On October 22, 2023 InxMed Co., Ltd, a clinical-stage biotechnology company dedicated on developing innovative therapies to overcome drug resistance for hard-to-treat solid tumors, reported that clinical data of Ifebemtinib (IN10018), a highly potent and selective oral inhibitor of focal adhesion kinase (FAK), in platinum-resistant recurrent ovarian cancer (PROC) and triple-negative breast cancer (TNBC) has been presented at the 2023 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress taking place October 20-24 in Madrid, Spain (Press release, InxMed, OCT 22, 2023, View Source [SID1234636221]). Both of the two studies showed that patients receiving IN10018 containing regimens demonstrated promising antitumor activities with trends toward survival benefit.

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Platinum-Resistant Recurrent Ovarian Cancer（Poster #：753P）

In a single-arm, open-label, phase Ib trial, PROC patients received IN10018 in combination with pegylated liposomal doxorubicin (PLD) treatment.

The combination of IN10018 with PLD showed prolonged survival in PROC patients and manageable safety profile. As of cutoff date of April 28, 2023, a total of 61 patients were enrolled with median follow-up duration of 14.0 months. Comparing with historical data by PLD alone with an ORR (Objective Response Rate) of ~10%, median PFS (Progression-Free Survival) of 3.3 months and median OS (Overall Survival) of 12 months, the ORR of PLD in combination with IN10018 was 46.3% (95% CI：32.6-60.4), the DCR (Disease Control Rate) was 83.3% (95% CI 70.7-92.1), the median PFS was 7.56 months (95% CI: 5.5 – 9.1 months), the median OS was 20.9 months (95% CI: 14.4 months – NA) and still maturing. The safety profile of the combination is comparable to these single agents alone without additive toxicities.

Triple-Negative Breast Cancer (Poster#：398P)

This phase Ib/II study was to evaluate the safety, tolerability, and antitumor activity of IN10018 combined with PLD with/without anti-PD-1 antibody Toripalimab in previously-treated solid tumors with metastatic TNBC who had failed in 1-2 lines of systemic therapy.

As of the cutoff date of August 31, 2023, 12 patients received IN10018 + PLD (doublet) and 14 patients received IN10018 + PLD + Toripalimab (triplet). Historical data showed a median PFS was 4.3 months when PLD and low dose of cyclophosphamide is combined with anti-PD-1. In doublet group, the median PFS was 3.65 months (95% CI：1.77-7.29), and median OS was 8.26 months (95% CI, 5.59-NA). In triplet group, the median PFS was 7.43 months (95% CI：3.02-10.8), and median OS was not reached with the low boundary of 95% CI as 9.26 months. The safety profiles of both doublet group and triplet group in metastatic TNBC are tolerable and comparable to each single agent alone.

FAK signaling has been shown to be critical in pathologic fibrosis and is hyperactivated in many cancer types. FAK activation is correlated with poor survival and treatment resistance of tumors.

InxMed is developing IN10018 globally. IN10018 has received fast track designation from the U.S. Food and Drug Administration (FDA) and breakthrough designation from China National Medical Products Administration (NMPA).

A placebo-controlled, randomized, double-blind Phase II pivotal trial is ongoing to confirm the observed efficacy and safety of IN10018 in PROC. New Drug Application (NDA) is expected to be submitted in 2024.

On October 22, 2023 Astrazeneca reported updated results from the BEGONIA Phase Ib/II trial for the cohort of patients treated with datopotamab deruxtecan (Dato-DXd) plus Imfinzi (durvalumab) (Arm 7) showed that the combination demonstrated durable tumour responses and no new safety signals in patients with previously untreated advanced or metastatic triple-negative breast cancer (TNBC) with six months additional follow-up from the previous data cut-off (Press release, AstraZeneca, OCT 22, 2023, View Source [SID1234636219]).

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These data will be presented today in a mini oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress in Madrid, Spain (379MO).

