On October 23, 2023 Transcenta Holding Limited ("Transcenta") (HKEX: 06628), a clinical-stage biopharmaceutical company with fully-integrated capabilities in discovery, research, development and manufacturing of antibody-based therapeutics, reported that it has presented updated efficacy data from the expansion cohort of the TranStar102 of Osemitamab (TST001) plus CAPOX chemotherapy study as the first-line treatment of advanced G/GEJ Cancer at the ESMO (Free ESMO Whitepaper) Congress 2023 in Madrid, Spain (Press release, Transcenta, OCT 23, 2023, View Source [SID1234636276]). The updated data continued to show encouraging efficacy from previously disclosed data in patients with CLDN18.2 expression ≥10%, ≥1+ per the LDT assay used to select patients. Two additional posters were presented: one on preclinical data supporting the triple combination of Osemitamab (TST001), nivolumab and chemotherapy over Osemitamab (TST001) and chemotherapy including in PD-L1 negative tumors; and one detailing the clinical pharmacology explorations supporting the recommended Phase III dose.

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"These latest datasets further solidify the evidence affirming the efficacy that Osemitamab (TST001) plus CAPOX chemotherapy can provide as a first-line treatment for advanced gastric and gastroesophageal cancer including in tumors with lower levels of CLDN18.2 expression, and provide the rationale to explore the triple combination of Osemitamab (TST001), nivolumab and chemotherapy regardless of the PD-L1 CPS levels." said Dr. Caroline Germa, Transcenta’s Executive Vice President, Global Medicine Development and Chief Medical Officer. "We are highly encouraged by the compelling efficacy outcomes from this study in addition to the recent FDA approval to initiate a global Phase III clinical trial, which signifies that Osemitamab (TST001) is poised to redefine the prevailing standard of care for patients with CLDN18.2 positive, HER2 negative gastric and gastroesophageal cancers."

Study Design

Cohort C from Transtar102 study (NCT04495296) was designed to explore the safety and efficacy of Osemitamab (TST001) plus CAPOX as first-line treatment in advanced G/GEJ cancer. In this study, 49 patients were enrolled and treated with 6mg/kg Q3W Osemitamab (TST001) and CAPOX in the efficacy expansion cohort.

Among the 49 patients enrolled, 41 patients had CLDN18.2 positive tumors, and the other 8 patients did not have the biomarker tested. CLDN18.2 expression were tested using the IHC 14G11 LDT assay in a central laboratory. CLDN18.2 positive tumor was defined as ≥ 10% tumor cells staining at least 1+ by the LDT assay, which represents approximately 55% of all the G/GEJ cancer patients.

Encouraging and Durable mDOR and mPFS

At the cut-off date reported here, the median follow-up for the 49 patients was 11.3 months with the longest treatment duration over 1.5 years. Among the 49 patients, 42 patients had measurable lesions at baseline and at least one post-baseline tumor assessment, and 28 of them achieved partial response, with 23 as confirmed response (54.8%, 23/42). The median duration of response (DoR) of these 23 responders was 12.7 months. 20 patients of the 49 patients had progression of disease or death, with an estimated median progression-free survival (PFS) of 14 months. The median overall survival (OS) was not reached because of the limited number of events, the 12-month survival rate for the overall population of cohort-C (64 patients, all doses) was 88.9% (95% CI: 74.2, 95.4). This further supports the Phase III trial strategy of combining Osemitamab (TST001) with nivolumab and chemotherapy in 1L CLDN18.2 positive G/GEJ cancer which Transcenta received FDA clearance recently.

Favorable and Manageable Safety Profile

The safety profile of these 49 patients was mainly characterized by manageable on-target-off-tumor effects, including nausea, hypoalbuminemia, and vomiting, most of them were grade 1 or 2 and occurred during the first 2 cycles.

In addition, preclinical data presented at the congress (#1560P) showed significant upregulation of PD-L1 in gastric cancer cells and increased TIL infiltration into tumor upon treatment with Osemitamab (TST001). The combination of anti-CLDN18.2 Osemitamab (TST001) with PD1 inhibitor nivolumab and chemotherapy resulted in significant synergy including in a CLDN18.2 positive/PD-L1 negative PDX model of gastric cancer. 5/8, 2/8, 0/8, 0/8 of the mice treated with Osemitamab (TST001) plus nivolumab and chemotherapy, Osemitamab (TST001) and chemotherapy, nivolumab and chemotherapy or chemotherapy only achieved tumor clearance in the mouse model respectively.

