On September 9, 2024 Jazz Pharmaceuticals plc (Nasdaq: JAZZ) reported that the Company, along with its partners, will present five abstracts at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 from September 13-17, 2024, in Barcelona, Spain (Press release, Jazz Pharmaceuticals, SEP 9, 2024, View Source [SID1234646451]). Presentations include data from trials of zanidatamab and Zepzelca (lurbinectedin).

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New and updated data with longer follow-up, including overall survival findings, will be presented from an ongoing Phase 2 trial of zanidatamab, an investigational dual HER2-targeted bispecific antibody, in combination with chemotherapy for the first-line treatment of HER2-positive metastatic gastroesophageal adenocarcinoma (mGEA). Additional data from a Phase 2 study evaluating zanidatamab in combination with chemotherapy and bevacizumab as first-line treatment in HER2-positive metastatic colorectal cancer demonstrating encouraging antitumor activity will be presented as a mini-oral presentation at the congress.

"We look forward to presenting new and more mature data from our oncology solid tumor clinical development program at this year’s ESMO (Free ESMO Whitepaper) congress, in particular for zanidatamab in HER2-positive metastatic gastroesophageal adenocarcinoma," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development, and chief medical officer of Jazz Pharmaceuticals. "We look forward to continuing to advance our clinical development program for zanidatamab in GEA, including the Phase 3 clinical trial expected to read out in the second quarter of 2025 that could support global regulatory submissions."

Data on Zepzelca will also be presented at the congress, including findings from a Phase 2 trial evaluating the safety and efficacy of lurbinectedin and irinotecan in relapsed small cell lung cancer (SCLC) patients, including those with CTFI (Chemotherapy-Free Interval) 30-90 days, who typically have a poor prognosis. These findings support the rationale for this combination in the ongoing LAGOON confirmatory trial.

The full ESMO (Free ESMO Whitepaper) abstracts for posters are available at:
View Source

The full ESMO (Free ESMO Whitepaper) abstracts for presentations are available at: ESMO (Free ESMO Whitepaper) Congress 2024 – Conference Calendar – ESMO (Free ESMO Whitepaper) Congress 2024 (ctimeetingtech.com)

The full list of Jazz or partner-supported presentations at the 2024 ESMO (Free ESMO Whitepaper) Congress includes:

Zanidatamab Presentations

Topic

Author

Presentation Details

Zanidatamab + Chemotherapy for First-
Line (1L) Treatment of HER2+
Advanced or Metastatic Gastro-
oesophageal Adenocarcinoma
(mGEA): New and Updated Data From
a Phase 2 Trial

Elena Elimova,
et al.

Type: Poster

Date: Monday, September 16

Presentation Number: 1432P

Zanidatamab (Zani) + Chemotherapy
(CT) in First-Line (1L) Human
Epidermal Growth Factor Receptor 2-
Positive (HER2+) Advanced/Metastatic
Colorectal Cancer (mCRC)

Sun Young Rha,
et al.

Type: Mini Oral session

Date: Saturday, September 14,
2:50-2:55 p.m. CEST

Presentation Number: #516MO

HERIZON-BTC-02: A Phase 3 Study of
Zanidatamab With Standard-of-Care
(SOC) Therapy vs SOC Alone For
First-Line (1L) Treatment of Human
Epidermal Growth Factor Receptor 2
(HER2)-Positive Advanced/Metastatic
Biliary Tract Cancer (BTC)

Tesca
Macarulla, et al.

Type: Poster

Date: Monday, September 16

Presentation Number: 62TiP

Zepzelca Presentations

Topic

Author

Presentation Details

Phase 2 data of lurbinectedin and
irinotecan in relapsed SCLC: efficacy
and safety results in patients with
CTFI>30 days [PharmaMar]

Jon
Zugazagoitia, et
al.

Type: Poster

Date: Saturday, September 14

Presentation Number: 1790P

LINNOVATE: A phase 1/2 study of
safety/efficacy of lurbinectedin
combined with ipilimumab and
nivolumab for advanced soft tissue
sarcoma [IST]

Erlinda Gordon
et al.

Type: Poster

Date: Saturday, September 14

Presentation Number: 1739P

About Zanidatamab
Zanidatamab is an investigational dual HER2-targeted bispecific antibody that simultaneously binds to two distinct sites on HER2, known as biparatopic binding. This unique design and enhanced binding results in multiple mechanisms of action, including HER2 and HER3 signal inhibition, removal of HER2 protein from the cell surface and enhanced immune effector functions, such as complement-dependent cytotoxicity (CDC), which leads to encouraging antitumor activity. Zanidatamab is being developed in multiple clinical trials as a targeted treatment option for patients with solid tumors that express HER2. Zanidatamab is being developed by Jazz and BeiGene, Ltd. (BeiGene) under license agreements from Zymeworks, which first developed the molecule.

