On June 4, 2023 VITRAC Therapeutics, LLC (VITRAC) reported a poster on the Phase 1a/1b clinical trial of aurora kinase A (AURKA) inhibitor, VIC-1911, as monotherapy and in combination with KRAS G12C inhibitor, sotorasib (Press release, VITRAC Therapeutics, JUN 4, 2023, View Source [SID1234632439]). The study targets the treatment of KRAS G12C-mutant non-small cell lung cancer (NSCLC). The findings were presented at the prestigious 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in Chicago on June 4.

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The clinical investigators involved in the study include S. B. Goldberg, MD, MPH, Principal Investigator (PI) and Study Chair at Yale Cancer Center, S. R. Punekar, MD, PI, NYU Langone-Laura and Isaac Perlmutter Cancer Center, V. Velcheti, MD, PI, New York University Perlmutter Cancer Center, J. W. Riess, MD, PI, University of California Davis Comprehensive Cancer Center, K. A. Scilla, MD, PI, University of Maryland Cancer Center, J. W. Carlisle, MD, PI, Emory University Winship Cancer Center, K. Politi, PhD, J.W. Lee, PhD, and B. Burtness, MD, Yale School of Medicine and Yale Cancer Center, T. Myers, MD, and L. Paradiso, DVM, Vitrac Therapeutics.

VIC-1911 is a highly selective, orally administered small molecule inhibitor of AURKA. Overexpression of the AURKA is found in multiple tumors, including NSCLC. New treatment approaches are urgently needed to mitigate and overcome resistance to KRAS G12C inhibitors.

Preclinical studies indicate that AURKA could play a role in resistance to KRAS G12C inhibitors. VIC-1911, both as monotherapy and in combination with a KRAS G12C inhibitors sotorasib and adagrasib, has shown effectiveness against NSCLC with intrinsic and acquired resistance to KRAS G12C inhibitors in preclinical models. These findings suggest the potential of VIC-1911, both as a monotherapy and in combination with sotorasib, for patients with KRASG12C-mutated NSCLC.

"We now have two approved KRAS G12C inhibitors, sotorasib and adagrasib, to treat patients with KRAS G12C-mutated NSCLC," stated Sarah Goldberg, MD, Study Chair. "Despite the satisfactory response rates in patients naïve to KRAS G12C inhibitor therapy, over 50% of patients exhibit primary resistance. Moreover, many patients who do respond soon develop acquired resistance and relapse. With this innovative approach combining AURKA and KRAS G12C inhibitors, we aim to enhance therapeutic outcomes for our patients with KRAS G12C-mutant NSCLC."

"VIC-1911 is a potent, selective AURKA inhibitor. The supporting preclinical studies strongly advocate for the combination of AURKA inhibition with VIC-1911 and KRAS G12C inhibitors in KRAS G12C-mutant NSCLC," said Thomas Myers, MD, Chief Medical Officer at VITRAC. "Through this multi-targeted approach, we hope to deliver more effective therapeutic outcomes for patients with KRAS G12C-mutant NSCLC

On June 4, 2023 Servier, a leader in oncology committed to bringing innovative therapies to the patients we serve, today presented results from the pivotal Phase 3 INDIGO clinical trial investigating vorasidenib, an investigational, oral, selective, highly brain-penetrant dual inhibitor of mutant IDH1/2 enzymes in patients with residual or recurrent isocitrate dehydrogenase 1 or 2 (IDH1/2) mutant low-grade glioma who have been treated with surgery only (Press release, Servier, JUN 4, 2023, View Source [SID1234632436]). INDIGO succeeded in meeting its primary endpoint of progression free survival (PFS) per blinded independent review committee (BIRC) and key secondary endpoint of time to next intervention (TTNI) at the prespecified second interim analysis. The data were presented as a late breaking abstract during the plenary session at the 2023 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), and simultaneously published in the New England Journal of Medicine.