In an ER analysis of data from 58 patients with 1L G/GEJ adenocarcinoma treated with Osemitamab (TST001) and CAPOX, trends of longer PFS/DoR and higher durable ORR were associated with higher Osemitamab (TST001) exposure and was aligned with exposure range achieved by 6 mg/kg Q3W. Safety ER analyses didn’t demonstrate clinically significant increase in risk when dose increased from 3 to 6 mg/kg Q3W. Preliminary efficacy, safety and PK/PD data demonstrates favorable benefit risk profile and support future exploration of Osemitamab (TST001) at the dose of 6mg/kg Q3W or 4mg/kg Q2W.

About Osemitamab (TST001)

Osemitamab (TST001) is a high affinity humanized anti-CLDN18.2 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity ("ADCC"). It has shown potent anti-tumor activities in tumor xenograft models. Osemitamab (TST001) is the second most advanced CLDN18.2 targeting antibody being developed globally. Osemitamab (TST001) was generated using Transcenta’s Immune Tolerance Breaking Technology (IMTB) platform. Osemitamab (TST001) kills CLDN18.2 expressing tumor cells by mechanisms of ADCC. Leveraging advanced bioprocessing technology, the fucose content of Osemitamab (TST001) was significantly reduced during the production, which further enhanced NK cells mediated ADCC activity of Osemitamab (TST001). Clinical trials for Osemitamab (TST001) are ongoing in the U.S. and China (NCT05190575, NCT04396821, NCT04495296, NCT05608785 / CTR20201281). Osemitamab (TST001) was granted Orphan Drug Designation in the U.S. by FDA for the treatment of patients with gastric or gastroesophageal junction (G/GEJ) and pancreatic cancer.

On October 23, 2023 The Janssen Pharmaceutical Companies of Johnson & Johnson reported results from the Phase 3 MARIPOSA-2 study showing the regimen of RYBREVANT (amivantamab-vmjw) given with or without lazertinib and combined with chemotherapy reduced the risk of disease progression or death by 56 and 52 percent respectively (Hazard Ratio [HR]=0.44; 95 percent Confidence Interval [CI], 0.35–0.56; p value P<0.001 and HR=0.48; 95 percent CI, 0.36–0.64; P<0.001) compared to chemotherapy alone in patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or L858R substitution, after disease progression on or after osimertinib (Press release, Johnson & Johnson, OCT 23, 2023, View Source [SID1234636275]). Results also showed that the two RYBREVANT regimens significantly improved objective response rate (ORR), intracranial progression-free survival (PFS), and duration of response (DOR) compared to chemotherapy alone in these patients. These data were presented in a Presidential Symposium at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress taking place October 20-24, 2023 in Madrid, Spain (Abstract #LBA15) and simultaneously published in Annals of Oncology.1

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"The promising results from the MARIPOSA-2 study show that by combining RYBREVANT with chemotherapy, both with and without lazertinib, patients achieved longer progression-free survival compared with chemotherapy alone," said Antonio Passaro,* M.D., Ph.D., medical oncologist of the Division of Thoracic Oncology, European Institute of Oncology in Milan, Italy, and presenting author. "The efficacy seen across the two RYBREVANT regimens suggests that this treatment combination may address the diverse and often varied resistance that can occur in the post-osimertinib setting."

RYBREVANT plus chemotherapy reduced the risk of disease progression or death by 52 percent compared to chemotherapy alone (HR=0.48; 95 percent CI, 0.36–0.64; P<0.001). RYBREVANT plus chemotherapy with lazertinib reduced the risk of disease progression or death by 56 percent compared to chemotherapy alone (HR=0.44; 95 percent CI, 0.35–0.56; P<0.001). The improved PFS was consistent across all pre-specified patient subgroups, including age, sex, race, history of brain metastasis, smoking history, and lines of prior osimertinib therapy. Additionally, RYBREVANT plus chemotherapy showed an ORR of 64 percent and RYBREVANT plus chemotherapy and lazertinib demonstrated an ORR of 63 percent, compared to a response rate of 36 percent with chemotherapy alone.1