The U.S. Food and Drug Administration (FDA) has granted priority review for the Biologics License Application (BLA) for zanidatamab for the treatment of previously treated, unresectable, locally advanced, or metastatic HER2-positive biliary tract cancer (BTC) with a Prescription Drug User Fee Act (PDUFA) target action date of November 29, 2024. The FDA granted Breakthrough Therapy designation for zanidatamab development in patients with previously treated HER2 gene-amplified BTC, and two Fast Track designations for zanidatamab: one as a single agent for refractory BTC and one in combination with standard of care chemotherapy for 1L gastroesophageal adenocarcinoma (GEA). Additionally, zanidatamab has received Orphan Drug designations from FDA for the treatment of BTC and GEA, as well as Orphan Drug designation from the European Medicines Agency for the treatment of BTC and gastric cancer. Zanidatamab was also granted Breakthrough Therapy designation from the Center for Drug Evaluation (CDE) in China.

About Zepzelca (lurbinectedin)
Zepzelca is an alkylating drug that binds guanine residues within DNA. This triggers a cascade of events that can affect the activity of DNA binding proteins, including transcription factors, and DNA repair pathways, resulting in disruption of the cell cycle and eventual cell death.1

The FDA approved Zepzelca under accelerated approval in June 2020 for the treatment of adult patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy. The approval is based on overall response rate (ORR) and duration of response demonstrated in an open-label, monotherapy clinical study. In December 2021, Jazz and PharmaMar announced the initiation of LAGOON, a confirmatory Phase 3 clinical trial of Zepzelca for the treatment of patients with relapsed small cell lung cancer. If positive, LAGOON could confirm the benefit of Zepzelca in the treatment of small cell lung cancer (SCLC) when patients progress following 1L treatment with a platinum-based regimen and support full approval in the U.S.

Zepzelca is a prescription medicine used to treat adults with SCLC that has spread to other parts of the body (metastatic) and who have received treatment with chemotherapy that contains platinum, and it did not work or is no longer working. Zepzelca is approved based on response rate and how long the response lasted. Additional studies will further evaluate the benefit of Zepzelca for this use.

Important Safety Information for ZEPZELCA

Before receiving ZEPZELCA, tell your healthcare provider about all of your medical conditions, including if you:

have liver or kidney problems.
are pregnant or plan to become pregnant. ZEPZELCA can harm your unborn baby.
Females who are able to become pregnant:

Your healthcare provider should do a pregnancy test before you start treatment with ZEPZELCA.
You should use effective birth control (contraception) during treatment with and for 6 months after your last dose of ZEPZELCA.
Tell your healthcare provider right away if you become pregnant or think that you are pregnant during treatment with ZEPZELCA.
Males with female partners who are able to become pregnant should use effective birth control during treatment with and for 4 months after their last dose of ZEPZELCA.

are breastfeeding or plan to breastfeed. It is not known if ZEPZELCA passes into your breastmilk. Do not breastfeed during treatment with ZEPZELCA and for 2 weeks after your last dose of ZEPZELCA. Talk to your healthcare provider about the best way to feed your baby during treatment with ZEPZELCA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Certain other medicines may affect how ZEPZELCA works.

What should I avoid while using ZEPZELCA?
Avoid eating or drinking grapefruit, Seville oranges, or products that contain grapefruit juice and Seville oranges during treatment with ZEPZELCA.
ZEPZELCA can cause serious side effects, including:

Low blood cell counts. Low blood counts including low neutrophil counts (neutropenia) and low platelet counts (thrombocytopenia) are common with ZEPZELCA, and can also be severe. Some people with low white blood cell counts may get fever, or an infection throughout the body (sepsis), that can cause death. Your healthcare provider should do blood tests before you receive each treatment with ZEPZELCA to check your blood cell counts.
Tell your healthcare provider right away if you develop:

fever or any other signs of infection
unusual bruising or bleeding
tiredness
pale colored skin
Liver problems. Increased liver function tests are common with ZEPZELCA and can also be severe. Your healthcare provider should do blood tests to check your liver function before you start and during treatment with ZEPZELCA.
Tell your healthcare provider right away if you develop symptoms of liver problems including:

loss of appetite
nausea or vomiting
pain on the right side of your stomach area (abdomen)
Leakage of ZEPZELCA out of your vein during the infusion. If ZEPZELCA leaks into the tissues around your infusion site, it can cause damage and death of tissue cells around the infusion site. You may need to have surgery to remove any dead tissue. Tell your healthcare provider right away if you see any ZEPZELCA leaking out of your vein or around the catheter during your infusion, or if you notice any redness, swelling, itching or discomfort at the infusion site at any time.
Severe muscle problems (rhabdomyolysis). Tell your healthcare provider if you have severe muscle pain or weakness.
Your healthcare provider may temporarily stop treatment, lower your dose, or permanently stop ZEPZELCA if you develop serious side effects during treatment with ZEPZELCA.

The most common side effects of ZEPZELCA include:

tiredness
low white and red blood cell counts
increased kidney function blood test (creatinine)
increased liver function blood tests
increased blood sugar (glucose)
nausea
decreased appetite
muscle and joint (musculoskeletal) pain
low level of albumin in the blood
constipation
trouble breathing
low levels of sodium and magnesium in the blood
vomiting
cough
diarrhea
These are not all of the possible side effects of ZEPZELCA.

Call your doctor for medical advice about side effects. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. You may also report side effects to Jazz Pharmaceuticals at 1-800-520-5568.

Please see full Prescribing Information including Patient Information, and discuss with your doctor.

ZEPZELCA is a trademark of Pharma Mar, S.A. used by Jazz Pharmaceuticals under license.