Datopotamab deruxtecan is a specifically engineered TROP2-directed DXd antibody drug conjugate (ADC) being jointly developed by AstraZeneca and Daiichi Sankyo.

Approximately 300,000 people worldwide are diagnosed annually with TNBC, the most aggressive breast cancer subtype.1-2 Less than half of patients with metastatic TNBC respond to current 1st-line treatment options which can include chemotherapy alone or in combination with an immunotherapy.2-4 Among patients with tumours that do respond to initial treatment, disease progression is common and rapid, often occurring within two years.2,4-6

Results showed that datopotamab deruxtecan plus Imfinzi, an anti-PD-L1 therapy, demonstrated a confirmed objective response rate (ORR) of 79% (n=49 of 62) including six complete responses (CRs) and 43 partial responses (PRs). Responses were observed regardless of PD-L1 expression level. Median progression-free survival (PFS) was 13.8 months (95% confidence interval [CI] 11-not calculable [NC]) and median duration of response (DoR) was 15.5 months (95% CI: 9.9-NC) with 11.7 months of follow-up.

Peter Schmid, MD, Barts Cancer Institute, London, United Kingdom, and investigator in the trial, said: "These results for datopotamab deruxtecan plus durvalumab in the first-line triple-negative breast cancer setting are highly encouraging, particularly the 79% objective response rate. This magnitude of response is especially notable given the majority of patients in this cohort have PD-L1-low tumours, representing a population for whom treatment has long been limited to standard chemotherapy."

Cristian Massacesi, Chief Medical Officer and Oncology Chief Development Officer, AstraZeneca, said: "Progress in the first-line advanced triple-negative breast cancer setting has been modest for years and new therapeutic strategies are needed to improve outcomes for patients with this aggressive breast cancer subtype. These updated results from the BEGONIA trial reinforce our confidence in the potential for datopotamab deruxtecan to become a new, important treatment modality in this setting as we eagerly await results from our ongoing Phase III triple-negative breast cancer programme."

Mark Rutstein, MD, Global Head, Oncology Clinical Development, Daiichi Sankyo, said: "Disease progression after initial treatment is a reality for patients with triple-negative breast cancer, underscoring the need for more durable treatment options. These findings showcase the potential of datopotamab deruxtecan in previously untreated advanced triple-negative breast cancer and, following the positive results of our TROPION-Breast01 Phase III trial, build on the growing body of evidence for the potential use of this TROP2-directed antibody drug conjugate, alone and in combinations, in several subtypes of breast cancer."

The safety profile of datopotamab deruxtecan in combination with Imfinzi was consistent with the known safety profiles of both agents. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 57% of patients. The most common Grade 3 or higher TEAEs were increased amylase (18%), stomatitis (11%), constipation (2%), fatigue (2%), vomiting (2%) and decreased appetite (2%). There were three interstitial lung disease (ILD) events adjudicated as drug-related by an independent committee including two Grade 2 events and one Grade 1 event.

In Arm 7 of the BEGONIA trial (n=62), the majority of patients (n=54) had tumours with low PD-L1 expression (tumour area positivity [TAP] <10%). Seven patients had tumours with high PD-L1 expression (TAP ≥10%). As of the 2 February 2023 data cut-off, 29 patients (47%) remained on study treatment.

Summary of BEGONIA Arm 7 Efficacy Results

Efficacy Measure (as assessed by investigator)

All Patients (n=62)

ORR, confirmed (95% CI)

79% (n=49) (66.8-88.3)

CR rate

10% (n=6)

PR rate

69% (n=43)

Median DoR (95% CI)

15.5 months (9.9-not calculable)

Median PFS (95% CI)

13.8 months (11.0-not calculable)

CR; complete response; CI, confidence interval; DCR, disease control rate; ORR, objective response rate; PR, partial response; PD, progressive disease; SD, stable disease
i ORR is (complete response + partial response)

AstraZeneca and Daiichi Sankyo have two Phase III trials evaluating datopotamab deruxtecan in TNBC. TROPION-Breast02 is comparing datopotamab deruxtecan to chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC who are not candidates for anti-PD-L1 therapy. TROPION-Breast03 is evaluating datopotamab deruxtecan with and without Imfinzi versus investigator’s choice of therapy in patients with Stage I-III TNBC with residual disease after neoadjuvant therapy.

