On September 19, 2024 researchers from City of Hope, one of the largest and most advanced cancer research and treatment organizations in the U.S., and The University of Texas M.D. Anderson Cancer Center, reported safety and efficacy results from a Phase 1 trial that featured a personalized vaccine to treat lymphoplasmacytic lymphoma, a rare and slow-growing type of blood cancer, according to a study published recently in Nature Communications (Press release, City of Hope, SEP 19, 2024, View Source [SID1234646756]).

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The current approach to lymphoplasmacytic lymphoma care is active surveillance of a patient’s possible symptoms. There is a median time of 3.5 years from diagnosis to progression of symptoms — such as fever, night sweats, weight loss and fatigue — that require chemotherapy.

"By doing an early intervention with the vaccine, we nearly doubled the disease-free progression time to an average of just under seven years," said Larry Kwak, M.D., Ph.D., director of City of Hope’s Toni Stephenson Lymphoma Center within the Hematologic Malignancies Research Institute, who developed the vaccine and is the study’s corresponding author. "In addition to being effective, the vaccine appears to be safe. It didn’t have any of the harsh side effects associated with other types of common cancer treatments."

Toxicity among trial participants was also limited, Dr. Kwak said. That’s because the vaccine uses patient-specific biologic components called tumor neoantigens that can help the body mount an immune response to a particular tumor type.

The clinical trial, led by M.D. Anderson, enrolled nine patients, who were able to tolerate the therapy without negative side effects. After a median follow up of 7.5 years, all of the patients had stable disease and more than half had not progressed to a symptomatic state.

"Using sophisticated technology called single-cell sequencing, we could see that these personalized vaccines activated T cells in the tumor microenvironment, which help destroy tumor cells," said Dr. Kwak, who is also the deputy director of City of Hope’s comprehensive cancer center and the Dr. Michael Friedman Professor in Translational Medicine. "Furthermore, we saw that the tumor cells rely on signaling from myeloid cells to survive, which we didn’t know before, and the vaccine reduced that protumoral signaling, too."

According to Dr. Kwak, disease progression was halted and one patient had a minor reduction in tumor shrinkage. The research teams believe this is because two different subtypes of cells give rise to tumors in lymphoplasmacytic lymphoma — mature B cells and plasma cells — and the vaccine only had an effect on the B cell population.

"The takeaway from that observation is that when we do the next phase clinical trial, we will want to combine the vaccine with another agent that does have more of a direct effect on plasma cells, like a monoclonal antibody," he said.

Dr. Kwak and the research team are working on the next generation of the vaccine for a possible clinical trial that may take place at City of Hope. As part of a Sponsored Research Agreement with Renhaim Inc., Dr. Kwak and team plan to adapt the vaccine to an mRNA platform, which has become a new frontier for vaccine production since the original was developed using DNA nearly a decade ago. The team is also exploring additional therapies to pair with the neoantigen for more vaccine efficacy. Dr. Kwak is a paid consultant with Renhaim Inc.

The neoantigen vaccine research builds upon three decades of investigations by Dr. Kwak, who is a world-renowned physician and pioneering scientist in immunology and cancer vaccines. Dr. Kwak was named one of TIME magazine’s "100 Most Influential People" in 2010 for his work in cancer immunology.

In 2011, Dr. Kwak and colleagues published research in the Journal of Clinical Oncology on the first iteration of the neoantigen vaccine. It was a protein-based vaccine for follicular lymphoma that garnered positive results.

"It was actually one of the first positive cancer vaccine positive trials in the field, but 15 years ago, no drug company was interested in talking with us about a personalized vaccine," Dr. Kwak said. He noted that the "one drug for one patient" model was a tough sell until CAR T cell therapies set a precedent for individualized cancer medicines. "Now they’re much more open to it. I think the future of cancer vaccines is really in this kind of setting, where we’ve shown the effectiveness of early intervention as a way to prolong and maybe even prevent progression to symptomatic disease."

The research reported in the Nature Communications paper, "Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial," was supported by the National Cancer Institute and the International Waldenstrom’s Macroglobulinemia Foundation.