On September 9, 2024 AbbVie (NYSE: ABBV) reported that new data from its innovative antibody-drug conjugate (ADC) platform will be showcased at the upcoming European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 (September 13-17, 2024) (Press release, AbbVie, SEP 9, 2024, View Source [SID1234646450]). Presentations include data on mirvetuximab soravtansine (ELAHERE) and c-Met targeting ADCs, telisotuzumab vedotin (Teliso-V) and telisotuzumab adizutecan (ABBV-400). AbbVie’s ADCs are designed to target protein biomarkers such as folate receptor-alpha (FRα) and c-Met (MET protein) which are over expressed across various tumor types and are associated with poor prognoses.1-9 The ADCs are designed to deliver potent cancer cell-death inducing agents called ‘payloads’ specifically to the tumor, by utilizing these biomarkers as targets.

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Data from the primary analysis of the Phase 2 PICCOLO trial evaluating investigational mirvetuximab soravtansine monotherapy in heavily pre-treated patients with FRα positive, platinum-sensitive ovarian cancer (PSOC) showed that the trial met its primary endpoint with an objective response rate (ORR) of 51.9% (95% CI 40.4, 63.3), including 6 complete and 35 partial responses. Among the 79 enrolled patients, 81% had prior poly (ADP-ribose) polymerase inhibitors (PARPi) treatment; 74.7% of whom progressed while on PARPi. The median duration of response (DOR), a key secondary endpoint, was 8.3 months (95% CI 5.5, 10.8) and median progression-free survival (PFS), an additional secondary endpoint, was 6.9 months (95% CI 5.9, 9.6). The safety profile of mirvetuximab soravtansine was consistent with findings from previous studies, and no new safety concerns were identified. The most common treatment-emergent adverse events (TEAEs) (grade ≥ 3) were blurred vision (10%), dry eye (3%), nausea (1%), keratopathy (4%), and diarrhea (3%). Additional data will be presented at the meeting.

"There is an urgent patient-driven unmet need to identify novel, effective and tolerable therapies for patients with platinum-sensitive ovarian cancer, including the PARPi pre-treated setting where diminished response to subsequent platinum-based chemotherapy has been reported," said Angeles Alvarez Secord, M.D., M.H.Sc., from the Duke Cancer Institute. "The response rate seen with mirvetuximab soravtansine in PICCOLO highlights the potential of mirvetuximab soravtansine for platinum-sensitive ovarian cancer patients."

Mirvetuximab soravtansine is also being studied in PSOC in the Phase 3 GLORIOSA trial (NCT05445778), in combination with bevacizumab versus bevacizumab alone, in maintenance after second-line platinum-doublet therapy. Additionally, a Phase 2 study IMGN853-0420 (NCT05456685), is investigating the combination of mirvetuximab soravtansine with carboplatin as second-line treatment of PSOC with a wider range of FRα expression.

Patient reported outcome (PRO) data from the Phase 2 LUMINOSITY trial of Teliso-V, in c-Met protein overexpressing, epidermal growth factor receptor (EGFR) wild type, advanced/metastatic non-squamous non-small cell lung cancer (NSCLC) patients, will be presented at the meeting. Trends in PROs observed in LUMINOSITY will be further evaluated in the ongoing Phase 3 TeliMET NSCLC-01 trial (NCT04928846).

"The data at ESMO (Free ESMO Whitepaper) showcase the depth of our ADC pipeline and highlights the significant progress we are making across key programs in various stages of development, as we strive to deliver new and innovative medicines for patients in need," said Daejin Abidoye, M.D., vice president, head of solid tumors, oncology development, AbbVie. "A testament to these efforts is our plan to submit Teliso-V for accelerated approval as a monotherapy in patients with previously treated c-Met overexpressing, epidermal growth factor receptor (EGFR) wild-type non-squamous non-small cell lung cancer in Q3 2024."

The accelerated approval submission for Teliso-V will be reviewed under FDA’s real-time oncology review program with an approval decision anticipated in 2025. AbbVie announced FDA breakthrough therapy designation for Teliso-V in 2022.

New safety and efficacy data from a Phase 1 study (NCT05029882) of ABBV-400, a next-generation, potential best-in-class c-Met directed ADC, highlights the potential of ABBV-400 in previously-treated NSCLC and gastroesophageal cancer (GEA) patients, and are supportive of further exploration of this novel ADC in these tumor types and other solid tumors:

Preliminary data show that among 48 previously treated EGFR wild type non-squamous NSCLC patients, antitumor activity was observed with ABBV-400 when dosed at 2.4 and 3.0 mg/kg administered once every 3 weeks (n=39 and 9, respectively), with a confirmed ORR of 43.8% and clinical benefit rate of 85.4%. The most common (≥10%) TEAEs (grade ≥ 3) were anemia (25%) and neutropenia (15%). Additional endpoints (such as progression free survival), association between c-Met protein expression and treatment response, and detailed safety data will be presented at the meeting.
In GEA patients, the preliminary data show that among 42 patients, antitumor activity was observed at a dose of ABBV-400 of 3.0 mg/kg administered once every 3 weeks, with confirmed ORR of 28.6%. The clinical benefit rate was 71.4%. The most common (≥20%) TEAEs (any grade) were gastrointestinal (76.2%), anemia (66.7%), nausea (47.6%), thrombocytopenia and constipation (26.2% each) and neutropenia (23.8%). Additional safety and efficacy data will be presented at the meeting.
ABBV-400 is also being evaluated in a Phase 1b basket study (NCT06084481) in advanced solid tumors as a monotherapy and a Phase 2 study (NCT06107413) in second line metastatic colorectal cancer (CRC) in combination with fluorouracil, folinic acid, and bevacizumab.