Several presentations featured during the ESMO (Free ESMO Whitepaper) 2023 Congress are showcasing the strength and depth of data for datopotamab deruxtecan across multiple tumour types and settings, including results from the TROPION-Lung01 and TROPION-Breast01 Phase III trials.

Notes

Triple-negative breast cancer
Breast cancer is the most common cancer in the world and leading cause of cancer-related death.1 More than two million breast cancer cases were diagnosed in 2020 with nearly 685,000 deaths globally.1

While some breast cancers may test positive for oestrogen receptors, progesterone receptors or overexpression of human epidermal growth factor receptor 2 (HER2), TNBC tests negative for all three.2 Approximately 15% of breast cancer tumours (300,000 cases annually) are considered triple-negative which is the most aggressive breast cancer subtype.1-2 1st-line treatment for advanced or metastatic TNBC usually consists of chemotherapy alone or in combination with an immunotherapy – options generally associated with response rates between 30 to 50%.2-4 Among patients with tumours that do respond to initial treatment, disease progression is common and rapid, often occurring within two years.2,4-6 The average overall survival of patients living with advanced or metastatic TNBC is 12 to 18 months, with only about 12% of patients living five years following diagnosis.7-8

TROP2 is a protein broadly expressed in several solid tumours, including TNBC.9 TROP2 is associated with increased tumour progression and poor survival in patients with breast cancer.9-10

BEGONIA
BEGONIA is an open-label, two-part, multicentre Phase Ib/II trial evaluating Imfinzi in combination with oncology therapies with or without paclitaxel for the 1st-line treatment of metastatic TNBC. Arm 7 of the trial is evaluating the safety, tolerability and preliminary efficacy of datopotamab deruxtecan (6.0 mg/kg) in combination with Imfinzi (1120 mg) in patients with previously untreated, unresectable locally advanced or metastatic TNBC. The primary endpoints are safety and tolerability. Secondary endpoints are investigator-assessed ORR, PFS and DOR.

Enrolment is currently underway for Arm 8 of the BEGONIA trial, which is evaluating datopotamab deruxtecan plus Imfinzi in patients with TNBC whose tumours have high levels of PD-L1 expression.

Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of six lead ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programmes in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers.

A comprehensive development programme called TROPION is underway globally with more than 12 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple TROP2-targetable tumours, including non-small cell lung cancer (NSCLC), TNBC and HR-positive, HER2-low or negative breast cancer. Beyond the TROPION programme, datopotamab deruxtecan is also being evaluated in novel combinations in several ongoing trials. AstraZeneca is also researching a potential diagnostic test to help identify patients most likely to benefit from treatment with datopotamab deruxtecan.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III NSCLC in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (SCLC) based on the CASPIAN Phase III trial. Additionally, Imfinzi is approved in combination with a short course of Imjudo (tremelimumab) and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial.

In addition to its indication in lung cancer, Imfinzi is also approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer (BTC) and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC) in the US, EU, Japan and several other countries based on the TOPAZ-1 and HIMALAYA Phase III trials, respectively. Imfinzi is approved in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 200,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combination with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal cancers and other solid tumours.

On October 22, 2023 Sutro Biopharma, Inc. (Sutro or the Company) (NASDAQ: STRO), a clinical-stage oncology company pioneering site-specific and novel-format antibody drug conjugates (ADCs), reported initial results from a Phase 1 dose-expansion study of luveltamab tazevibulin (luvelta), a novel Folate receptor alpha (FolRα)-targeting ADC, in patients with endometrial cancer, in a mini oral presentation at the 2023 European Society For Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Madrid, Spain (Press release, Sutro Biopharma, OCT 22, 2023, View Source [SID1234636218]).