On September 19, 2024 Rakuten Medical, Inc., a global biotechnology company developing and commercializing precision, cell-targeting therapies based on its proprietary Alluminox platform, reported that the research results of the preclinical studies for PD-L1-targeted photoimmunotherapy were presented at the 83rd Annual Meeting of the Japanese Cancer Association (JCA2024) in Fukuoka, Japan on September 20, 2024 (JST) (Press release, Rakuten Medical, SEP 19, 2024, View Source [SID1234646755]).

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The key findings presented at JCA2024
Abstract Title: PD-L1 photoimmunotherapy kills immunosuppressive myeloid cells to activate local and systemic antitumor immunity
Presenter: Amy H. Thorne, Ph.D. (Rakuten Medical, Inc.)
Abstract Number: 30050

It has been observed in in vitro studies that this photoimmunotherapy has a dual mechanism of action (MoA): depletion of PD-L1 expressing tumor cells and depletion of PD-L1 expressing immunosuppressive cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). In addition to this dual MoA, the potential for systemic immune checkpoint inhibition was also observed.
It has been observed in in vivo studies that the treatment resulted in more effective tumor growth suppression compared to anti-PD-L1 antibody alone in an anti-PD-L1 sensitive mouse tumor model and tumor growth suppression compared to saline control in an anti-PD-L1 resistant mouse tumor model.
It has been observed in in vivo studies that the treatment affects the tumor microenvironment balance by depleting immunosuppressive tumor microenvironment cells and maintains checkpoint inhibition to enhance CD8+ T cell activation.
RM-0256 was well-tolerated in a GLP toxicity study in which the drug was administered repeatedly to cynomolgus monkeys.
Based on the preclinical study data, Rakuten Medical is currently considering new clinical development opportunities.

About RM-0256
RM-0256 is a conjugate of a newly developed anti-PD-L1 antibody and IRDye700DX (IR700), a light-activatable dye, that accumulates specifically on PD-L1-expressing cells. PD-L1 is a protein that inhibits the anti-cancer immune response by deactivating killer T cells, via binding to PD-1 which is abundantly expressed on the T cell surface1. PD-L1 is expressed in many solid tumors such as melanoma, lung, urothelial, gastrointestinal, gynecological, breast, and head and neck, among others, helping these tumors evade the immune system2. In addition to being present on tumor cells, PD-L1 is also expressed on suppressive immune cells within the tumor microenvironment such as tumor associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs)3. In preclinical studies, PD-L1-targeted photoimmunotherapy resulted in the necrosis of PD-L1 expressing target cells and activation of an anti-cancer immune response. Furthermore, RM-0256 was shown to inhibit the PD-L1:PD-1 interaction, and thus is expected to act systemically as an immune checkpoint inhibitor, further enhancing the anticancer immune response after PD-L1-targeted photoimmunotherapy.

On September 19, 2024 Biosyngen, an innovative biotechnology company specializing in immune cell therapies, reported its groundbreaking "Conditional Activation + Armor Enhancement" T-cell technology at this year’s ESMO (Free ESMO Whitepaper) conference (Press release, BioSyngen, SEP 19, 2024, View Source;armor-enhancement-super-t-technology-at-esmo-2024-302253153.html [SID1234646754]).

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Biosyngen has secured ten clinical trial approvals in China and the U.S. for its innovative fourth-generation oncology therapies. Currently, our leading pipeline product, BRG01, is in the pivotal Phase II clinical trial stage for solid tumors. Additionally, the first patients have been enrolled in the Phase I trials for our other groundbreaking therapies, BST02 and BRL03, with completion of Phase I trials anticipated later this year.

Abstract Title
Anti-tumor Efficacy and Safety of Conditionally Activated Armored CAR-T Cells against Gastrointestinal Tumor

Title No.
1033P

Gastrointestinal tumors have been found to exhibit significantly elevated levels of tumor-associated antigens (TAAs) compared to normal tissues, presenting potential targets for immune cell therapies. However, these TAAs are also expressed at certain levels in normal tissues, which poses a challenge for CAR-T cell therapies. Current CAR-T cells often fail to distinguish between tumor and normal tissues, leading to damage to normal organs and adverse clinical reactions. This on-target off-tumor toxicity not only raises safety concerns in clinical treatment but also limits dosage and efficacy enhancement.