Teliso-V and ABBV-400 both target c-Met with the same parental antibody but have different designs and mechanisms of action.10,11 Teliso-V, AbbVie’s most advanced c-Met targeted ADC in development, utilizes a microtubule polymerization inhibitor (MMAE) payload.10 ABBV-400, a next-generation c-Met targeted ADC utilizes a novel, proprietary topoisomerase 1 inhibitor (Top1i) payload.11

AbbVie will also present real-world data on the prevalence, stability, and prognostic value of c-Met protein overexpression in NSCLC from the METPRO and METEXPRESS studies at the meeting.

Further information on AbbVie clinical trials is available at View Source

Additional details on key presentations at ESMO (Free ESMO Whitepaper) are available below:

Title

Date/Time

Session

Abstract
number

Mirvetuximab soravtansine (MIRV) in
recurrent platinum-sensitive ovarian
cancer (PSOC) with high folate receptor-
alpha (FRα) expression: Results from
the PICCOLO trial

Sept 15,
15:20-15:25 CEST

Mini oral session

Gynaecological cancers
(Santander Auditorium, Hall 5)

718MO

Patient-reported outcomes (PROs) in the
LUMINOSITY trial: Evaluating
telisotuzumab vedotin (Teliso-V) in
patients (Pts) with c-Met protein
overexpressing (OE), EGFR wildtype,
non-squamous non-small cell lung
cancer (NSQ NSCLC)

Sept 14

Poster

NSCLC, metastatic

1313P

ABBV-400, a c-Met protein–targeting
antibody-drug conjugate (ADC), in
patients (Pts) with advanced EGFR
wildtype (WT) non-squamous (NSQ)
non-small cell lung cancer (NSCLC):
Results from a phase 1 study

Sept 14,

10:45 – 10:50 CEST

Mini oral session

NSCLC metastatic
(Santander Auditorium,
Hall 5)

1257MO

ABBV-400, a c-Met protein–targeting
antibody-drug conjugate (ADC), in
patients (pts) with advanced
gastric/gastroesophageal junction
adenocarcinoma (GEA): Results from a
phase 1 study

Sept 16

Poster

Oesophagogastric cancer

1439P

METPRO: Evaluating prognostic
value of c-Met protein overexpression
and concurrent biomarker presence

Sept 14

Poster

NSCLC, metastatic

1303P

Consistency analysis of c-Met protein
expression over time in patients with
non-squamous non-small cell lung
cancer

Sept 15

Poster

Biomarkers and
translational research
(agnostic)

165P

About the PICCOLO trial
PICCOLO is a single-arm Phase 2 trial evaluating the efficacy and safety of mirvetuximab soravtansine monotherapy in patients with FR-alpha high platinum-sensitive ovarian cancer who have received at least two prior lines of platinum containing therapy or have a documented platinum allergy. The primary end point is objective response rate (ORR), and the key secondary endpoint is duration of response (DOR).

The PICCOLO study was designed to statistically rule out an objective response rate of 28% or lower, as excluded by the lower bound of the confidence interval, a response rate which has been observed with non-platinum, single-agent chemotherapy in platinum-sensitive disease. Patients with PSOC with multiple prior lines of platinum-based therapy or who are ineligible for platinum-based therapy, as in the population in PICCOLO, have no established benchmark standard of care, particularly after disease progression on a PARP inhibitor.

AbbVie previously announced positive topline results from the study in June 2024.

About the LUMINOSITY trial
The LUMINOSITY trial (M14-239), is an ongoing single-arm Phase 2 study designed to identify the target NSCLC populations that overexpress c-Met best suited for Teliso-V monotherapy in the second line or third line setting, and then to expand the groups to further evaluate efficacy in the selected populations. The endpoints include overall response rate (ORR), duration of response (DoR), disease control rate (DCR) and progression-free survival (PFS) per independent central review (ICR) as well as overall survival (OS). AbbVie previously announced positive topline results from the LUMINOSITY study in November 2023.

About Mirvetuximab soravtansine
Mirvetuximab soravtansine is a first-in-class ADC comprising a folate receptor-alpha binding antibody, cleavable linker, and the maytansinoid payload DM4, a potent tubulin inhibitor designed to kill the targeted cancer cells.

The Marketing Authorization Application (MAA) for mirvetuximab soravtansine in Europe has been accepted by the European Medicines Agency (EMA) and regulatory submissions are also under review in multiple other countries. The safety and efficacy of mirvetuximab soravtansine has not been established for platinum-sensitive ovarian cancer.

ELAHERE (mirvetuximab soravtansine-gynx) U.S. INDICATION and IMPORTANT SAFETY INFORMATION
ELAHERE is indicated for the treatment of adult patients with folate receptor-alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Select patients for therapy based on an FDA-approved test.