The data from MARIPOSA-2 are also the first to show that RYBREVANT combination regimens may provide intracranial activity, which is critical for a disease where nearly 30 percent of patients develop brain metastases. Specifically, RYBREVANT plus chemotherapy and RYBREVANT plus chemotherapy and lazertinib reduced the risk of intracranial progression or death by 45 percent and 42 percent, respectively compared to chemotherapy alone (HR=0.55; 95 percent CI, 0.38–0.79; P=0.001 and HR=0.58; 95 percent CI, 0.44–0.78; P<0.001, respectively).1

Early interim overall survival (OS) data show a trend favoring RYBREVANT plus chemotherapy compared with chemotherapy alone (HR=0.77; 95 percent CI, 0.49–1.21). No difference in OS was observed at the interim analysis for RYBREVANT plus chemotherapy and lazertinib compared with chemotherapy alone (HR=0.96; 95 percent CI, 0.67–1.35).1

The safety profile for RYBREVANT was consistent with prior reports. The most common adverse events (AEs) in the RYBREVANT-containing arms were hematologic, EGFR, and MET-related. RYBREVANT plus chemotherapy had lower rates of hematologic AEs than treatment with RYBREVANT plus chemotherapy with lazertinib. The overall incidence of adverse events of special interest for the RYBREVANT combination arms, including infusion-related reaction, rash, and pneumonitis, was comparable to that seen with RYBREVANT monotherapy experience. Serious AEs occurred in 52 percent of patients receiving RYBREVANT plus chemotherapy with lazertinib and 32 percent of patients treated with RYBREVANT plus chemotherapy, compared with 20 percent of patients who received chemotherapy alone. The incidence of treatment-related AEs leading to death was low and comparable between all treatment arms. Rates of venous thromboembolism (VTE) were higher in the RYBREVANT combinations, mostly Grade 1 or 2 with no Grade 5 events and rates of discontinuations due to VTEs were less than or equal to one percent. Incidence of interstitial lung disease (including pneumonitis) was three percent or less in all RYBREVANT combinations.1

"RYBREVANT plus chemotherapy, given with and without lazertinib, showed consistent disease control across all pre-specified patient subgroups in the MARIPOSA-2 study," said Craig Tendler, M.D., Vice President, Late Development and Global Medical Affairs, Janssen Research & Development, LLC. "These encouraging results reinforce the distinct profile of RYBREVANT-based regimens as potential practice-changing treatment options and mark another important key milestone in our pursuit to transform the treatment of EGFR-mutated NSCLC."

RYBREVANT is a bispecific antibody targeting EGFR and MET with immune cell-directing activity, and in the MARIPOSA-2 study was combined with chemotherapy (carboplatin and pemetrexed) and given with and without lazertinib, an oral third-generation EGFR tyrosine kinase inhibitor (TKI) in patients with locally advanced or metastatic EGFR-mutated NSCLC after disease progression on or after osimertinib. In the study, 657 patients were randomized to receive treatment with RYBREVANT and chemotherapy, either with or without lazertinib, or chemotherapy alone. Dual primary endpoints were used to compare PFS, as assessed by blinded independent central review (BICR), for each experimental arm to chemotherapy alone. Secondary endpoints included OS, ORR, DOR, and intracranial PFS.1

Results from MARIPOSA-2 will support future planned health authority submissions.

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 lazertinib) and chemotherapy. 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 lazertinib, or chemotherapy alone. The dual primary endpoint was used to compare the PFS (using RECIST v1.1 guidelines†) as assessed by BICR for each experimental arm to chemotherapy alone. Secondary endpoints included objective response as assessed by BICR, OS, DOR, time to subsequent therapy, PFS2 and intracranial PFS.2

All study participants underwent serial brain imaging to allow for the robust assessment of intracranial endpoints and to assess the CNS activity of RYBREVANT with and without lazertinib. As brain metastases can lead to significant burden and poor outcomes for patients, this aspect of the study design provides critical information in an area of high unmet need. The study enrolled 657 patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC who had disease progression on or after treatment with osimertinib.2

About RYBREVANT

RYBREVANT (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, 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.3 This indication is approved under accelerated approval based on ORR and DOR. 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. In August 2023, Janssen submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration for the expanded approval of RYBREVANT in combination with chemotherapy (carboplatin-pemetrexed) for the first-line treatment of patients with NSCLC with EGFR exon 20 insertion mutations. A marketing authorization application has also been submitted to the European Medicines Agency seeking approval for the combination of RYBREVANT and chemotherapy.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer‡ prefer next-generation sequencing-based strategies over polymerase chain reaction-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.4§∥