To overcome this technical challenge and balance safety with efficacy in solid tumor immune cell therapies, Biosyngen has developed the SUPER-T T cell safety optimization platform and created the Conditional Activation CAR-T cell BTRP003L. This technology allows CAR-T cells to activate only under hypoxic conditions typical of the tumor microenvironment (0.3% ~ 2.0% O2), while remaining inactive in normal tissues (3.4% ~ 6.8% O2). Remarkably, this approach not only regulates CAR-T cell activation levels under different conditions effectively but also enhances their antitumor capabilities (Figure 1). Further advancements include the co-expression of a TGFβRII dominant-negative mutant, resulting in the "Conditional Activation + Armor Enhancement" CAR-T cell BTRP011L, which shows improved efficacy and in vivo persistence at lower doses (Figure 2). Toxicology studies using the SUPER-T platform showed no weight loss or other adverse effects in mice injected with BTRP003L or BTRP011L, demonstrating robust safety.

On September 19, 2024 Ryvu Therapeutics (WSE: RVU), a clinical-stage drug discovery and development company focusing on novel small molecule therapies that address emerging targets in oncology, reported that the first patient has been dosed in the REMARK study, a Phase II clinical trial investigating RVU120 as a monotherapy for the treatment of patients with LR-MDS (Press release, Ryvu Therapeutics, SEP 19, 2024, View Source [SID1234646753]).

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"We are glad to announce the initiation of the REMARK study for RVU120, which can potentially help patients with lower-risk MDS. This study builds upon the promising results from our Phase Ib study in patients with AML and high-risk MDS, where we observed hematologic improvement in several patients, including cases of transfusion independence. The objective is to further assess the safety and efficacy of RVU120 in patients with lower-risk MDS, underpinned by robust preclinical and mechanistic evidence. We believe this represents a significant advancement toward our objective of developing effective treatments for hematological diseases and offering therapeutic options for patients. I am delighted that we can count on the support of the EMSCO network and Prof Uwe Platzbecker in this endeavor." – said Hendrik Nogai, M.D., Chief Medical Officer of Ryvu Therapeutics.

REMARK is an open-label, multicenter Phase II study of RVU120, a novel small-molecule cyclin-dependent kinase (CDK) 8/19 inhibitor. The study aims to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS). In REMARK, RVU120 is being explored as a single agent in patients with LR-MDS who have exhausted available treatment options.

The REMARK study is being conducted as an investigator-initiated study through the EMSCO network with Prof. Uwe Platzbecker, a globally renowned expert in the field of LR-MDS, as the Coordinating Principal Investigator.

"I am proud that we could start the REMARK study in line with our ambitious plans. RVU120 has shown promising hematologic improvement in patients with off-hematologic impaired bone marrow function. I am optimistic that this clinical evidence will translate into a positive outcome of the REMARK study. RVU120 has important features that should be considered a potential new treatment option for patients with LR-MDS. It may aid in achieving our ultimate aim to alleviate the need for red blood cell transfusions in these patients." – said Uwe Platzbecker, M.D., Director of the Clinic and Poliklinik for Hematology, Cell Therapy and Hemostaseology at the Leipzig University Hospital.

REMARK is being initiated based on the clinical safety and efficacy data gathered so far, as well as strong preclinical and mechanistic rationale. MDS pathogenesis is influenced by gene expression alterations that hinder the maturation of hematopoietic cells. RVU120 triggers erythroid gene expression programs orchestrated by STAT5 and GATA1 in aberrant stem cells from MDS patients. Importantly, RVU120’s activity does not lead to significant toxicity in the hematopoietic system. As a result, RVU120 emerges as a promising drug candidate for treating transfusion-dependent MDS patients.

In REMARK, patients will receive RVU120 for at least 8 complete cycles (24 weeks). The primary goal is to achieve hematologic improvement in the form of an erythroid response (HI-E), with secondary goals including independence from RBC transfusions, improvement in hemoglobin levels, quality of life, disease progression, and analysis of specific gene mutations.

REMARK represents the third of four planned RVU120 Phase II clinical studies scheduled for launch in 2024. Ryvu has already started patient treatment in the RIVER-52 and RIVER-81 studies in AML, and the fourth Phase II trial is the planned to be initiated shortly POTAMI-61 study, evaluating both monotherapy and combination therapy for the treatment of patients with myelofibrosis (MF).