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The primary endpoint, PFS per BIRC, was statistically significant and clinically meaningful in favor of the vorasidenib arm (HR, 0.39; 95% CI, 0.27 to 0.56; 1-sided P=0.000000067), median PFS for vorasidenib and placebo was 27.7 vs 11.1 months, respectively. TTNI was also statistically significant (HR, 0.26; 95% CI, 0.15 to 0.43; 1-sided P=0.000000019). Median TTNI was not reached for vorasidenib and 17.8 months for placebo.

"Grade 2 gliomas are progressive, malignant brain tumors with a poor prognosis, and the current treatment paradigm, which can be associated with short- and long-term toxicities, has not seen progress in more than two decades," said Ingo K. Mellinghoff, M.D., Chair, Department of Neurology, Memorial Sloan Kettering Cancer Center. "For patients living with IDH mutant low-grade glioma, as determined by molecular testing, treatment with a targeted therapy such as vorasidenib has the potential to provide transformative benefits."

"The overwhelmingly positive INDIGO results convincingly demonstrate the impact of targeting IDH mutations early in cancer biology where a monotherapy approach can lead to a profoundly meaningful outcome for patients with recurrent or residual IDH-mutant grade 2 gliomas," said Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "IDH mutations are disease defining alterations in IDH-mutant diffuse gliomas and these pivotal data coupled with vorasidenib’s especially high penetration of the blood-brain barrier, offer opportunities to evolve the treatment landscape for patients living with this malignancy. We look forward to working with the FDA on its review of vorasidenib as a potential therapy in IDH-mutant diffuse glioma."

INDIGO is a registration-enabling Phase 3 global, randomized, double-blinded placebo-controlled study of vorasidenib in patients with residual or recurrent grade 2 glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation who have undergone surgery as their only treatment. IDH1/2 mutations occur in approximately 80% and 4% of grade 2 gliomas, respectively.

As of September 6, 2022 (2nd planned interim analysis data cutoff), 331 patients were randomized globally to receive vorasidenib (n=168) 40 mg daily or placebo (n=163) continuously in 28-day cycles. Of the 331 patients, 172 had oligodendroglioma (88 vorasidenib; 84 placebo) and 159 patients had astrocytoma (80 vorasidenib; 79 placebo). Median time from the last surgery until randomization was 2.5 years on the vorasidenib arm vs 2.2 years on the placebo arm.

The safety profile for vorasidenib was well tolerated and consistent with Phase 1 results. The most common Grade ≥3 adverse events for patients receiving vorasidenib vs placebo were alanine aminotransferase increased (9.6% vs 0), aspartate aminotransferase increased (4.2% vs 0) and seizure (4.2% vs 2.5%).

Vorasidenib was granted fast track designation by the U.S. Food & Drug Administration (FDA) in March 2023. Servier is working to determine timelines for submission of a New Drug Application (NDA) for vorasidenib to the FDA.

"Patients with brain cancer live with the constant fear of what their future looks like. For over twenty years, the lack of new treatment options has put patients in a position of making the difficult decision to accept a treatment that has significant side effects or to preserve cognitive function for as long as possible," said Brock Greene, Founder of Oligo Nation, a leading brain cancer patient organization. "Servier’s positive clinical trial data for a targeted therapy in IDH-mutant glioma that may possibly improve outcomes for patients provides this community with new hope that they have been waiting decades for."

About the INDIGO Phase 3 Trial

INDIGO is a registration-enabling Phase 3 global, randomized, double-blinded placebo-controlled study of vorasidenib in patients with residual or recurrent grade 2 glioma with an isocitrate dehydrogenase 1/2 (IDH1/2) mutation who have undergone surgery as their only treatment. (NCT04164901).