IMPORTANT SAFETY INFORMATION

WARNING: OCULAR TOXICITY

ELAHERE can cause severe ocular toxicities, including visual impairment, keratopathy, dry eye, photophobia, eye pain, and uveitis.
Conduct an ophthalmic exam including visual acuity and slit lamp exam prior to initiation of ELAHERE, every other cycle for the first 8 cycles, and as clinically indicated.
Administer prophylactic artificial tears and ophthalmic topical steroids.
Withhold ELAHERE for ocular toxicities until improvement and resume at the same or reduced dose.
Discontinue ELAHERE for Grade 4 ocular toxicities.
WARNINGS and PRECAUTIONS
Ocular Disorders

ELAHERE can cause severe ocular adverse reactions, including visual impairment, keratopathy (corneal disorders), dry eye, photophobia, eye pain, and uveitis.

Ocular adverse reactions occurred in 59% of patients with ovarian cancer treated with ELAHERE. Eleven percent (11%) of patients experienced Grade 3 ocular adverse reactions, including blurred vision, keratopathy (corneal disorders), dry eye, cataract, photophobia, and eye pain; two patients (0.3%) experienced Grade 4 events (keratopathy and cataract). The most common (≥5%) ocular adverse reactions were blurred vision (48%), keratopathy (36%), dry eye (27%), cataract (16%), photophobia (14%), and eye pain (10%).

The median time to onset for first ocular adverse reaction was 5.1 weeks (range: 0.1 to 68.6). Of the patients who experienced ocular events, 53% had complete resolution; 38% had partial improvement (defined as a decrease in severity by one or more grades from the worst grade at last follow up). Ocular adverse reactions led to permanent discontinuation of ELAHERE in 1% of patients.

Premedication and use of lubricating and ophthalmic topical steroid eye drops during treatment with ELAHERE are recommended. Advise patients to avoid use of contact lenses during treatment with ELAHERE unless directed by a healthcare provider.

Refer patients to an eye care professional for an ophthalmic exam including visual acuity and slit lamp exam prior to treatment initiation, every other cycle for the first 8 cycles, and as clinically indicated. Promptly refer patients to an eye care professional for any new or worsening ocular signs and symptoms.

Monitor for ocular toxicity and withhold, reduce, or permanently discontinue ELAHERE based on severity and persistence of ocular adverse reactions.

Pneumonitis

Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ELAHERE.

Pneumonitis occurred in 10% of patients treated with ELAHERE, including 1% with Grade 3 events and 1 patient (0.1%) with a Grade 4 event. One patient (0.1%) died due to respiratory failure in the setting of pneumonitis and lung metastases. One patient (0.1%) died due to respiratory failure of unknown etiology. Pneumonitis led to permanent discontinuation of ELAHERE in 3% of patients.

Monitor patients for pulmonary signs and symptoms of pneumonitis, which may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded through appropriate investigations. Withhold ELAHERE for patients who develop persistent or recurrent Grade 2 pneumonitis until symptoms resolve to ≤ Grade 1 and consider dose reduction. Permanently discontinue ELAHERE in all patients with Grade 3 or 4 pneumonitis. Patients who are asymptomatic may continue dosing of ELAHERE with close monitoring.

Peripheral Neuropathy (PN)

Peripheral neuropathy occurred in 36% of patients with ovarian cancer treated with ELAHERE across clinical trials; 3% of patients experienced Grade 3 peripheral neuropathy. Peripheral neuropathy adverse reactions included peripheral neuropathy (20%), peripheral sensory neuropathy (9%), paraesthesia (6%), neurotoxicity (3%), hypoaesthesia (1%), peripheral motor neuropathy (0.9%), polyneuropathy (0.3%), and peripheral sensorimotor neuropathy (0.1%). Monitor patients for signs and symptoms of neuropathy, such as paresthesia, tingling or a burning sensation, neuropathic pain, muscle weakness, or dysesthesia. For patients experiencing new or worsening PN, withhold dosage, dose reduce, or permanently discontinue ELAHERE based on the severity of PN.

Embryo-Fetal Toxicity

Based on its mechanism of action, ELAHERE can cause embryo-fetal harm when administered to a pregnant woman because it contains a genotoxic compound (DM4) and affects actively dividing cells.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ELAHERE and for 7 months after the last dose.

ADVERSE REACTIONS

The most common (≥20 %) adverse reactions, including lab abnormalities, were increased aspartate aminotransferase, fatigue, increased alanine aminotransferase, blurred vision, nausea, increased alkaline phosphatase, diarrhea, abdominal pain, keratopathy, peripheral neuropathy, musculoskeletal pain, decreased lymphocytes, decreased platelets, decreased magnesium, decreased hemoglobin, dry eye, constipation, decreased leukocytes, vomiting, decreased albumin, decreased appetite, and decreased neutrophils.

DRUG INTERACTIONS

DM4 is a CYP3A4 substrate. Closely monitor patients for adverse reactions with ELAHERE when used concomitantly with strong CYP3A4 inhibitors.

USE IN SPECIAL POPULATIONS

Lactation
Advise women not to breastfeed during treatment with ELAHERE and for 1 month after the last dose.

Hepatic Impairment
Avoid use of ELAHERE in patients with moderate or severe hepatic impairment (total bilirubin >1.5 ULN).