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Initial data from the Phase 1 dose-expansion study of luvelta were presented by Bhavana Pothurri, M.D., Professor, Department of Obstetrics and Gynecology at NYU Grossman School of Medicine and Director, Gynecologic Oncology Research at NYU Langone, Perlmutter Cancer Center.

Advanced endometrial cancer is the only gynecologic malignancy with increasing incidence and mortality in both the US and Europe1. Estimated incidence in the EU: 92,746 pts with 23,047 deaths (2022)2 and in the US: 66,000 pts with 13,030 deaths (2023)3.

"We are pleased to have the opportunity to present these encouraging early data at ESMO (Free ESMO Whitepaper) this year," said Anne Borgman, M.D., Sutro’s Chief Medical Officer. "The late-stage endometrial cancer treatment landscape is still evolving. With checkpoint inhibitors moving to first line, single agent chemotherapy with response rates in the 15% range4 may once again be the default therapy for patients whose tumors recur. We are optimistic that luvelta may be able to address this tremendous unmet need with a new targeted treatment option, given endometrial cancer expresses FolRα, along with the manageable tolerability profile and preliminary anti-tumor activity seen in the trial."

FolRα is a validated anti-tumor target in ovarian cancer that is overexpressed in endometrial cancer compared with normal tissue5. As presented in June 2023 at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), luvelta has already demonstrated compelling preliminary efficacy and safety in patients with a broad range of FolRα-expressing recurrent epithelial ovarian cancers (EOC) in a Phase 1 dose escalation/expansion study.

ESMO Presentation Highlights:

17 patients were enrolled and initial data were presented on 16 patients with at least one post baseline scan
Luvelta demonstrated encouraging preliminary anti-tumor activity in patients with FolRα-expressing endometrial cancer
In patients with TPS >25% FolRα expression (n=7):
Confirmed partial response (PR) was seen in 29% (2/7)
Disease Control Rate (DCR) was 86% (6/7)
In patients with TPS ≥1% FolRα expression (n=16):
Confirmed PR was seen in 19% (3/16)
DCR was 69% (11/16)
Consistent with previous reported luvelta safety results, the most common adverse event was neutropenia; no new safety signals were observed
The Presentation will be accessible through the News & Events page of the Investor Relations section of the company’s website at www.sutrobio.com.

On October 22, 2023 Seagen Inc. (Nasdaq: SGEN) and Genmab A/S (Nasdaq: GMAB) reported results today from the Phase 3 innovaTV 301 randomized global trial, which showed treatment with TIVDAK demonstrated a statistically significant and clinically meaningful 30% reduction in the risk of death in recurrent or metastatic cervical cancer patients with disease progression on or after first-line therapy, compared with chemotherapy (HR: 0.70, 95% CI: 0.54-0.89, p=0.00381). Data were presented during the Presidential Symposium at the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (Press release, Seagen, OCT 22, 2023, View Source [SID1234636217]).

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"Patients with cervical cancer have few treatment options once their cancer comes back or spreads after initial treatment," said Ignace B. Vergote, M.D., Ph.D., co-founder of European Network of Gynaecological Oncological Trial groups (ENGOT), and lead investigator on the innovaTV 301/ENGOT cx-12/GOG 3057 clinical trial. "The positive data, seen in a representative patient population of recurrent or metastatic cervical cancer, demonstrate the potential for TIVDAK to reshape clinical practice and provide hope for patients who need a new treatment option."