About Glioma1

Gliomas are tumors that arise from glial or precursor cells within the central nervous system (CNS). The 2021 WHO classification recognizes four general groups of gliomas, one of which is adult-type diffuse gliomas. These diffuse gliomas are the most common primary malignant brain tumors in adults. The pathogenesis and prognosis of these tumors are tightly linked to mutations (or lack thereof) in the metabolic enzyme isocitrate dehydrogenase (IDH), and molecular testing is required for proper diagnosis. As of 2021, adult-type diffuse gliomas are sub-divided into only three categories:

Astrocytoma, IDH-mutant (CNS WHO grades 2-4)
Oligodendroglioma, IDH-mutant and1p19q-codeleted (CNS WHO grades 2-3)
Glioblastoma, IDH-wildtype (CNS WHO grade 4)

On June 4, 2023 A Phase 3 trial has reported that patients with advanced Stage (3 or 4) classic Hodgkin lymphoma who underwent initial treatment with nivolumab, a PD-1 checkpoint inhibitor, and AVD chemotherapy (N-AVD) had a significantly lower risk of their cancer getting worse than patients treated with brentuximab vedotin, a monoclonal antibody, and AVD (BV-AVD) a year after starting treatment (Press release, City of Hope, JUN 4, 2023, View Source [SID1234632437]).

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Ninety-four percent of adolescent and adult patients in the N-AVD group had progression-free survival compared with 86% in the BV-AVD arm. N-AVD was also well-tolerated as there were few serious immune-related side effects in the S1826 trial. The median follow-up was 12.1 months.

SWOG Cancer Research Network trial, led by City of Hope researcher, shows potential new therapy for a lymphoma

These late-breaking findings will be presented by City of Hope’s Alex Herrera, M.D., at ASCO (Free ASCO Whitepaper)’s 2023 Plenary Session, June 4, at 2:53 p.m. CT in Hall B1 and will be featured in the official ASCO (Free ASCO Whitepaper) press program.

Lead investigator on the study, Herrera is chief of the Division of Lymphoma at City of Hope, one of the largest cancer research and treatment organizations in the United States, and is an investigator with the SWOG Cancer Research Network, a clinical trials group funded by the National Cancer Institute (NCI), part of the National Institutes of Health.

"The results are remarkable. The combination of nivolumab and chemotherapy is potent and safe in patients with Stage 3 or 4 classic Hodgkin lymphoma as an initial treatment," said Herrera, "The therapy is poised to be a standard for treatment of advanced Hodgkin lymphoma. This is indeed great news for patients with this cancer as there is another effective and safe treatment option for them."

Georgie Garabet, 43, of Glendora, California, was one of the patients who participated in the trial. When Garabet began to feel sick in early 2020, he was a 40-year-old father of two children under the age of 3. His symptoms included uncontrollable itching all over his body and severe weight loss. After a few trips to emergency rooms and to his primary care doctor, he was eventually diagnosed with Stage 3 Hodgkin lymphoma.

"I panicked when I heard the word cancer," Garabet said. At the same time, he was relieved to know what was causing his symptoms.

Garabet met Herrera and instantly felt he was in good hands. "He explained everything so well," he added. Garabet enrolled in the trial. After his first infusion, he felt exhausted but that was the worst he felt during treatment. After only four infusions, he was in remission. He was advised to continue the treatment in case any cancer lingered, and he did. "Now when people tell me they have cancer, I tell them not to panic. There are a lot of cures now," he added.

The S1826 trial, supported by the NCI and led by SWOG, is the largest classic Hodgkin lymphoma study ever conducted in the NCI’s National Clinical Trials Network and is also representative of a diverse patient population. About a quarter of the enrolled patients were Black or Hispanic. A partnership with the Children’s Oncology Group (COG) helped ensure the trial included young adolescents, and a quarter of enrolled patients were younger than 18 years old. Nearly two-thirds of all patients had Stage 4 cancer.

"This study speaks to the power of the National Clinical Trials Network and is an excellent example of the transformative work that the NCI funds," said Jonathan Friedberg, M.S., M.M.Sc., senior author of the study, chair of the SWOG Cancer Research Network’s lymphoma committee and director of the Wilmot Cancer Institute at the University of Rochester. "Hodgkin lymphoma is not a common disease and the NCTN enabled a large network of more than 200 pediatric and adult community providers and academic medical centers to work together. Because of that, we were able to get data very quickly and directly impact patient care. This was a critical investment in cancer research and treatment."

