On October 21, 2023 Immunocore Holdings plc (Nasdaq: IMCR), a commercial-stage biotechnology company pioneering the development of a novel class of T cell receptor (TCR) bispecific immunotherapies designed to treat a broad range of diseases, including cancer, infectious diseases and autoimmune conditions, reported that the three-year overall survival (OS) data from the KIMMTRAK (tebentafusp-tebn) Phase 3 trial in previously untreated HLA-A*02:01 positive patients with metastatic uveal melanoma has been published in The New England Journal of Medicine, and presented as a late breaking abstract in a mini oral session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023 (Press release, Immunocore, OCT 21, 2023, View Source [SID1234636209]).

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"These long-term overall survival results further solidify KIMMTRAK as the first-line standard of care for HLA-A*02:01 positive patients with metastatic uveal melanoma," said Mohammed Dar, Immunocore Chief Medical Officer. "The survival benefit appears early, within the first six weeks, and the survival curve remains separated from the control arm; this long-term survival benefit is a hallmark of cancer immunotherapy."

In the Phase 3 trial follow up – the longest of any randomized trial for metastatic uveal melanoma – the three-year OS rate was 27% in the KIMMTRAK arm, versus 18% in the control arm (investigator’s choice, predominantly [82%] single agent pembrolizumab). The median OS was 21.6 months on KIMMTRAK, versus 16.9 months on investigator’s choice. The OS Hazard Ratio (HR) favored KIMMTRAK, HR=0.68 (95% CI: 0.54 to 0.87), over investigator’s choice.

Overall response rate remained in favor of KIMMTRAK when compared with the control arm (11% vs 5%) and the median duration of response for KIMMTRAK patients was 11.1 months. The rate of disease control (complete response, partial response, or stable disease for ≥12 weeks) was also higher in the KIMMTRAK arm (46% vs 27%) versus the control arm. Over half (57%; n=139) of all patients treated with KIMMTRAK were treated beyond initial radiographic progression.

The trial evaluated circulating tumor DNA (ctDNA) clearance as a predictor of overall survival. ctDNA clearance on KIMMTRAK occurred in 37% of evaluable patients (compared with previously reported 13% in second-line patients1) and was associated with longer OS.

No new adverse events (AEs) related to long-term KIMMTRAK treatment were observed. The rate of discontinuation due to treatment-related AEs continued to be lower (2%) in the KIMMTRAK arm than for the control arm (5%). There were no treatment-related deaths.

In a separate poster at the Congress, an analysis of the role of subsequent therapy from the Phase 3 trial in first-line mUM patients confirmed that the survival benefit mostly comes from KIMMTRAK treatment rather than subsequent therapy.

A further poster included an analysis from the Phase 1b study in previously treated metastatic cutaneous melanoma patients, demonstrating the safety and activity of KIMMTRAK by BRAF mutation status. A third poster investigated the reprogramming effect of KIMMTRAK on immunosuppressive M2 macrophages from Phase 2 unresectable or metastatic uveal melanoma patients, as well as in vitro.

Presentation and poster details

Title: Three-year survival with tebentafusp in previously untreated metastatic uveal melanoma in a phase 3 trial
Presenting author: Sophie Piperno-Neumann
Session: Mini oral session – Melanoma and other skin tumours, Saturday 21 October, 2023

Title: Tebentafusp reprograms immunosuppressive tumor-associated M2 macrophages towards anti-tumoral M1 macrophages
Presenting author: Josep M. Piulats
Session: Poster display, Saturday 21 October, 2023

Title: BRAF mutation status does not impact outcomes with tebentafusp in advanced cutaneous melanoma
Presenting author: Alexander N. Shoushtari
Session: Poster display, Sunday 22 October, 2023

Title: Effect of subsequent therapies including checkpoint inhibitors on overall survival in a phase 3 randomized trial of tebentafusp in first line metastatic uveal melanoma: long-term follow up
Presenting author: Marcus Butler
Session: Poster display, Sunday 22 October, 2023