In addition to the Phase 3 MARIPOSA-2 study, RYBREVANT is being studied in multiple clinical trials in NSCLC, including:

The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT in combination with lazertinib versus osimertinib and versus lazertinib alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations. Topline data for this randomized Phase 3 study demonstrated statistically significant and clinically meaningful improvement in PFS in patients receiving RYBREVANT plus lazertinib versus osimertinib.5
The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT in combination with carboplatin-pemetrexed versus carboplatin-pemetrexed in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Topline data for this randomized Phase 3 study demonstrated statistically significant and clinically meaningful improvement in PFS in patients receiving RYBREVANT versus chemotherapy.6
The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT in participants with advanced NSCLC.7
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.8
The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab SC delivery.9
The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in participants with advanced or metastatic solid tumors including EGFR-mutated NSCLC.10
The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in participants with EGFR-mutated advanced or metastatic NSCLC.11
The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT and capmatinib combination therapy in locally advanced or metastatic NSCLC.12
The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT and cetrelimab combination therapy in locally advanced or metastatic NSCLC.13
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 lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.14
For more information, visit: View Source

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. An analysis of the efficacy and safety of lazertinib from the Phase 3 LASER301 study was published in The Journal of Clinical Oncology in 2023.15 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.16,17 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.18 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.19 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.18,19,20,21,22,23 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.24 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent.25,26 Patients with EGFR ex19del or L858R mutations have a real-world five-year OS of 19 percent.27

RYBREVANT IMPORTANT SAFETY INFORMATION3

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 (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%).

Please read the full Prescribing Information for RYBREVANT. 

On October 23, 2023 Medigene AG (Medigene, the "Company", FSE: MDG1, Prime Standard) an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported data showing significantly enhanced T cell activity when combining the PD1-41BB costimulatory switch protein (CSP) with recombinant T cell receptors (rTCR) not only when directed at the cancer-testis antigen (CTA) New York esophageal squamous cell carcinoma-1 (NY-ESO-1)/L Antigen Family Member-1a (LAGE-1a), but also, presented here for the first time, against the neoantigen mutant Kirsten rat sarcoma virus (mKRAS) G12V at the ESMO (Free ESMO Whitepaper) Congress 2023 held October 20-24, 2023, in Madrid, Spain (Press release, MediGene, OCT 23, 2023, View Source [SID1234636273]).

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The poster with the title "Mitigation of Tumor Microenvironment-Mediated Immunosuppression Using a PD1-41BB Switch Protein with Optimal Affinity TCRs for First-In-Class, 3rd Generation TCR-T Therapies" will be available on Monday, October 23, 2023, following the conference presentation on Medigene’s website: View Source

"The immunosuppressive tumor microenvironment remains a major challenge for many T cells, including engineered T cells when applied against solid tumors. We are pleased to report encouraging pre-clinical data showing significantly enhanced T cell functionality by engaging our PD1-41BB CSP with different optimal affinity TCRs not only targeting CTAs like NY-ESO-1/LAGE-1a, but also against the neoantigen mKRAS G12V," said Prof. Dolores Schendel, Chief Scientific Officer at Medigene. "Armoring and enhancing our optimal affinity TCRs with the PD1-41BB costimulatory switch protein has the potential to overcome an immunosuppressive tumor microenvironment, leading to TCR-T therapies that improve safety, efficacy and durability outcomes for patients."

Within the solid tumor microenvironment (TME) T cell functionality is strongly impaired by the expression of the programmed cell death 1 ligand 1 (PD-L1) on tumor cells. The engagement of PD-L1 on tumor cells with PD-1 on T cells prevents specific killing of tumor cells. Moreover, PD-L1 signalling to T cells via the PD-1 receptor limits proliferation, cytokine secretion and cytotoxic response, while exhaustion is induced by repetitive TCR signalling in the absence of T cell costimulation.

The presented data showed that by combining optimal affinity TCRs with a PD1-41BB CSP, not only is the PD-1/PD-L1 axis blocked, but also T cell proliferation, cytokine secretion and cytotoxic response are increased through positive 4-1BB signaling, resulting in mitigation of the immunosuppressive TME through enhanced T cell functionality.