Patients with Stage 3 or 4 classic Hodgkin lymphoma who had not been previously treated and were age 12 or older were eligible for the trial. Of a total of 976 eligible patients, 489 were enrolled in the N-AVD arm (nivolumab plus Adriamycin, vinblastine and dacarbazine), while 487 were part of the BV-AVD group. Each group received six infusion cycles of each combination therapy.

As expected with combination chemotherapy, the most common side effects included gastrointestinal and hematologic toxicities, and fatigue. However, less than 1% of patients needed radiation after trial treatment, which is a dramatic reduction in the proportion of patients being initially treated for Hodgkin lymphoma who need radiation, especially among pediatric patients.

"The ability to maintain high rates of relapse-free survival with minimal use of radiation therapy in children with newly diagnosed advanced stage Hodgkin lymphoma will be a paradigm shift," said Sharon Castellino, M.D., M.Sc., chair of the COG Hodgkin lymphoma committee and director of the Leukemia and Lymphoma Program at the Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Winship Cancer Institute at Emory University.

Brentuximab vedotin was the first antibody-drug conjugate developed for classic Hodgkin lymphoma. Several studies have demonstrated that incorporating the therapy into frontline treatment improves progression-free survival and overall survival. Despite improved outcomes, there are still serious side effects; relapses can occur.

"There is definitely a need to improve frontline therapies for Hodgkin lymphoma, particularly because a disproportionate number of patients with this disease are teens and young adults," Herrera added.

PD-1 checkpoint inhibitors are a powerful and growing form of immunotherapy used to treat melanoma, kidney cancer, head and neck cancers, relapsed or difficult to treat Hodgkin lymphoma and other cancers. The PD-L1 protein is expressed on Hodgkin lymphoma tumor cells and aids the cancer by signaling to immune cells, such as T cells, to stop working against tumors.

Checkpoint inhibitors block the PD-L1 protein to help the immune system and, specifically, T cells, do what they’re designed to do, eradicate cancer. In this study, adding nivolumab to chemotherapy worked so well that some patients experienced remission after only a few treatments.

Next steps for the trial include following patients to measure the durability of progression-free survival, overall survival and other patient outcomes.

Funding was provided by: National Cancer Institute of the National Institutes of Health U10CA180888, U10CA180819, U10CA180820, U10CA180821, U10CA180863, U10CA180886 and Bristol-Myers Squibb through a Cooperative Research and Development Agreement between the NCI and BMS. Brentuximab vedotin was provided by Seagen.

In addition to Herrera and Friedberg, co-authors on the presentation include Michael L. LeBlanc, Ph.D., SWOG Statistical Center and Fred Hutchinson Cancer Center; Sharon M. Castellino, M.D., M.Sc., Emory University, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta; Hongli Li, M.S., SWOG Statistical Center and Fred Hutchinson Cancer Center; Sarah C. Rutherford, M.D., Weill Cornell Medicine-New York Presbyterian Hospital; Andrew M Evens, D.O., M.Sc., Rutgers Cancer Institute of New Jersey; Kelly Davison, M.D., McGill University; Angela Punnett, M.D., Hospital for Sick Children, Toronto; David C. Hodgson, M.D., M.P.H., Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network; Susan K Parsons, M.D., M.R.P., Tufts Medical Center, Tufts University School of Medicine; Sairah Ahmed, M.D., University of Texas MD Anderson Cancer Center; Carla Casulo, M.D., Division of Hematology/Oncology, University of Rochester; Nancy L. Bartlett, M.D., Washington University School of Medicine in St. Louis; Joo Y. Song, M.D., Department of Pathology, City of Hope; Richard F. Little, M.D., Cancer Therapy Evaluation Program, National Cancer Institute; Brad S. Kahl, M.D., Washington University School of Medicine in St. Louis; John P. Leonard, M.D., Weill Cornell Medicine-New York Presbyterian Hospital; Sonali M. Smith, M.D., Department of Oncology, University of Chicago; and Kara M. Kelly, M.D., Department of Pediatric Oncology, Roswell Park Comprehensive Cancer Center.