Please see full Prescribing Information, including BOXED WARNING

On September 9, 2024 Phanes Therapeutics, Inc. (Phanes), a clinical stage biotech company focused on innovative drug discovery and development in oncology, reported that the first patient has been dosed in the clinical study of PT886 in combination with chemotherapy (Press release, Phanes Therapeutics, SEP 9, 2024, View Source [SID1234646449]). Dosing has been completed in two cohorts: one for first-line treatment of pancreatic cancers and another for second-line treatment of gastric, gastroesophageal junction cancers.

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PT886 is a first-in-class native IgG-like bispecific antibody (bsAb) targeting claudin 18.2 and CD47. It was granted orphan drug designation (ODD) for the treatment of pancreatic cancer by the FDA in 2022 and was granted Fast Track designation for the treatment of patients with metastatic claudin 18.2-positive pancreatic adenocarcinoma earlier this year. In 2023, Phanes entered into a clinical collaboration agreement with Merck (known as MSD outside the US and Canada) to study PT886 in combination with Merck’s anti-PD-1 therapy, KEYTRUDA (pembrolizumab).

The multi-center Phase I/II clinical trial of PT886 (NCT05482893), known as the TWINPEAK study, is currently evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of PT886 in patients with locally advanced or metastatic gastric, gastroesophageal junction and pancreatic cancers that have progressed after all available standard therapy or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate. A Phase I clinical trial of PT886 is also ongoing in China (CTR20241655).

On September 9, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high quality medicines for the treatment of oncology, cardiovascular and metabolic, autoimmune, ophthalmology and other major diseases, reported an oral presentation of updated results from a pivotal Phase 2 clinical trial of Dupert（fulzerasib）for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation at the 2024 World Conference on Lung Cancer (WCLC) (Press release, Innovent Biologics, SEP 9, 2024, View Source [SID1234646448]).

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Fulzerasib is a novel, orally active, potent KRAS G12C inhibitor. Based on the results from this single-arm registrational Phase 2 clinical study (NCT05005234).

Dupert (fulzerasib) received approval by the NMPA in August 2024 for the treatment of adult patients with advanced NSCLC harboring the KRAS G12C mutation who have received at least one systemic therapy.

As of the data cutoff date (Dec 13, 2023), a total of 116 NSCLC subjects were enrolled and evaluable.

Fulzerasib showed encouraging antitumor activity. The confirmed objective response rate (ORR) assessed by the Independent Radiology Review Committee (IRRC) was 49.1% (95% CI: 39.7-58.6). The disease control rate (DCR) was 90.5% (95%CI: 83.7, 95.2). The median duration of response (DoR) has not yet been reached, while the median progression-free survival (PFS) was 9.7 months (95%CI: 5.6-11.0). Median overall survival (OS) has not been reached.
Fulzerasib was generally well-tolerated, with no additional safety signals observed. Treatment-related adverse events (TRAEs) occurred in 92.2% of patients (107 individuals), mostly Grade 1-2. The most common TRAEs included anemia, increased alanine aminotransferase, increased aspartate aminotransferase, asthenia and proteinuria.
Professor Yi-Long Wu from Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, stated: "As a potent KRAS G12C inhibitor, Dupert monotherapy has demonstrated encouraging efficacy in advanced lung cancer with KRAS G12C mutations, with the pivotal registry study meeting the prespecified primary endpoints and overall favorable safety profile. As the first KRAS G12C inhibitor approved in China, Dupert provides a new treatment option for cancer patients harboring this gene mutation in China. We look forward to seeing more KRAS G12C-mutated patients with advanced lung cancer benefit from this drug soon."

Dr. Hui Zhou, Senior Vice President of Innovent, stated: "We are pleased to share the latest clinical data from the registration study of Dupert at the WCLC. Thanks to the exceptional efficacy and good tolerability demonstrated in this study, Dupert was recently approved as the first KRAS G12C inhibitor in China. Moving forward, we remain committed to advancing Dupert as both a monotherapy and in combination treatments, aiming to maximize the clinical value of this innovative targeted drug and benefit more patients."

About Dupert (Fulzerasib, KRAS G12C Inhibitor)

The RAS protein family is categorized into KRAS, HRAS and NRAS categories. KRAS mutation are detected in nearly 90% of pancreatic cancers, 30-40% of colon cancers, and 15-20% lung cancers. The KRAS G12C mutation is more prevalent than the combined occurrence of ALK, ROS1, RET and NTRK 1/2/3 mutations.

Fulzerasib is a novel, orally active and potent KRAS G12C inhibitor designed to effectively target the GTP/GDP exchange—an essential step in pathway activation—by covalently and irreversibly modifying the cysteine residue of KRAS G12C protein. Preclinical cysteine selectivity studies demonstrated high selectivity of fulzerasib towards G12C, leading to inhibition of downstream signaling, resulting in tumor cells apoptosis and cell cycle arrest.

In September 2021, Innovent and GenFleet Therapeutics entered an exclusive license agreement for the development and commercialization of fulzerasib (Innovent R&D code: IBI351, GenFleet R&D code: GFH925) in China, including mainland China, Hong Kong, Macau and Taiwan.

