clinical trial designed to evaluate the efficacy and safety of ENHERTU (5.4 mg/kg) in patients with previously treated advanced/metastatic HER2 positive breast cancer. The study includes patients with or without baseline brain metastases who have experienced disease progression following prior anti-HER2-based regimens and have received no more than two lines of therapy in the metastatic setting. Patients were enrolled into one of two cohorts according to the presence or absence of brain metastases at baseline.

The primary endpoints of DESTINY-Breast12 were PFS (brain metastases cohort; cohort 2) or ORR (non-brain metastases cohort; cohort 1) as assessed by independent central review. Additional endpoints included CNS PFS, CNS ORR, ORR in the brain metastases cohort and safety.

DESTINY-Breast12 enrolled 504 patients across multiple sites in Asia, Europe, North America and Oceania. For more information about the trial, visit ClinicalTrials.gov.

About Breast Cancer, HER2 Expression and Brain Metastases
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.1 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.1 While survival rates are high for those diagnosed with early breast cancer, only about 30% of patients diagnosed with or who progress to metastatic disease are expected to live five years following diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers.3 HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis in breast cancer.4 Approximately one in five cases of breast cancer are considered HER2 positive.5

Brain metastases occur when cancer cells spread from their original location to the brain. An estimated 10% to 15% of patients diagnosed with metastatic breast cancer will develop brain metastases.6 The risk is higher for those with HER2 positive or triple negative metastatic breast cancer, with brain metastases occurring in 30% to 50% of these patients.7

The median overall survival for patients with breast cancer who have developed brain metastases is eight months; however, this varies based on subtype and the availability of effective treatments.8 Current guidelines do not recommend screening patients with breast cancer for brain metastases. As a result, when brain metastases are eventually diagnosed, patients may already present with advanced disease.7

About ENHERTU
ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC Technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

ENHERTU (5.4 mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 positive (immunohistochemistry [IHC] 3+ or in-situ hybridization (ISH)+) 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 based on the results from the DESTINY-Breast03 trial.

ENHERTU (5.4 mg/kg) is approved in more than 65 countries worldwide for the treatment of adult patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy based on the results from the DESTINY-Breast04 trial.

ENHERTU (5.4 mg/kg) is approved in more than 35 countries worldwide for the treatment of adult patients with unresectable or metastatic NSCLC whose tumors have activating HER2 (ERBB2) mutations, as detected by a locally or regionally approved test, and who have received a prior systemic therapy based on the results from the DESTINY-Lung02 trial. Continued approval in the U.S. for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

ENHERTU (6.4 mg/kg) is approved in more than 45 countries worldwide for the treatment of adult patients with locally advanced or metastatic HER2 positive (IHC 3+ or IHC 2+/ISH+) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01, DESTINY-Gastric02 and/or DESTINY-Gastric06 trials. Full approval in China for this indication will depend on whether a randomized controlled confirmatory clinical trial can demonstrate clinical benefit in this population.

ENHERTU (5.4 mg/kg) is approved in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options based on efficacy results from the DESTINY-PanTumor02, DESTINY-Lung01 and DESTINY-CRC02 trials. Continued approval for this indication in the U.S. may be contingent upon verification and description of clinical benefit in a confirmatory trial.

About the ENHERTU Clinical Development Program
A comprehensive global clinical development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

About the Daiichi Sankyo and AstraZeneca Collaboration
Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

About the ADC Portfolio of Daiichi Sankyo
The Daiichi Sankyo ADC portfolio consists of seven ADCs in clinical development crafted from two distinct ADC technology platforms discovered in-house by Daiichi Sankyo.

The ADC platform furthest in clinical development is Daiichi Sankyo’s DXd ADC Technology where 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. The DXd ADC portfolio currently consists of ENHERTU, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca. Patritumab deruxtecan (HER3-DXd), a HER3 directed ADC, ifinatamab deruxtecan (I-DXd), a B7-H3 directed ADC, and raludotatug deruxtecan (R-DXd), a CDH6 directed ADC, are being jointly developed and commercialized globally with Merck. DS-3939, a TA-MUC1 directed ADC, is being developed by Daiichi Sankyo.

The second Daiichi Sankyo ADC platform consists of a monoclonal antibody attached to a modified pyrrolobenzodiazepine (PBD) payload. DS-9606, a CLDN6 directed PBD ADC, is the first of several planned ADCs in clinical development utilizing this platform.