On June 4, 2023 Gracell Biotechnologies Inc. ("Gracell" or the "Company", NASDAQ: GRCL), a global clinical-stage biopharmaceutical company dedicated to developing innovative and highly efficacious cell and gene therapies for the treatment of cancer and autoimmune disease, reported long-term follow-up data from a multicenter study evaluating GC012F, a B-cell maturation antigen (BCMA) and CD19 dual-targeted autologous CAR-T therapeutic candidate, in RRMM during an oral abstract presentation (abstract #8005) at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting (Press release, Gracell Biotechnologies, JUN 4, 2023, View Source [SID1234632438]).

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In the single-arm, open label, multicenter investigator-initiated trial (IIT), 29 RRMM patients were enrolled and treated with GC012F, between October 2019 and January 2022, at three target dose levels of 1×105, 2×105, and 3×105 cells/kg. Patients had a median of five prior lines of therapy (range: 2-9), with 97% (28/29) patients being triple-exposed to immunomodulatory drugs (IMiDs), proteasome inhibitor (PI) and anti-CD38 monoclonal antibody treatment. 90% (26/29) of patients were classified as high-risk based on mSMART 3.0 criteria.

As of the April 12, 2023 data cutoff date, with a median follow-up of 30.7 months (range: 14.6-43.6 months), patients treated with GC012F achieved the following:

93.1% (27/29) overall response rate (ORR), with 89.6% (26/29) of patients achieving a very good partial response (VGPR) or better;
82.8% (24/29) of patients achieved MRD- sCR;
100.0% (29/29) of treated patients achieved MRD negativity.
In this predominantly high-risk patient population, GC012F demonstrated durable responses:

Median duration of response (DOR) was 37.0 months (95% CI: 11.0-NR);
Median progression free survival (PFS) was 38.0 months (95% CI: 11.8-NR);
Longer PFS was achieved in patients with 12-month sustained MRD negativity;
34% (10/29) of patients sustained MRD- sCR for more than 12 months and had an estimated PFS rate of 100% at 36 months.
GC012F continued to show a favorable safety profile:

No new safety findings in the longer-term follow-up, including no any neurotoxicity;
No second primary malignancies reported;
Cytokine release syndrome (CRS) were mostly low grade (Grade 1/2: 79%). Grade 3 CRS was observed in two patients (2/29, 7%) with quick recovery after standard of care treatment. No Grade 4/5 CRS events occurred;
No neurotoxicity or immune effector cell-associated toxicity (ICANS) of any grade was observed;
"Longer-term results for our evaluation of GC012F in patients with RRMM further demonstrate the potential of our lead candidate," said Dr. Wendy Li, Chief Medical Officer of Gracell. "Empowered by the BCMA/CD19 dual-targeted approach and the FasTCAR-T next-day manufacturing technology, GC012F showed impressive clinical outcomes in a challenging patient population. We are highly encouraged by the depth and durability of responses shown in this study, including 93.1% ORR, 82.8% MRD- sCR, 100% MRD negativity rate and median PFS of 38 months. Notably, the patients with 12-month sustained MRD negativity demonstrated an estimated PFS of 100% at 36 months, reinforcing the clinical importance of achieving a deep response. We look forward to presenting additional results of GC012F in B-NHL at ASCO (Free ASCO Whitepaper) and again at the European Hematology (EHA) (Free EHA Whitepaper) Congress in the coming week."

On June 5, Gracell will also present updated results from the IIT evaluating GC012F for the treatment of B-cell non-Hodgkin’s lymphoma (B-NHL) as a poster (abstract # 7562) during the Hematologic Malignancies – Lymphoma and Chronic Lymphocytic Leukemia poster abstract session at the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting. The updated data from the ongoing IIT shows an ORR of 100% in all nine patients enrolled and treated, 100% (9/9) of which are diffuse large B-cell lymphoma (DLBCL) patients. The complete response (CR) rate was 77.8% (7/9) at Month 3 and 67.7% (6/9) at Month 6, respectively.