Robust expression of rTCR directed against NY-ESO-1/LAGE-1a and/or the neoantigen mKRAS G12V as well as the PD1-41BB CSP was demonstrated in TCR-T cells. The combination of NY-ESO-1/LAGE-1a or mKRAS G12V-specific rTCRs with PD1-41BB CSP displayed elevated polyfunctionality by increased levels of effector, stimulatory and chemoattractive cytokines as compared to TCR-T cells without PD1-41BB CSP in melanoma and pancreatic tumor cell lines.

Interferon-gamma (IFNγ) release measured in several tumor cell lines of different origin was enhanced in TCR-T cells co-expressing the rTCR and PD1-41BB CSP as compared to TCR-T cells lacking PD1-41BB CSP. The co-stimulatory effects of PD1-41BB were highly dependent on the rTCR-mediated recognition of the specific tumor-antigen NY-ESO-1/LAGE-1a or mKRAS G12V, respectively, and on the expression of the inhibitory ligand PD-L1 on tumor cells.

Elevated and sustained killing of 3D tumor spheroids was observed with TCR-T cells co-expressing the rTCR targeting mKRAS G12V and PD1-41BB CSP compared to TCR-T cells without the PD1-41BB CSP.

Additional data on Medigene’s library of KRAS mutation-specific TCRs will be presented at the Society of Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting held in San Diego, November 1 to 5, 2023.

SITC 2023 Presentation Details:

Title: A novel library of optimal affinity KRAS mutation-specific T cell receptors associated with multiple HLAs, in combination with a PD1-41BB armoring and enhancement costimulatory switch receptor

Authors: Dolores Schendel, Giulia Longinotti, Mario Catarinella, Melanie Salvermoser, Julia Bittmann, Kirsty Crame, Kathrin Davari

Presenter: Selwyn Ho

Abstract number: 388

Date/ time: Saturday, November 4, 2023; Poster lunch session (11:55 am to 1:25 pm) and poster reception (7:00 pm to 8:30 pm); poster will be on display from 9:00 am to 8:30 pm (all times PDT)

Location: Poster Hall, San Diego Convention Center

The abstract will be available on the SITC (Free SITC Whitepaper) website on October 31, 2023 at 9 am EDT, and the poster will be available on Medigene’s website following the presentation.

On October 23, 2023 AstraZeneca and Daiichi Sankyo reported that (trastuzumab deruxtecan) has been approved in the European Union (EU) as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) whose tumours have an activating HER2 (ERBB2) mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy (Press release, AstraZeneca, OCT 23, 2023, View Source [SID1234636272]).

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Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the DESTINY-Lung02 Phase II trial presented at the IASLC 2023 World Conference on Lung Cancer and simultaneously published in the Journal of Clinical Oncology.

In the trial, Enhertu 5.4mg/kg demonstrated a confirmed objective response rate (ORR) of 49.0% (95% confidence interval [CI] 39.0-59.1), as assessed by blinded independent central review (BICR), in patients with previously treated advanced or metastatic HER2-mutant (HER2m) NSCLC. One (1.0%) complete response (CR) and 49 (48.0%) partial responses (PR) were observed. The median duration of response (DoR) was 16.8 months (95% CI 6.4-not estimated [NE]).

Martin Reck, MD, PhD, Head of the Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Germany, said: "HER2-mutant non-small cell lung cancer is more commonly diagnosed in patients who are younger and female, and there are limited treatment options which often results in a poor prognosis. Enhertu is the first HER2-directed therapy to demonstrate strong and durable results for these patients, and this EU approval marks an important step forward in how the disease can be treated."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "Understanding the molecular drivers behind a lung cancer diagnosis is critical, and while there are now targeted options for many patients, those with HER2-mutant non-small cell lung cancer have had few treatment options, none of which have been approved to treat their specific type of lung cancer. Enhertu is the first HER2-directed option approved for HER2-mutant disease and confirms the relevance of HER2 as a target in lung cancer."

Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc., said: "Since our initial approval of Enhertu for metastatic breast cancer in the EU more than two years ago, we have remained committed to bringing this innovative antibody drug conjugate to more patients with HER2-targetable tumours, especially those that have previously not been eligible for treatment with a HER2-directed therapy. With today’s news, Enhertu is the first antibody drug conjugate approved for lung cancer in the EU and is now approved in three different tumour types."

The safety profile of Enhertu in the DESTINY-Lung02 trial was consistent with previous clinical trials with no new safety signals identified.