Datopotamab deruxtecan, ifinatamab deruxtecan, patritumab deruxtecan, raludotatug deruxtecan, DS-3939 and DS-9606 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 (IHC 3+ or ISH 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 therapy

This 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 (IHC 3+ or IHC 2+/ISH positive) gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen

Unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options

This 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.
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.

HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU.

HER2-Positive 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.

HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 63% of patients. Seventeen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1% of patients.

HER2-Positive 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.

HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.8% of patients, of which 0.6% were Grade 3.

HER2-Positive 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
HER2-Positive and HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 1799 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 65% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (73%), decreased white blood cell count (70%), decreased hemoglobin (66%), decreased neutrophil count (63%), decreased lymphocyte count (58%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (47%), increased alanine aminotransferase (43%), vomiting (40%), increased blood alkaline phosphatase (38%), alopecia (34%), constipation (33%), decreased appetite (32%), decreased blood potassium (31%), diarrhea (29%), musculoskeletal pain (24%), and abdominal pain (20%).

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 once 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%), decreased blood potassium (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), headache (22%), respiratory infection (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 once 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 decreased blood potassium (25%).

HER2-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg)
DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.

The safety of ENHERTU was evaluated in 101 patients with HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity in DESTINY-Lung02. Nineteen percent of patients were exposed for >6 months.

Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%).

ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%).

HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), decreased blood potassium (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%).

HER2-Positive (IHC3+) Unresectable or Metastatic Solid Tumors
The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2).

Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea.

The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (75%), nausea (69%), decreased hemoglobin (67%), decreased neutrophil count (66%), fatigue (59%), decreased lymphocyte count (58%), decreased platelet count (51%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (36%), vomiting (35%), decreased appetite (34%), alopecia (34%), diarrhea (31%), decreased blood potassium (29%), constipation (28%), decreased sodium (22%), stomatitis (20%), and upper respiratory tract infection (20%).

Use in Specific Populations

Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU.
Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: 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. Infertility: ENHERTU may impair male reproductive function and fertility.
Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
Geriatric Use: Of the 1287 patients with HER2-positive or HER2-low breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.8% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (59%) as compared to younger patients (49%). Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02, 39% were 65 years or older and 9% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

On September 13, 2024 Agenus Inc, a leader in developing novel immunological agents to treat various cancers, reported the company presented data at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress held in Barcelona, Spain (Press release, Agenus, SEP 13, 2024, View Source [SID1234646593]). The data from a Phase 1 study of botensilimab (BOT), an investigational Fc-enhanced CTLA-4 inhibitor, in combination with balstilimab (BAL), an investigational PD-1 antibody, showed clinical activity in patients with refractory sarcomas, a population with limited treatment options.

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"The continued activity with additional patients and longer follow-up of BOT/BAL in this study reinforces it’s potential as an important treatment option for patients with sarcomas," said Dr. Breelyn A Wilky, University of Colorado Cancer Center. "The deep and durable responses we are observing, particularly in late line patients with poorly immunogenic or ‘cold’ sarcomas like visceral angiosarcoma, leiomyosarcoma, and dedifferentiated liposarcoma, are significant. These findings highlight the potential of BOT/BAL to deliver extended survival and a meaningful clinical benefit for patients who previously had very limited options."

Study Highlights

64 patients with relapsed/refractory sarcomas (median of 3 prior lines of therapy) were treated with 1 or 2 mg/kg BOT + 3 mg/kg BAL.
52 patients were efficacy evaluable with at least one post-baseline 6-week imaging scan. ORR and DOR reporting will be based on the unconfirmed response in this cohort.
Majority of sarcoma subtypes included angiosarcoma (39%) and leiomyosarcoma (34%).
Clinical Findings

23% overall response rate (ORR) was observed in the full sarcoma cohort, with a median duration of response (DOR) of 21.7 months. 12-month overall survival (OS) was 69% and the median OS was not reached.
39% ORR achieved in the angiosarcoma subtype (33% in cutaneous and 44% in visceral), with a median DOR of 21.7 months. 12-month OS was 64% and the median OS was not reached.
A representative patient with visceral angiosarcoma achieved a durable response, ongoing beyond 3 years, that has been maintained off-therapy.
The adverse event profile of BOT+ BAL was manageable and reversible with no new safety signals identified.
"The updated sarcoma data presented at ESMO (Free ESMO Whitepaper) underscore the transformative potential of botensilimab and balstilimab for patients with refractory sarcomas who have exhausted other treatment options," said Dr. Steven O’Day, Chief Medical Officer at Agenus. "Seeing these metastatic sarcoma patients experience tumor reduction, with significant and durable responses is incredibly encouraging. BOT/BAL not only offers hope to patients with sarcoma but also holds promise for redefining the standard of care across other historically IO-resistant cancers."