Additional information about the presentation and the 2023 ASCO (Free ASCO Whitepaper) Annual Meeting is available on the ASCO (Free ASCO Whitepaper) website.

About GC012F

GC012F is Gracell’s FasTCAR-enabled BCMA/CD19 dual-targeting autologous CAR-T cell therapy, which aims to transform cancer and autoimmune disease treatment by driving fast, deep and durable responses with improved safety profile. GC102F is currently being evaluated in investigator-initiated trials in multiple myeloma and B-cell non-Hodgkin’s lymphoma (B-NHL), and has demonstrated a consistently strong efficacy and safety profile. In February 2023, Gracell announced regulatory clearance of Investigational New Drug applications in the United States and China to commence clinical trials evaluating GC012F for the treatment of relapsed/refractory multiple myeloma. Gracell has also initiated an investigator-initiated trial evaluating GC012F for the treatment of systemic lupus erythematosus (SLE).

About FasTCAR

Introduced in 2017, FasTCAR is Gracell’s revolutionary next-day autologous CAR-T cell manufacturing platform. FasTCAR is designed to lead the next generation of therapy for cancer and autoimmune diseases, and improve outcomes for patients by enhancing effect, reducing costs, and enabling more patients to access critical CAR-T treatment. FasTCAR drastically shortens cell production from weeks to overnight, potentially reducing patient wait times and probability for their disease to progress. Furthermore, FasTCAR T-cells appear younger and are more robust than traditional CAR-T cells, making them more proliferative and effective at killing cancer cells. In November 2022, FasTCAR was named the winner of the Biotech Innovation category of the 2022 Fierce Life Sciences Innovation Awards for its ability to address major industry obstacles.

On June 4, 2023 The Janssen Pharmaceutical Companies of Johnson & Johnson reported long-term results from the CHRYSALIS study, which showed the combination of RYBREVANT (amivantamab-vmjw) and lazertinib*, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), was associated with sustained antitumor activity as a first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC) (Abstract #9134) (Press release, Johnson & Johnson, JUN 4, 2023, View Source;301841867.html [SID1234632433]). These findings and additional data, including an analysis of predictive biomarkers from Cohort D of the Phase 1/1b CHRYSALIS-2 study evaluating a chemotherapy-free regimen of RYBREVANT in combination with lazertinib (Abstract #9013)2 and updated safety results from the Phase 1 PALOMA study evaluating the subcutaneous (SC) administration of RYBREVANT as a monotherapy (Abstract #9126)3 were presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting.

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Patients enrolled in the treatment-naïve cohort from the ongoing CHRYSALIS (NCT02609776) study had NSCLC characterized by either an EGFR exon 19 deletion (ex19del) (n=11) or L858R mutation (n=9).1,4 After a median follow-up of nearly three years (33.6 months), the median duration of response (DOR), median progression-free survival (PFS) and overall survival (OS) were not yet reached. The estimated PFS rate was 85 percent after one year, 65 percent at two years and 51 percent at three years. The longest ongoing duration of treatment is over three years (37.2 months), and longest DOR is nearly three years (35.7 months).1

Safety among patients in this cohort was consistent with previous reports and no new safety signals were identified. Treatment-related dose interruptions, reductions and discontinuations of either RYBREVANT or lazertinib occurred in seven patients (35 percent), eight patients (40 percent) and one patient (5 percent), respectively.1

"Advanced NSCLC and EGFR-mutated lung cancer has a five-year survival rate of less than 20 percent, underscoring an urgent need for more targeted treatment options, especially in earlier lines of therapy," said Se-Hoon Lee**, M.D., Ph.D., professor of medicine at the Samsung Medical Center and Sungkyunkwan University School of Medicine, and presenting author. "These long-term data for amivantamab and lazertinib introduce the potential for this combination therapy to be used as first-line treatment for this patient population."