TIVDAK demonstrated the following results compared with chemotherapy across primary and key secondary efficacy endpoints:

Overall survival (OS) was statistically significantly prolonged with TIVDAK, demonstrating a 30% reduction in the risk of death compared with chemotherapy (Hazard ratio [HR]: 0.70 [95% CI: 0.54, 0.89], p=0.00381).
Progression-free survival (PFS) results were statistically significant with TIVDAK, demonstrating a 33% reduction in the risk of disease worsening or death compared with chemotherapy (HR: 0.67 [95% CI, 0.54-0.82], p<0.0001).
The confirmed objective response rate (ORR) was also statistically significantly improved with TIVDAK (17.8%) compared with chemotherapy (5.2%); odds ratio: 4.0 [95% CI, 2.1-7.6], p<0.0001). All the complete responses were seen in the TIVDAK arm, defined as patients with no detectable evidence of a tumor over a specified time period.
The disease control rate (DCR), defined as the percentage of patients who achieved complete response, partial response, or stable disease, was 75.9% (95% CI, 70.1-80.0) in the TIVDAK arm compared with 58.2% (95% CI, 51.8-64.4) in the chemotherapy arm.
The safety profile of TIVDAK in innovaTV 301 was consistent with its known safety profile as presented in the U.S. prescribing information, and no new safety signals were observed.

The U.S. Prescribing Information for TIVDAK includes a BOXED WARNING for Ocular Toxicity as well as the following Warnings and Precautions: peripheral neuropathy, hemorrhage, pneumonitis, severe cutaneous adverse reactions, and embryo-fetal toxicity. Please see below for additional Important Safety Information.

In innovaTV 301, treatment-related adverse events (TRAEs) occurring in patients with TIVDAK were generally low grade and manageable with supportive care and dose modifications. The proportion of patients who experienced TRAEs of grade 3 or higher with chemotherapy was 45.2% compared with TIVDAK (29.2%), and grade 3 or higher treatment-related adverse events of special interest with TIVDAK were peripheral neuropathy (5.2%), ocular events (3.2%), and bleeding events (0.8%).

The results of innovaTV 301, a global, randomized, open-label Phase 3 trial, add to the previous results of innovaTV 204, which served as the basis for the accelerated approval of TIVDAK in the U.S. Subject to discussions with regulatory authorities, the results from innovaTV 301 are intended to serve as the confirmatory trial for the U.S. accelerated approval and support potential global regulatory applications.

"Recurrent or metastatic cervical cancer is a devastating disease," said Roger Dansey, M.D., President of Research and Development and Chief Medical Officer at Seagen. "In this study, TIVDAK was proven to extend the lives of patients with advanced cervical cancer, demonstrating its value as the first-ever antibody drug conjugate approved in the U.S. for this hard-to-treat patient population."

"We are excited to share the results of the innovaTV 301 trial, which demonstrated benefit in prolonging survival in patients with recurrent or metastatic cervical cancer compared with chemotherapy," said Jan van de Winkel, Ph.D., Chief Executive Officer, Genmab. "Together with our partners at Seagen, we look forward to discussing the results of this pivotal confirmatory trial with regulatory authorities with a view to potentially delivering TIVDAK to more patients in need of alternative treatment options in the future."

About Cervical Cancer

Cervical cancer remains a disease with high unmet need despite advances in effective vaccination and screening practices to prevent and diagnose pre-/early-stage cancers for curative treatment. Recurrent and/or metastatic cervical cancer is a particularly devastating and mostly incurable disease; up to approximately 16% of adults with cervical cancer are diagnosed with metastatic disease at diagnosis2,3 and, for adults diagnosed at earlier stages who receive treatment, up to 61% will experience disease recurrence and progress to metastatic cervical cancer.4 It is estimated that in 2023, more than 13,960 new cases of invasive cervical cancer will be diagnosed in the U.S. and 4,310 adults will die from the disease.5

About the innovaTV 301 Trial

The innovaTV 301 trial (NCT04697628) is a global, randomized, open-label Phase 3 trial evaluating TIVDAK (tisotumab vedotin-tftv) versus investigator’s choice of single agent chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed) in 502 patients (n=253 TIVDAK; n=249 chemotherapy) with recurrent or metastatic cervical cancer who received no more than two prior systemic regimens, with a median survival follow-up of 10.8 months (95% CI, 10.3-11.6). The treatment arms were balanced for demographics and disease characteristics, and reflective of the real-world patient population in advanced cervical cancer.