##

About ImmTAC molecules for cancer
Immunocore’s proprietary T cell receptor (TCR) technology generates a novel class of bispecific biologics called ImmTAC (Immune mobilizing monoclonal TCRs Against Cancer) molecules that are designed to redirect the immune system to recognize and kill cancerous cells. ImmTAC molecules are soluble TCRs engineered to recognize intracellular cancer antigens with ultra-high affinity and selectively kill these cancer cells via an anti-CD3 immune-activating effector function. Based on the demonstrated mechanism of T cell infiltration into human tumors, the ImmTAC mechanism of action holds the potential to treat hematologic and solid tumors, regardless of mutational burden or immune infiltration, including immune "cold" low mutation rate tumors.

About KIMMTRAK
KIMMTRAK is a novel bispecific protein comprised of a soluble T cell receptor fused to an anti-CD3 immune-effector function. KIMMTRAK specifically targets gp100, a lineage antigen expressed in melanocytes and melanoma. This is the first molecule developed using Immunocore’s ImmTAC technology platform designed to redirect and activate T cells to recognize and kill tumor cells. KIMMTRAK has been approved for the treatment of HLA-A*02:01-positive adult patients with unresectable or metastatic uveal melanoma in the United States, European Union, Canada, Australia, and the United Kingdom.

About Phase 3 IMCgp100-202 Trial
IMCgp100-202 (NCT03070392) is a randomized pivotal trial that evaluated overall survival (OS) of KIMMTRAK compared to investigator’s choice (either pembrolizumab, ipilimumab, or dacarbazine) in HLA-A*02:01-positive adult patients with previously untreated mUM. KIMMTRAK demonstrated an unprecedented OS benefit with a Hazard Ratio (HR) in the intent-to-treat population favoring KIMMTRAK, HR=0.51 (95% CI: 0.37, 0.71); p< 0.0001, over investigator’s choice (82% pembrolizumab; 13% ipilimumab; 6% dacarbazine).

IMPORTANT SAFETY INFORMATION

Cytokine Release Syndrome (CRS), which may be serious or life-threatening, occurred in patients receiving KIMMTRAK. Monitor for at least 16 hours following first three infusions and then as clinically indicated. Manifestations of CRS may include fever, hypotension, hypoxia, chills, nausea, vomiting, rash, elevated transaminases, fatigue, and headache. CRS occurred in 89% of patients who received KIMMTRAK with 0.8% being grade 3 or 4. Ensure immediate access to medications and resuscitative equipment to manage CRS. Ensure patients are euvolemic prior to initiating the infusions. Closely monitor patients for signs or symptoms of CRS following infusions of KIMMTRAK. Monitor fluid status, vital signs, and oxygenation level and provide appropriate therapy. Withhold or discontinue KIMMTRAK depending on persistence and severity of CRS.

Skin Reactions

Skin reactions, including rash, pruritus, and cutaneous edema occurred in 91% of patients treated with KIMMTRAK. Monitor patients for skin reactions. If skin reactions occur, treat with antihistamine and topical or systemic steroids based on persistence and severity of symptoms. Withhold or permanently discontinue KIMMTRAK depending on the severity of skin reactions.

Elevated Liver Enzymes

Elevations in liver enzymes occurred in 65% of patients treated with KIMMTRAK. Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total blood bilirubin prior to the start of and during treatment with KIMMTRAK. Withhold KIMMTRAK according to severity.

Embryo-Fetal Toxicity
KIMMTRAK may cause fetal harm. Advise pregnant patients of potential risk to the fetus and patients of reproductive potential to use effective contraception during treatment with KIMMTRAK and 1 week after the last dose.