The presentation is available on the Agenus website at View Source

On September 13, 2024 Alligator Bioscience AB and Aptevo Therapeutics reported that positive interim data from the dose escalation portion of the companies’ Phase 1 study evaluating ALG.APV-527 will be presented at a poster on Saturday, September 14, 2024, at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Annual Congress, taking place September 13-17, 2024, in Barcelona, ​​Spain (Press release, Alligator Bioscience, SEP 13, 2024, View Source [SID1234646560]).

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Information om presentationen
Posternummer: #668P
Titel: First-in-Human Phase I Dose Escalation Study of ALG.APV-527, a 5T4 Tumor Antigen-Conditional 4-1BB Bispecific Antibody, in Patients with Advanced Solid Tumors, Demonstrates Positive Safety, Signals of Biological Activity and Patients with Lasting Stable Disease
Presentatör: Thomas Marron, MD, PhD
Datum: Lördag, 14 september, 2024

About the study
The Phase 1 study with ALG.APV-527 is an open-label, multicenter study that will include six cohorts in a 3+3 design*. The study will be conducted in adult patients with multiple solid tumor types/histologies likely to express the 5T4 antigen, including (but not limited to) non-small cell lung cancer (NSCLC), gastric/gastroesophageal cancer, and head and neck cancer, in up to 10 clinics in the US. ALG.APV-527 will be administered intravenously every two weeks. The study will evaluate the safety and tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity of ALG.APV-527.

*In a 3+3 design, cohorts of three patients are treated with increasing dose levels. If at least two out of three or six patients suffer a so-called Dose Limiting Toxicity (DLT), the dose escalation is stopped at the current dose level.

About ALG.APV-527
ALG.APV-527 is a bispecific 4-1BB agonist, which is active only upon simultaneous binding to 4-1BB and 5T4. The molecule has the potential to be of clinical utility as 4-1BB has the ability to stimulate the immune cells (anti-tumor-specific T cells) involved in tumor fighting, making 4-1BB a particularly attractive target for cancer immunotherapy. 5T4 is a tumor-associated antigen that is expressed during fetal development but is also overexpressed on a number of solid tumors, including non-small cell lung cancer (NSCLC), breast, head and neck, cervical, renal, gastric, colon and rectal cancers.

Preclinical studies have been published in the peer-reviewed publication Molecular Cancer Therapeutics , a journal of the American Association for Cancer Research (AACR) (Free AACR Whitepaper). The study, which highlights the molecule’s differentiated design that minimizes systemic immune activation, while enabling highly effective tumor-specific responses, demonstrates the drug candidate’s potent activity in preclinical models.

On September 13, 2024 Moffitt Cancer Center reported a strategic collaboration with AstraZeneca that aims to accelerate the development of cell therapies, specifically chimeric antigen receptor T cell (CAR T) and T cell receptor (TCR T) therapies (Press release, Moffitt Cancer Ctr, SEP 13, 2024, View Source [SID1234646594]).

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Under this collaboration, AstraZeneca will have priority access to Moffitt’s leading clinical environment and forge strong connections between physician-scientists to accelerate the investigation of novel cell therapies.

Advances in cell therapy, including CAR Ts and TCR Ts, are reshaping cancer care by offering potential new treatments for cancers with limited treatment options. The field has grown exponentially since the first CAR T therapies were approved in 2017. Moffitt was pivotal in the clinical trials that led to several FDA approvals for cell therapies and continues to grow its capabilities in this field, with an extensive network of cancer centers across the United States.

The collaboration aims to address cell therapy development challenges and expand cell therapies’ reach to more patients in the United States and beyond. A key focus will be on advancing clinical studies to investigate cell therapies in solid tumors and further optimizing clinical operations to streamline and expedite the delivery of autologous cell therapies to patients.

"We are excited to collaborate with AstraZeneca to push the boundaries of what’s possible in cancer treatment. By combining our clinical expertise with AstraZeneca’s innovative pipeline of investigational cell therapies, global footprint and leadership in oncology, we aim to bring potential new cell therapies to patients faster and more efficiently," said Patrick Hwu, M.D., president and CEO of Moffitt.

"This collaboration will strengthen our connections with the Moffitt Cancer Center to accelerate the development of our autologous cell therapy pipeline as we strive to redefine cancer treatment for more people living with hematological and solid cancers," said Carsten Linnemann, Head of Oncology Cell Therapy Clinical Development, AstraZeneca.

About Moffitt Cancer Center