Financial considerations
Following EU approval, an amount of $75m is due from AstraZeneca to Daiichi Sankyo as a milestone payment for this HER2-mutant (HER2m) NSCLC indication. The milestone payment will be capitalised as an addition to the upfront payment made by AstraZeneca to Daiichi Sankyo in 2019 and subsequent capitalised milestones.

Sales of Enhertu in most EU territories are recognised by Daiichi Sankyo. AstraZeneca reports its share of gross profit margin from Enhertu sales in those territories as alliance revenue in the Company’s financial statements. AstraZeneca will record product sales in respect of sales made in territories where AstraZeneca is the selling party.

Further details on the financial arrangements were set out in the March 2019 announcement of the collaboration.

Notes

HER2m NSCLC
Lung cancer is the second most common form of cancer globally with more than two million cases diagnosed in 2020.1 In Europe, lung cancer is the third most commonly diagnosed cancer with more than 477,000 cases diagnosed in 2020.2 Lung cancer is also the leading cause of cancer-related deaths in Europe, with nearly 400,000 deaths reported in 2020.2 Prognosis is particularly poor for patients with metastatic NSCLC as only approximately 9% will live beyond five years after diagnosis.3

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of multiple tumour types. Certain HER2 (ERBB2) gene alterations (called HER2 mutations) have been identified in patients with non-squamous NSCLC as a distinct molecular target, and occur in approximately 2-4% of patients with this type of lung cancer.4,5 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7 Next-generation sequencing has been utilised in the identification of HER2 (ERBB2) mutations.8,9

DESTINY-Lung02
DESTINY-Lung02 is a global, randomised Phase II trial evaluating the safety and efficacy of Enhertu in patients with HER2m advanced or metastatic NSCLC with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. Patients were randomised 2:1 to receive Enhertu 5.4mg/kg (n=102) or Enhertu 6.4mg/kg (n=50).

The primary endpoint of the trial is confirmed ORR as assessed by BICR. Secondary endpoints include DoR, confirmed disease control rate, and progression-free survival assessed by investigator and BICR, overall survival and safety.

DESTINY-Lung02 enrolled 152 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

Enhertu
Enhertu 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 programme 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 (5.4mg/kg) is approved in more than 55 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a (or one or more) 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 (5.4mg/kg) is approved in more than 40 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 (5.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with unresectable or metastatic NSCLC whose tumours 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 for this indication in the US may be contingent upon verification and description of clinical benefit in a confirmatory trial.

Enhertu (6.4mg/kg) is approved in more than 30 countries for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 and/or DESTINY-Gastric02 trials.

Enhertu development programme
A comprehensive clinical development programme is underway globally, evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

On October 23, 2023 Adaptimmune Therapeutics plc (Nasdaq: ADAP), a leader in cell therapy to treat cancer, reported clinical and translational data from its Phase 1 SURPASS clinical trial (NCT04044859) investigating the next-generation engineered T-cell therapy ADP-A2M4CD8 at the Annual European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress (Press release, Adaptimmune, OCT 23, 2023, View Source [SID1234636271]). The oral presentation was presented by Dr. Victor Moreno of START Madrid-FJD, Fundación Jiménez Díaz Hospital, in the proffered paper session – investigational monotherapy.

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Dr. Victor Moreno, Director of Clinical Research at START Madrid-FJD, Fundación Jiménez Díaz Hospital, clinical investigator in SURPASS trial and presenter at ESMO (Free ESMO Whitepaper): "The findings from the SURPASS study represent a groundbreaking milestone in the field of cell therapy for solid tumors. For the first time, the utilization of modified T-cells targeting MAGE-A4 has demonstrated remarkable efficacy in generating substantial responses across a spectrum of diseases, including head & neck, urothelial, and ovarian cancers. These results give us confidence that the field of cell therapy for solid tumors will continue to advance in the forthcoming years."

Dr. Elliot Norry, Chief Medical Officer at Adaptimmune: "Advanced-stage solid tumors remain a tremendous challenge to manage, as the current standard of care treatments often have limited efficacy and can be a tremendous burden on patients, healthcare providers, and caregivers. We are pleased to see promising responses and safety results with ADP-A2M4CD8 in people with advanced tumors who have generally received extensive prior therapies. Based on clear efficacy signals thus far in the Phase 1 SURPASS trial, we are eager to now focus on the head & neck and bladder cancer cohorts in earlier lines of treatment as well as the Phase 2 SURPASS-3 ovarian cancer trial."