Patients with recurrent or metastatic cervical cancer with squamous cell, adenocarcinoma, or adenosquamous histology, and disease progression during or after treatment with a standard of care systemic chemotherapy doublet or platinum-based therapy (if eligible) are included. The main efficacy outcome measure is overall survival. The key secondary endpoints are progression-free survival and objective response rate, as assessed by the investigator, as well as safety and quality of life outcomes.

The study was conducted by Seagen in collaboration with Genmab, European Network of Gynaecological Oncological Trial Groups (ENGOT, study number ENGOT cx-12) and the Gynecologic Oncology Group (GOG) Foundation (study number GOG 3057). For more information about the Phase 3 innovaTV 301 clinical trial and other clinical trials with tisotumab vedotin, please visit www.clinicaltrials.gov.

About TIVDAK (tisotumab vedotin-tftv)

TIVDAK (tisotumab vedotin-tftv) is an antibody-drug conjugate (ADC) composed of Genmab’s human monoclonal antibody directed to tissue factor (TF) and Seagen’s ADC technology that utilizes a protease-cleavable linker that covalently attaches the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody. Determination of TF expression is not required. Nonclinical data suggest that the anticancer activity of TIVDAK is due to the binding of the ADC to TF-expressing cancer cells, followed by internalization of the ADC-TF complex, and release of MMAE via proteolytic cleavage. MMAE disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. In vitro, TIVDAK also mediates antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity.

In September 2021, the U.S. Food and Drug Administration granted accelerated approval for TIVDAK in adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TIVDAK is the first and only approved ADC for the treatment of these patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

Indication

TIVDAK is indicated in the U.S. for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Important Safety Information

BOXED WARNING: OCULAR TOXICITY

TIVDAK caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold TIVDAK until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

WARNINGS AND PRECAUTIONS

Ocular adverse reactions occurred in 60% of patients with cervical cancer treated with TIVDAK across clinical trials. The most common were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. One patient experienced ulcerative keratitis with perforation requiring corneal transplantation. Cases of symblepharon were reported in patients with other tumor types treated with TIVDAK at the recommended dose.

In innovaTV 204, 4% of patients experienced visual acuity changes to 20/50 or worse including 1% of patients who experienced a visual acuity change to 20/200. Of the patients who experienced decreased visual acuity to 20/50 or worse, 75% resolved, including the patient who experienced decreased visual acuity to 20/200.

Refer patients to an eye care provider for an ophthalmic exam, including visual acuity and slit lamp exam, at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care to reduce the risk of ocular adverse reactions. Promptly refer patients to an eye care provider for any new or worsening ocular signs and symptoms. Withhold dose, reduce the dose, or permanently discontinue TIVDAK based on the severity of the adverse reaction.

Peripheral Neuropathy (PN) occurred in 42% of cervical cancer patients treated with TIVDAK across clinical trials; 8% of patients experienced Grade 3 PN. PN adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (11%), peripheral sensorimotor neuropathy (5%), motor neuropathy (3%), muscular weakness (3%), and demyelinating peripheral polyneuropathy (1%). One patient with another tumor type treated with TIVDAK at the recommended dose developed Guillain- Barre syndrome.

Hemorrhage occurred in 62% of cervical cancer patients treated with TIVDAK across clinical trials. The most common all grade hemorrhage adverse reactions were epistaxis (44%), hematuria (10%), and vaginal hemorrhage (10%). Grade 3 hemorrhage occurred in 5% of patients.

Monitor patients for signs and symptoms of hemorrhage. For patients experiencing pulmonary or central nervous system (CNS) hemorrhage, permanently discontinue TIVDAK. For Grade ≥2 hemorrhage in any other location, withhold until bleeding has resolved, blood hemoglobin is stable, there is no bleeding diathesis that could increase the risk of continuing therapy, and there is no anatomical or pathologic condition that can increase the risk of hemorrhage recurrence. After resolution, either resume treatment or permanently discontinue TIVDAK.