On September 19, 2024 Johnson & Johnson (NYSE: JNJ) reported that the U.S. Food and Drug Administration (FDA) approved RYBREVANT (amivantamab-vmjw) in combination with standard of care chemotherapy (carboplatin and pemetrexed) for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or L858R substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor (TKI) (Press release, Johnson & Johnson, SEP 19, 2024, View Source [SID1234646752]).

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"RYBREVANT plus chemotherapy may address the most common mechanisms of treatment resistance to third generation EGFR TKIs, such as osimertinib, in the first line," said Martin Dietrich*, M.D., Ph.D., Oncologist, Cancer Care Centers of Brevard. "This multitargeted combination extended progression-free survival and improved overall response compared to chemotherapy alone, offering an important and effective new second-line option for patients."

The five-year survival rate is less than 20 percent for all people with advanced EGFR-mutated NSCLC.2,3 Acquired resistance mechanisms after TKI monotherapy are diverse and polyclonal, making targeted therapy at progression more difficult, thus limiting the efficacy of targeted therapies at progression.4,5 Adding immunotherapy to chemotherapy has also failed to demonstrate clinically meaningful improvements.6,7

"The progression-free survival benefits seen in the MARIPOSA-2 study are exciting," said Andrea Ferris**, President and CEO, LUNGevity Foundation. "It is good to see new therapeutic options like the combination of RYBREVANT and chemotherapy helping to address unmet needs impacting individuals with EGFR-mutated lung cancer, with the potential for positive change, which gives hope to more patients and their families."

The FDA approval is based on results from the Phase 3 MARIPOSA-2 (NCT04988295) study evaluating the efficacy and safety of RYBREVANT in combination with chemotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations after disease progression on or after osimertinib.1 Results showed RYBREVANT plus chemotherapy reduced the risk of disease progression or death (progression-free survival [PFS]) by 52 percent vs. chemotherapy alone, the study’s primary endpoint.1 The median PFS for patients receiving RYBREVANT plus chemotherapy was 6.3 months, compared to 4.2 months for chemotherapy alone.1 Additionally, RYBREVANT plus chemotherapy showed a confirmed overall response rate (ORR) of 53 percent compared to 29 percent with chemotherapy alone.1

Amivantamab-vmjw (RYBREVANT) in combination with chemotherapy is the only National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) Category 1 treatment option for patients with EGFR-mutated NSCLC progressing on osimertinib who are symptomatic with multiple lesions.8 †‡

"This milestone reinforces RYBREVANT as an important treatment option for patients with EGFR-mutated NSCLC who continue to face high unmet needs after disease progression on or after TKI therapy," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "Patients need and deserve effective, targeted approaches across all lines of therapy. With RYBREVANT-based regimens, we are bringing potential new standards of care to the nearly 30,000 patients diagnosed with EGFR-mutated NSCLC in the United States each year."

The safety profile of RYBREVANT in combination with chemotherapy was consistent with the established profiles of the individual treatments. Permanent discontinuation of RYBREVANT due to adverse reactions occurred in 11 percent of patients.1

MARIPOSA-2 Publications & Presentations
Results from MARIPOSA-2 were first presented in a Presidential Symposium at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress (Abstract #LBA15) and simultaneously published in the Annals of Oncology.9

Regulatory Milestones
This approval marks the third new indication for RYBREVANT this year, following the August 20, 2024, U.S. FDA approval announcement of RYBREVANT 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, based on the Phase 3 MARIPOSA study, and the March 1, 2024, U.S. FDA approval announcement of RYBREVANT in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, based on the Phase 3 PAPILLON study.1

On June 17, 2024, Johnson & Johnson also announced the submission of a Biologics License Application to the U.S. FDA for a fixed combination of amivantamab and recombinant human hyaluronidase for subcutaneous administration (SC amivantamab) for all currently approved or submitted indications of intravenous (IV) RYBREVANT. This application is based on the Phase 3 PALOMA-3 study, with preliminary results which showed a five-fold reduction in infusion-related reactions (IRR) with a five-minute administration of SC amivantamab.10 Longer overall survival (OS), PFS and duration of response (DOR) were also observed with SC amivantamab.10 On August 14, 2024, the U.S. FDA designated this application for Priority Review.