Positive data from the Phase 1 SURPASS trial (ESMO 2023)

Clinical data demonstrate efficacy signals supporting further development in ovarian, urothelial and head & neck cancers. ADP-A2M4CD8 continues to show acceptable benefit to risk profile for people with a broad range of MAGE-A4 expressing unresectable or metastatic tumors, including in people receiving nivolumab combination therapy.

As of the data cut-off, there were 46 evaluable patients who received ADP-A2M4CD8 monotherapy, and 10 who received ADP-A2M4CD8 in combination with nivolumab.
In the monotherapy arm, 16 of 46 evaluable patients had clinical responses, resulting in a 35% overall response rate, with a median duration of response (DOR) of approximately 5 months.
Cannot view this image? Visit: View Source

CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease; ESMO (Free ESMO Whitepaper) 2023 data cut off August 14, 2023

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In the 26 people in the monotherapy arm with ovarian, urothelial, and head & neck cancers, there were 13 clinical responses, resulting in a 50% response rate. Among people with these indications who received 3 or fewer prior lines of systemic therapy, there was a 75% (9/12) response rate supporting future clinical development in earlier line treatment settings.

Early data from the nivolumab combination arm is still evolving. At the time of the data cut, there was 1 confirmed response. Subsequent to the data cut, there has been one additional confirmed response in the combination arm.

ADP-A2M4CD8 continues to show an acceptable benefit-to-risk profile among people with a broad range of MAGE-A4 expressing unresectable or metastatic tumors, including in those receiving nivolumab combination therapy. Cytokine release syndrome (CRS) was tolerable, and manageable with tocilizumab and corticosteroids when required.

Translational analyses performed on tumor biopsy and serum samples demonstrated that clinical responses are associated with strong evidence of ADP-A2M4CD8 tumor infiltration, broad immune engagement, and anti-MAGE-A4 tumor activity.

About the SURPASS Family of Trials

Phase 1 SURPASS trial (NCT04044859): ADP-A2M4CD8, a next-generation engineered T-cell therapy targeting the cancer testis antigen MAGE-A4, is being investigated for the treatment of advanced or unresectable solid tumors in the Phase 1 SURPASS clinical trial (NCT04044859). Enrollment is now focused on people with head & neck or urothelial cancers, in earlier lines of treatment and in combination with checkpoint inhibitors. This will facilitate further understanding of the early promising signals in these tumor types and enable decisions regarding later phase trials. Patients will receive a dose of 1 to 10 billion ADP-A2M4CD8 engineered T-cells following the lymphodepletion regimen of fludarabine (30 mg/m^2/day for 4 days) and cyclophosphamide (600 mg/m^2/day for 3 days). Key eligibility criteria include diagnosis of advanced head & neck or urothelial cancers; HLA-A*02 and MAGE-A4 positive tumor biopsies; ECOG performance status of 0 or 1; Aged ≥18 years and ≤75 years; Measurable disease per RECIST v1.1 prior to lymphodepletion.

SURPASS-3 trial (NCT05601752/ (GOG-3084): ADP-A2M4CD8 received FDA RMAT designation in 2022 for the treatment of patients with platinum resistant ovarian cancer and is currently enrolling.

This is a global Phase 2 clinical trial designed to evaluate ADP-A2M4CD8 TCR T-cell therapy alone or in combination with nivolumab in patients with recurrent or metastatic platinum resistant ovarian cancer (PROC). The SURPASS-3 trial will treat up to 66 patients randomized to receive ADP-A2M4CD8 either as monotherapy or in combination with nivolumab (checkpoint inhibitor) combination arms. Patients will receive a dose of 1 to 10 billion ADP-A2M4CD8 engineered T-cells following the lymphodepletion regimen of fludarabine (30 mg/m^2/day for 4 days) and cyclophosphamide (600 mg/m^2/day for 3 days). Patients enrolled in the combination arm will also receive nivolumab 480 mg every 4 weeks, starting at week 4 post engineered T-cell infusion. Key eligibility criteria include diagnosis of platinum-resistant ovarian carcinoma; HLA-A*02 and MAGE-A4 positive tumor biopsies; ECOG performance status of 0 or 1; Aged ≥18 years and ≤75 years; Measurable disease per RECIST v1.1 prior to lymphodepletion.