In January 2023, the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) granted Breakthrough Therapy Designation (BTD) to fulzerasib for the treatment of patients with advanced NSCLC harboring KRAS G12C mutation who have received at least one prior systemic therapy. In May 2023, another BTD was granted for the treatment of advanced CRC patients with KRAS G12C mutation who had undergone at least two systemic therapies.

As of August 2024, the CDE of NMPA has approved fulzerasib for the treatment of adult patients with advanced NSCLC harboring the KRAS G12C mutation who have received at least one systemic therapy.

On September 9, 2024 Astrazeneca reported detailed results from the TROPION-Lung01 Phase III trial showed a clinically meaningful trend toward improving overall survival (OS) with datopotamab deruxtecan (Dato-DXd) compared to docetaxel, the current standard of care chemotherapy, in adult patients with locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with at least one prior line of therapy (Press release, AstraZeneca, SEP 9, 2024, View Source [SID1234646447]).

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These results will be presented today during an oral presentation (OA08.03) at the IASLC 2024 World Conference on Lung Cancer (WCLC) hosted by the International Association for the Study of Lung Cancer and simultaneously published in the Journal of Clinical Oncology.

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

In the overall trial population, OS results numerically favoured datopotamab deruxtecan compared to docetaxel (12.9 versus 11.8 months) but did not reach statistical significance (hazard ratio [HR] 0.94; 95% confidence interval [CI] 0.78-1.14; p=0.530). In the prespecified subgroup of patients with nonsquamous NSCLC, datopotamab deruxtecan showed a 2.3-month improvement in OS compared to docetaxel (14.6 versus 12.3 months; HR 0.84; 95% CI 0.68-1.05). In patients with nonsquamous NSCLC, OS improvement was observed regardless of the presence of actionable genomic alterations. In patients with squamous NSCLC, consistent with the previous analysis, datopotamab deruxtecan did not show an OS improvement.

Jacob Sands, MD, Dana-Farber Cancer Institute, Medical Oncology and investigator in the trial, said: "Despite many efforts to surpass docetaxel with novel approaches in previously treated advanced or metastatic non-small cell lung cancer, patients only survive for about one year. For datopotamab deruxtecan to show a statistically significant improvement in progression-free survival along with improved response rate, duration of response and an overall survival improvement numerically consistent with progression-free survival is clinically meaningful for patients with nonsquamous lung cancer."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "TROPION-Lung01 showed a clinically meaningful trend towards improving the survival of patients with advanced or metastatic nonsquamous non-small cell lung cancer, building on the previously reported progression-free survival data. Together with the data we have presented for the potential TROP2-QCS biomarker and from NeoCOAST-2 in early-stage disease, these results underscore our confidence in the important role datopotamab deruxtecan can play across segments and settings of non-small cell lung cancer."

Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo, said: "For patients with nonsquamous non-small cell lung cancer, disease progression is common, making this patient population difficult to treat. The data from TROPION-Lung01 demonstrate the potential of datopotamab deruxtecan in this setting and support our comprehensive development programme where we are also evaluating this TROP2-directed antibody drug conjugate as part of combination strategies in earlier treatment settings of non-small cell lung cancer."

The safety profile of datopotamab deruxtecan in TROPION-Lung01 was consistent with the previous analysis including lower rates of dose reduction (20%, 30%) and discontinuation (8%, 12%) due to adverse events compared to docetaxel. The median treatment duration for datopotamab deruxtecan was 4.2 months versus 2.8 months for docetaxel. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 26% and 42% of patients in the datopotamab deruxtecan and docetaxel arms, respectively. The most common Grade 3 or higher TRAEs were neutropenia (1%, 23%), leukopenia (0%, 13%), stomatitis (7%, 1%), anemia (4%, 4%), interstitial lung disease (ILD) (4%, 1 %) and asthenia (3%, 2%). No new ILD events of any grade were adjudicated as drug-related since the previous analysis.

In TROPION-Lung01, patient enrollment by tumour histology was balanced across treatment arms and consistent with real-world incidence with approximately 75% of enrolled patients having nonsquamous NSCLC.1,2 In both arms, 17% of patients had tumours expressing actionable genomic alterations, such as epidermal growth factor receptor (EGFR) mutations.

This final analysis of OS builds on the positive progression-free survival (PFS) results presented at the 2023 European Society for Medical Oncology Congress, which showed datopotamab deruxtecan demonstrated a statistically significant improvement in PFS in the overall trial population and a clinically meaningful PFS benefit in patients with nonsquamous NSCLC. The OS data have been shared with health authorities currently reviewing applications for this indication.