About the MARIPOSA-2 Study

MARIPOSA-2 (NCT04988295), which enrolled 657 patients, is a randomized, open-label Phase 3 study evaluating the efficacy and safety of two combination regimens of RYBREVANT (with and without LAZCLUZE) and chemotherapy.11 Patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC who had disease progression on or after treatment with osimertinib were randomized to treatment with RYBREVANT plus chemotherapy, RYBREVANT plus chemotherapy with LAZCLUZE or chemotherapy alone.11 The dual primary endpoint was used to compare the PFS (using RECIST v1.1 guidelines§) as assessed by blinded independent central review (BICR) for each experimental arm to chemotherapy alone.11 Secondary endpoints included objective response as assessed by BICR, OS, DOR, time to subsequent therapy, PFS2 and intracranial PFS.11

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.1 In the subcutaneous formulation, amivantamab is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

RYBREVANT is approved in the U.S., Europe, and in other 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 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 IV RYBREVANT in certain patients with NSCLC. In August 2024, the U.S. FDA designated this application for Priority Review.

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.8 †‡
Amivantamab-vmjw (RYBREVANT) plus chemotherapy as a Category 1 recommendation for patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.8 †‡
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.8 †‡
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.8 †‡
In addition to MARIPOSA-2, RYBREVANT is being studied in multiple clinical trials in NSCLC, 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 substitution mutations.12
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.13
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.10
The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT in patients with advanced NSCLC.14
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.15
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.16
The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.17
The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT and capmatinib combination therapy in locally advanced or metastatic NSCLC.18
The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT and cetrelimab combination therapy in locally advanced or metastatic NSCLC.19
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.20
For more information, visit: View Source

Access to RYBREVANT

J&J offers comprehensive access and support information and resources to assist patients in gaining access to RYBREVANT. Our patient support program, J&J withMe, is available to provide personalized support to help patients start and stay on their J&J medicines. J&J withMe offers providers help supporting their patients by verifying patients’ insurance coverage, providing information on Prior Authorization and Appeals processes and educating on reimbursement processes. Patients can connect to RYBREVANT withMe to receive cost support, regardless of insurance type, free, personalized one-on-one support from a Care Navigator, and resources and community connections. Learn more at RYBREVANTwithMe.com or by calling 833-JNJ-wMe1 (833-565-9631).♠

About Non-Small Cell Lung Cancer (NSCLC)

Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases.21,22 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.23 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.24 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.23,24,25,26,27,28 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.29 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent.2,3 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.30 Patients with EGFR exon 20 insertion mutations have a real-world five-year OS of eight percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent.31

IMPORTANT SAFETY INFORMATION1

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

Based on the pooled safety population (n=281), IRR occurred in 50% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (3.2%) adverse reactions. The incidence of infusion modifications due to IRR was 46%, and 2.8% of patients permanently discontinued RYBREVANT due to IRR.

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

Based on the pooled safety population, ILD/pneumonitis occurred in 2.1% treated with RYBREVANT in combination with carboplatin and pemetrexed with 1.8% of patients experiencing Grade 3 ILD/pneumonitis. 2.1% discontinued RYBREVANT due to ILD/pneumonitis.

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%) permanently 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 (VTE) 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

Based on the pooled safety population, rash occurred in 82% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (15%) adverse reactions. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued RYBREVANT and 3.1% 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, reduce the dose, 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

Based on the pooled safety population, ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All events were Grade 1 or 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, reduce the dose, 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 130 patients in the MARIPOSA-2 clinical trial who received RYBREVANT in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (72%), infusion-related reactions (59%), fatigue (51%), nail toxicity (45%), nausea (45%), constipation (39%), edema (36%), stomatitis (35%), decreased appetite (31%), musculoskeletal pain (30%), vomiting (25%), and COVID-19 (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased neutrophils (49%), decreased white blood cells (42%), decreased lymphocytes (28%), decreased platelets (17%), decreased hemoglobin (12%), decreased potassium (11%), decreased sodium (11%), increased alanine aminotransferase (3.9%), decreased albumin (3.8%), and increased gamma-glutamyl transferase (3.1%).

In MARIPOSA-2, serious adverse reactions occurred in 32% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in >2% of patients included dyspnea (3.1%), thrombocytopenia (3.1%), sepsis (2.3%), and pulmonary embolism (2.3%). Fatal adverse reactions occurred in 2.3% of patients who received RYBREVANT in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each).

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%).

In PAPILLON, 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.