Pneumonitis that is severe, life-threatening, or fatal can occur in patients treated with antibody-drug conjugates containing vedotin, including TIVDAK. Among patients with cervical cancer treated with TIVDAK across clinical trials, 2 patients (1.3%) experienced pneumonitis, including 1 patient who had a fatal outcome.

Monitor patients for pulmonary symptoms of pneumonitis. Symptoms may include hypoxia, cough, dyspnea or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for symptoms should be excluded through appropriate investigations. Withhold TIVDAK for patients who develop persistent or recurrent Grade 2 pneumonitis and consider dose reduction. Permanently discontinue TIVDAK in all patients with Grade 3 or 4 pneumonitis.

Severe cutaneous adverse reactions, including events of fatal or life-threatening Stevens-Johnson syndrome (SJS), can occur in patients treated with TIVDAK.

Monitor patients for signs or symptoms of severe cutaneous adverse reactions, which include target lesions, worsening skin reactions, blistering or peeling of the skin, painful sores in mouth, nose, throat, or genital area, fever or flu-like symptoms, and swollen lymph nodes. If signs or symptoms of severe cutaneous adverse reactions occur, withhold TIVDAK until the etiology of the reaction has been determined.Early consultation with a specialist is recommended to ensure greater diagnostic accuracy and appropriate management. Permanently discontinue TIVDAK for confirmed Grade 3 or 4 severe cutaneous adverse reactions, including SJS.

Embryo-fetal toxicity: TIVDAK can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TIVDAK and for 2 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with TIVDAK and for 4 months after the last dose.

Adverse Reactions

Serious adverse reactions occurred in 43% of patients; the most common (≥3%) were ileus (6%), hemorrhage (5%), pneumonia (4%), PN, sepsis, constipation, and pyrexia (each 3%). Fatal adverse reactions occurred in 4% of patients who received TIVDAK, including septic shock, pneumonitis, sudden death, and multisystem organ failure (each 1%).

Adverse reactions leading to permanent discontinuation occurred in 13% of patients receiving TIVDAK; the most common (≥3%) were PN (5%) and corneal adverse reactions (4%). Adverse reactions leading to dose interruption occurred in 47% of patients; the most common (≥3%) were PN (8%), conjunctival adverse reactions (4%), and hemorrhage (4%). Adverse reactions leading to dose reduction occurred in 23% of patients; the most common (≥3%) were conjunctival adverse reactions (9%) and corneal adverse reactions (8%).

The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), PN (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%).

Drug Interactions

Strong CYP3A4 inhibitors: Concomitant use with strong CYP3A4 inhibitors may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the risk of TIVDAK adverse reactions. Closely monitor patients for TIVDAK adverse reactions.

Use in Specific Populations

Moderate or severe hepatic impairment: MMAE exposure and adverse reactions are increased. Avoid use.

Lactation: Advise lactating women not to breastfeed during TIVDAK treatment and for at least 3 weeks after the last dose.

Please see full prescribing information, including BOXED WARNING for TIVDAK here.

On October 22, 2023 Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, reported promising anti-tumor and safety data for RMC-6236, its RASMULTI(ON) Inhibitor, in patients with previously treated non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) across several dose levels and KRASG12X genotypes, including common KRAS-mutant genotypes G12D and G12V (Press release, Revolution Medicines, OCT 22, 2023, View Source [SID1234636216]). These initial results were presented during a Proffered Paper session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Madrid, October 20-24, 2023.