New Analyses on Predictive Biomarkers for Response to RYBREVANT and Lazertinib Combination Therapy

Patients with advanced NSCLC harboring common EGFR mutations including ex19del or L858R who have experienced disease progression on or after osimertinib are a population with substantial unmet medical need. There are no approved targeted therapies, and the standard of care is platinum-doublet chemotherapy. Data from Cohort D of the Phase 1/1b CHRYSALIS-2 study, which enrolled such patients, were highlighted in an oral presentation at ASCO (Free ASCO Whitepaper) this year. CHRYSALIS-2 (NCT04077463) is an open-label study to evaluate the safety and pharmacokinetics of lazertinib as monotherapy or in combination with RYBREVANT.5 Consistent with a prior presentation at ASCO (Free ASCO Whitepaper) 2021, these data indicate that immunohistochemical (IHC) staining (a testing method using antibodies to determine the relative level of certain antigens or markers in cancer tissue samples) for MET may identify patients more likely to benefit from treatment with the combination of RYBREVANT and lazertinib.2,6 Among patients with MET overexpression as identified by immunohistochemistry, the response rate was 61 percent with a median PFS of 12.2 months. In contrast, patients with low MET expression had a response rate of 14 percent with a median PFS of 4.2 months.2

Updated Safety Data from the Phase 1 PALOMA Study Evaluating the Investigational Use of Subcutaneous RYBREVANT

Results from the Phase 1 PALOMA study were featured in a poster presentation and showed RYBREVANT SC dose was administered on the first day in less than seven minutes, removing the need for split dosing.3 The current approved RYBREVANT intravenous (IV) infusion dosing is split over two days, with infusion times of approximately 4 to 6 hours for the RYBREVANT 1050 mg and 1400 mg dose, respectively.8 PALOMA (NCT04606381) is an ongoing, open-label, multicenter study assessing the investigational SC administration of RYBREVANT as a potential treatment for patients with advanced NSCLC.7 Meaningful reductions in the incidence and severity of infusion related reactions (IRRs) were also observed (16 percent [no grade 3 or higher IRR] with SC as compared to 67 percent [two percent grade 3 or higher IRR] previously reported with IV).3

"These data provide further evidence of the potential efficacy and safety profile of RYBREVANT as both monotherapy and combination therapy for the treatment of patients with EGFR-mutated NSCLC and support our commitment to advance personalized treatment regimens in areas of continued unmet need," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. "We look forward to continuing to evaluate the full potential of RYBREVANT in our ambition to make this novel therapy available earlier in the treatment paradigm for these patients and improve cancer care."

About the CHRYSALIS Study

CHRYSALIS (NCT02609776) is a Phase 1 open-label, multicenter, first-in-human study to evaluate the safety, pharmacokinetics and preliminary efficacy of RYBREVANT as a monotherapy and in combinations including with lazertinib, a novel third-generation EGFR TKI, in adults with advanced NSCLC. The study consists of two parts: RYBREVANT monotherapy and combination dose escalations (Part 1) and RYBREVANT monotherapy and combination dose expansions (Part 2). The study enrolled 780 patients with advanced NSCLC.4

The treatment-naive cohort of the ongoing CHRYSALIS study enrolled patients with EGFR ex19del or L858R-mutated advanced NSCLC. All patients received 1050 mg of RYBREVANT intravenously (1400 mg if weighing at least 80 kg or more) and 240 mg of lazertinib orally. Disease response using overall response rate (ORR), per Response Evaluation Criteria in Solid Tumors Version 1.1♦ (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR), was the primary endpoint. Circulating tumor DNA was analyzed from plasma samples prior to initiation of treatment, at Cycle 3 Day 1, and at end of treatment.1

About the CHRYSALIS-2 Study5

CHRYSALIS-2 (NCT04077463) is an open-label Phase 1/1b study to evaluate the safety and pharmacokinetics of lazertinib, a third generation EGFR-TKI, as monotherapy or in combinations with RYBREVANT, a human bispecific EGFR and cMet antibody in participants with advanced NSCLC. The study enrolled 460 patients with advanced NSCLC.