Summary of TROPION-Lung01 survival results

Overall trial population

Datopotamab deruxtecan (n=299)

Docetaxel

(n=305)

Median OS (95% CI)i

12.9 months (11.0-13.9)

11.8 months (10.0-12.8)

HR (95% CI)

0.94 (0.78-1.14)

p-value

0.530

Pre-specified boundary (2-sided)

0.045

Nonsquamous histology

Datopotamab deruxtecan (n=234)

Docetaxel

(n=234)

Median OS (95% CI)i

14.6 months (12.4-16.0)

12.3 months (10.7-14.0)

HR (95% CI)

0.84 (0.68-1.05)

OS probability at 12 months (95% CI)

58.8% (52.0-64.9)

52.8% (45.9-59.2)

OS probability at 24 months (95% CI)

29.0% (22.8-35.5)

21.7% (16.0-28.0)

Nonsquamous histology – with actionable genomic alterations

Datopotamab deruxtecan (n=48)

Docetaxel

(n=50)

Median OS (95% CI)i

15.6 months

9.8 months

HR (95% CI)

0.65 (0.40-1.08)

Nonsquamous histology – without actionable genomic alterations

Datopotamab deruxtecan (n=186)

Docetaxel

(n=184)

Median OS (95% CI)i

13.6 months

12.3 months

HR (95% CI)

0.89 (0.70-1.13)

CI, confidence interval; HR, hazard ratio; OS, overall survival
iMedian follow-up was 23.1 months for both the datopotamab deruxtecan and docetaxel arms

Datopotamab deruxtecan plus Imfinzi and chemotherapy showed promising response rates in patients with early-stage resectable NSCLC

Results from the NeoCOAST-2 Phase II platform trial evaluating Imfinzi (durvalumab) in multiple novel combinations, before and after surgery, in patients with early-stage (Stage IIA-IIIB) resectable NSCLC were featured in a WCLC Presidential Symposium (PL02.07). Preliminary results from the trial arm testing neoadjuvant Imfinzi plus datopotamab deruxtecan and carboplatin demonstrated a pathological complete response (pCR) rate of 34.1% (95% CI 20.5-49.9) and a major pathological response (mPR) rate of 65.9% (95% CI 50.1-79.5). This was numerically higher than the response rates shown by other combination regimens tested, however, the trial was not powered to make direct statistical comparisons between arms.

The safety profile of Imfinzi plus datopotamab deruxtecan and carboplatin was consistent with the known safety profiles of these agents. Surgical rates across arms were comparable and in line with those shown in recent Phase III trials. AstraZeneca and Daiichi Sankyo are evaluating datopotamab deruxtecan in combination with Imfinzi in multiple ongoing trials.

Also featured in a WCLC Presidential Symposium were results from an exploratory analysis of TROPION-Lung01 which showed TROP2 as measured by AstraZeneca’s proprietary computational pathology platform, quantitative continuous scoring (QCS), was predictive of clinical outcomes in patients with advanced or metastatic NSCLC treated with datopotamab deruxtecan.

Notes

Advanced non-small cell lung cancer
Nearly 2.5 million lung cancer cases were diagnosed globally in 2022.1 NSCLC is the most common type of lung cancer, accounting for about 80% of cases.2 Approximately 75% and 25% of NSCLC tumours are of nonsquamous or squamous histology, respectively.3 While immunotherapy and targeted therapies have improved outcomes in the 1st-line metastatic setting, most patients eventually experience disease progression and receive chemotherapy.4-6 For decades, chemotherapy has been the last treatment available for patients with advanced NSCLC, despite limited effectiveness and known side effects.4-6

TROP2 is a protein broadly expressed in the majority of NSCLC tumours.7 There is currently no TROP2-directed ADC approved for the treatment of lung cancer.8,9

TROPION-Lung01
TROPION-Lung01 is a global, randomised, multicentre, open-label Phase III trial evaluating the efficacy and safety of datopotamab deruxtecan (6.0mg/kg) versus docetaxel (75mg/m2) in adult patients with locally advanced or metastatic NSCLC with and without actionable genomic alterations who require systemic therapy following prior treatment. Patients with actionable genomic alterations were previously treated with platinum-based chemotherapy and an approved targeted therapy. Patients without known actionable genomic alterations were previously treated, concurrently or sequentially, with platinum-based chemotherapy and a PD-1 or PD-L1 inhibitor.

The dual primary endpoints of TROPION-Lung01 are PFS as assessed by blinded independent central review (BICR) and OS. Key secondary endpoints include investigator-assessed PFS, objective response rate (ORR), duration of response, time to response, disease control rate as assessed by both BICR and investigator, and safety.

TROPION-Lung01 enrolled approximately 600 patients in Asia, Europe, North America, Oceania and South America. For more information visit ClinicalTrials.gov.

NeoCOAST-2
NeoCOAST-2 is a global, randomised, multicentre, open-label, multi-arm Phase II platform trial evaluating the efficacy and safety of Imfinzi in multiple novel combinations, before and after surgery, in patients with resectable, early-stage (Stage II-IIIB) NSCLC.

The dual primary endpoints of NeoCOAST-2 are antitumour activity of neoadjuvant treatment assessed by pCR and the safety and tolerability of neoadjuvant and adjuvant treatment. Key secondary endpoints include event-free survival, disease-free survival and ORR as assessed by both RECIST version 1.1 and investigator, OS, tumour resection and mPR as defined by central blinded independent pathologist review.

NeoCOAST-2 will enrol approximately 490 patients in Asia, Europe and North America. For more information visit ClinicalTrials.gov.

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 DXd 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 humanised 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 global clinical development programme is underway with more than 20 trials evaluating the efficacy and safety of datopotamab deruxtecan across multiple cancers, including NSCLC, triple-negative breast cancer and HR-positive, HER2-negative breast cancer. The programme includes seven Phase III trials in lung cancer and five Phase III trials in breast cancer evaluating datopotamab deruxtecan as a monotherapy and in combination with other anticancer treatments in various settings.