The primary endpoint is overall response (ORR) rate by RECIST v1.1 by independent review. Safety endpoints will be reviewed by an Independent Data Safety Monitoring Board. The trial is currently underway in collaboration with The GOG Foundation, Inc. (GOG) in the United States, with additional sites initiating in Canada, the United Kingdom, and the EU.

About Ovarian Cancer

Ovarian cancer is a group of diseases that originate in female ovaries, or in the related areas of the fallopian tubes and the peritoneum. In the U.S. each year, there are approximately 20,000 new cases, with more than 50% women diagnosed with metastatic disease, and more than 13,000 deaths.1 Platinum chemotherapy is standard of care for patients but about 70% of advanced patients have a recurrence after standard treatment.2,3,4 Many of these patients become resistant to platinum-based treatments (approximately 18,000 cases in 2023).5 Those with platinum-resistant ovarian cancer have limited options.

1.NCI SEER 2. NCCN guidelines 3. Mcquire et al. 1996 Jan 4;334(1):1-6 4. Ushijima J Oncol. 2010; 2010: 497429
5. Decision Resources Group DRG Ovarian Forecast Aug 2023.

About Head & Neck Cancer

Head & neck cancer is categorized as any cancer that occurs in the epithelium of the paranasal sinuses, nasopharynx, oropharynx, oral cavity, hypopharynx or larynx. 68,000 people are diagnosed with this cancer in the US per year.1 These cancers are more than twice as common among men as they are among women and more often diagnosed in people over age 50.1 In the US, the five-year survival across all those diagnosed with head & neck cancers is approximately 61-68%, declining to less than 40% for people diagnosed with metastatic disease.2 Immunotherapies represent the main treatment option for those with recurrent or metastatic disease, but response rates remain low, at approximately 19% for checkpoint inhibitor monotherapy and 36% for checkpoint inhibitors in combination with chemotherapy with median progression-free survival of 3-to-5 months and median overall survival of 13 to 15 months.3 People with later-line disease have limited effective options, median progression-free survival with standard care treatment is less than 4 months and median overall survival is less than 8 months.4,5,6

1. www.cancer.gov/types/head-and-neck/head-neck-fact-sheet, data as of 2021. Visited 10.12.2023. 2. National Cancer Institute Surveillance, and End Results Program (SEER) Program: Cancer Stat Facts: View Source 3. Pembrolizumab/Keytruda Prescribing Information 4. Vermorken et al. 2008. Cancer. 112(12): 2710-9. 5.Knoedler et al. 2013. Oncology. 84:284-289. 6. Peron et. al. Anticancer Drugs. 2012. 23(9):996-1001.

About Urothelial Cancer/Bladder Cancers

Urothelial cancer is cancer that begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs1. In the U.S. there are an estimated 82,000 new cases of bladder cancer and about 17,000 deaths each year. In the US, while 77% of people are alive 5 years after diagnosis, treatment options are suboptimal for people with advanced/metastatic disease.2 Only about half of the people treated with standard of care first-line cisplatin-based chemotherapy respond and people progress at a median of approximately 8 months.3,4 People ineligible for platinum chemotherapy may be treated with alternative regimens, with response rates of 41% -68%.5,6,7,8 People receiving checkpoint inhibitors after progressing on platinum have a response rate of approximately 20%9,10 and, for certain checkpoint inhibitors, median progression-free survival of approximately 2 months and median overall survival of 10 months.9

1. www.cancer.gov/types/bladder. Visited 10.12.23. 2. www.cancer.org/cancer/types/bladder-cancer/ about/key-statistics.html. 2. National Cancer Institute Surveillance, and End Results Program (SEER) Program: Cancer Stat Facts: View Source 3. von der Maase et al. 2000. J Clin Oncol. 18(17):3068-77. 4. von der Maase et al. 2005. J Clin Oncol. 21:4602-4608. 5. De Santis et al. 2012. J Clin Oncol. 30(2):191-199. 6 Balar et al. 2017. Lancet. 389: 67-76. 7. Vuky et al. 2020. J Clin Oncol.. 38(23): 2658-2666. 8. Padcev Prescribing Information 9. Pembrolizumab/Keytruda Prescribing Information. 10. Nivolumab/Opdivo Prescribing Information.