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"Today’s presentation marks an important milestone in the clinical development of RMC-6236, an unprecedented, oral RASMULTI(ON) Inhibitor with an innovative mechanism of action. The findings reinforce our belief that by inhibiting the (ON), or active, form of diverse RAS cancer drivers, RMC-6236 can lead to meaningful clinical responses in patients at dose levels that are generally well tolerated," said Mark A. Goldsmith, M.D., Ph.D., chief executive officer and chairman of Revolution Medicines. "These data also confirm that RMC-6236 can target multiple common RAS variants that cause cancer, supporting its ongoing development as monotherapy in patients with NSCLC or PDAC harboring RAS mutations. Further, RMC-6236 has a compelling profile for evaluation in combination treatment strategies with RMC-6291, our mutant-selective RASG12C(ON) Inhibitor, and with immunotherapy and other cancer drugs."

The RMC-6236-001 Phase 1/1b trial is a multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate RMC-6236 as monotherapy in patients with advanced solid tumors harboring KRASG12X mutations. As of an October 12, 2023 data extraction, a total of 111 patients with NSCLC (n=46) or PDAC (n=65) were treated at dose levels administered once daily (QD) ranging from 80 mg to 400 mg. Common KRAS mutations in patients evaluated included G12D, G12V, G12R, G12A and G12S; patients with KRASG12C mutations were excluded from the study due to the availability of currently approved KRASG12C(OFF) inhibitors. All patients had previously been treated with standard of care appropriate for tumor type and stage. Patients with NSCLC had received a median of two prior lines of therapy (range 1–6) while patients with PDAC had received a median of three prior lines of therapy (range 1–7).

RMC-6236 demonstrated preliminary evidence of clinical activity and an acceptable safety profile that was generally well tolerated across the dose levels analyzed. Clinical activity was evaluated in patients who had received the first dose of RMC-6236 at least eight weeks prior to the data extraction date (n=86). Among the 40 efficacy evaluable NSCLC patients, the objective response rate was 38 percent, with one patient achieving a complete response (CR) as a best response and 14 patients achieving a partial response (PR) (including three unconfirmed PRs). The disease control rate (DCR) in this NSCLC population was 85 percent. Among the 46 efficacy evaluable PDAC patients, the objective response rate was 20 percent, with nine patients achieving a PR (including four unconfirmed PRs) as a best response. The DCR in this PDAC population was 87 percent. Confirmed objective responses included tumors harboring KRAS mutations G12D, G12V or G12R, and disease control was observed across all KRAS mutations, including G12A and G12S.

The most common treatment-related adverse events (TRAEs) were rash and GI-related toxicities that were primarily Grade 1 or 2 in severity. The reported Grade 3 TRAEs were rash (6%), stomatitis (2%), and diarrhea (1%). One previously reported Grade 4 TRAE occurred in a patient with PDAC at the 80 mg QD dose level who had a large intestine perforation at the site of an invasive tumor that reduced in size while on treatment, which resulted in treatment discontinuation. No safety signals were observed that indicated an elevated risk of hepatotoxicity, which has been reported for some KRASG12C(OFF) inhibitors.

"There is a high unmet need among patients living with KRAS-mutated NSCLC or PDAC, two aggressive cancer types for which current standard of care treatments are often inadequate," said Kathryn C. Arbour, M.D., thoracic oncologist at Memorial Sloan Kettering Cancer Center and a principal investigator for the RMC-6236-001 study. "It is quite encouraging to see this level of anti-tumor activity in previously treated patients by a generally well-tolerated investigational drug. We look forward to continuing the dose optimization portion of the Phase 1/1b study to inform future development and further our understanding of the effects of RMC-6236 on RAS-mutant cancers."

Investor Webcast
Revolution Medicines will host an investor webcast on Sunday, October 22, 2023 at 12:30 p.m. Eastern Time to discuss the data presented at both the 2023 AACR (Free AACR Whitepaper)-NCI-EORTC Triple meeting and ESMO (Free ESMO Whitepaper), in addition to other pipeline updates. To participate in the live webcast, participants may register in advance here: View Source A live webcast of the call will also be available on the Investors section of Revolution Medicines’ website at View Source Following the live webcast, a replay will be available on the company’s website for at least 14 days.