Cohort D of the ongoing CHRYSALIS-2 study seeks to validate one or both potential biomarker strategies (NGS and IHC), previously identified in Cohort E, in patients with osimertinib-relapsed and chemotherapy-naïve, EGFR ex19del or L858R-mutated NSCLC. Patients receive the recommended Phase 2 dose of lazertinib orally once daily and RYBREVANT every seven days for the first 28-day cycle and every two weeks thereafter.

About the PALOMA Study7

PALOMA (NCT04606381) is a Phase 1, open-label, multicenter study assessing the feasibility of the SC administration of RYBREVANT based on safety and pharmacokinetics, and to determine a dose, dose regimen and formulation for RYBREVANT SC delivery.

In the ongoing PALOMA study, patients with various advanced solid tumors must have progressed after standard-of-care therapy for metastatic disease, be ineligible for, or have declined current standard therapies. In Part 1, the feasibility of SC administration of RYBREVANT using the available intravenous (IV) formulation (50 mg/mL) at the recommended Phase 2 dose for IV administration, with and without recombinant human hyaluronidase (rHuPH20), will be assessed. In Part 2, dose escalation will be evaluated using a high-concentration formulation (160 mg/mL) of RYBREVANT, with and without rHuPH20. This study is also evaluating administration of the full dose of RYBREVANT on the first day.

About RYBREVANT

RYBREVANT (amivantamab-vmjw) received accelerated approval by the U.S. Food and Drug Administration (FDA) in May 2021 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.8 This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. RYBREVANT has also received approval from health authorities in Europe, as well as other markets around the world.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer◊ prefer NGS-based strategies over PCR-based approaches for the detection of EGFR exon 20 insertion variants and include amivantamab-vmjw (RYBREVANT) as a subsequent therapy option with 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.9†^

RYBREVANT is being studied in multiple clinical trials in NSCLC, including:

As first-line therapy in the Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT in combination with lazertinib, a novel third generation EGFR TKI, versus osimertinib and versus lazertinib alone in untreated advanced EGFR-mutated NSCLC.10
The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT (with or without lazertinib) and carboplatin-pemetrexed versus carboplatin-pemetrexed in patients with locally advanced or metastatic EGFR ex19del or exon 21 L858R substitution NSCLC after osimertinib failure.11
The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT in participants with advanced NSCLC.4
The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.5
The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT in combination with carboplatin-pemetrexed versus chemotherapy alone in patients with advanced or metastatic EGFR-mutated NSCLC and exon 20 insertion mutations.12
The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of RYBREVANT based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for RYBREVANT SC delivery.7
The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous RYBREVANT in participants with advanced or metastatic solid tumors including EGFR-mutated NSCLC.13
The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous RYBREVANT as compared to intravenous RYBREVANT in participants with EGFR-mutated advanced or metastatic NSCLC.14
The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT and capmatinib combination therapy in unresectable metastatic NSCLC.15
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About Lazertinib

Lazertinib is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. Integrated analysis of the efficacy and safety of lazertinib from the Phase 1/2 study were published in The Journal of Thoracic Oncology in 2022.16 In 2018, Janssen Biotech, Inc. entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib.

About Non-Small Cell Lung Cancer

Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases.17,18 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.19 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase supporting cell growth and division.20 EGFR mutations are present in 10 to 15 percent of people with NSCLC adenocarcinoma and occur in 40 to 50 percent of Asians.19-25 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.26 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent.27,28

RYBREVANT IMPORTANT SAFETY INFORMATION8

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. 

Based on the safety population, 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. Monitor patients for any 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 interstitial lung disease (ILD)/pneumonitis. Based on the safety population, 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). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Dermatologic Adverse Reactions

RYBREVANT can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT, 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. 

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad spectrum UVA/UVB sunscreen. Alcohol free emollient cream is recommended for dry skin.

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. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity.

Ocular Toxicity

RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population, 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 presenting with 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 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 final dose of RYBREVANT.

Adverse Reactions

The most common adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium. 

Please read full Prescribing Information for RYBREVANT