The most common adverse reactions (≥30%) in patients who received KIMMTRAK were cytokine release syndrome, rash, pyrexia, pruritus, fatigue, nausea, chills, abdominal pain, edema, hypotension, dry skin, headache, and vomiting. The most common (≥50%) laboratory abnormalities were decreased lymphocyte count, increased creatinine, increased glucose, increased AST, increased ALT, decreased hemoglobin, and decreased phosphate.

For more information, please see full Summary of Product Characteristics (SmPC) or full U.S. Prescribing Information (including BOXED WARNING for CRS).

On October 21, 2023 Agenus Inc. (Nasdaq:AGEN), a leader in developing novel immunological agents to treat various cancers, reported expanded data from the company’s phase 1b study of botensilimab (BOT, multifunctional immune activator) in combination with balstilimab (BAL, anti-PD-1) in patients with advanced sarcomas (Press release, Agenus, OCT 21, 2023, View Source [SID1234636195]). The results were presented in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023.

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Relapsed/refractory sarcoma represents a significant unmet medical need where existing standard of care options and previous immunotherapies have shown limited activity. At present, available treatments for advanced soft tissue sarcoma patients only have modest activity. The sarcoma cohort presented is part of a larger phase 1b study evaluating the safety, efficacy, and dose optimization of BOT alone and in combination with BAL in multiple advanced solid tumors.

"These results reinforce the promising potential of BOT+BAL in multiple cold, treatment-resistant solid tumors," said Dr. Steven O’Day, Chief Medical Officer. "Notably, we observed several durable responses extending past one year, including patients with visceral angiosarcoma, which is traditionally unresponsive to immunotherapy, as well as other cold subtypes like leiomyosarcoma. As we expand the study, we aim to focus on key subsets and dosing strategies to maximize benefit for patients."

"As the study has advanced, BOT+BAL continues to demonstrate encouraging results in a larger population of patients with difficult to treat sarcomas, with a median response duration of 19.4 months and a 40% 6-month progression-free survival rate. We’re also seeing a dose-dependent effect, with a 29% objective response rate at 2 mg/kg," said Dr. Breelyn Wilky, MD, Director of Sarcoma Medical Oncology at the University of Colorado, and study investigator.

Study Design and Highlights

A total of 41 evaluable patients received either 1 or 2 mg/kg BOT every 6 weeks and 3 mg/kg BAL every 2 weeks.

Patient Demographics

Majority of patients had either angiosarcoma (29%) or leiomyosarcoma (39%) subtypes
Patients were heavily pre-treated, with a median of three prior lines of therapy, including 16% who received prior PD-(L)1 therapy
Majority of patients had biomarkers associated with poor response to immunotherapy:
87% had a low tumor mutation burden (<10 mutations per megabase)
74% of patients were PD-L1 negative by immunohistochemistry
Clinical Findings

Efficacy in all comers (as measured by iRECIST; n=41)

40% 6-month PFS
20% ORR
29% ORR at the BOT 2 mg/kg dose level
15% ORR at the 1 mg/kg dose level
63% disease control rate (best response of a complete response + partial response + stable disease)
Median duration of response was 19.4 months
Safety in all comers (N=50)

No new safety signals reported, with tolerability consistent across tumor types
Adverse events were generally manageable and reversible
Diarrhea/colitis was the most clinically significant immune-mediated adverse event
No grade 4 or 5 treatment-related adverse events and no related cases of irreversible events such as hypophysitis, pneumonitis, hepatitis, or myocarditis were reported
Presentation Details

Abstract Title: Efficacy and safety of botensilimab (BOT) plus balstilimab (BAL) in patients (pts) with refractory metastatic sarcoma (NCT03860272)
Abstract Number: 1919MO
Presenting Author: Breelyn A. Wilky, MD, Director of Sarcoma Medical Oncology, Deputy Associate Director for Clinical Research, University of Colorado Cancer Center
Session Date and Time: 10/21/2023, 10:15 a.m. – 11:45 a.m. CEST
Presentation Date and Time: 10/21/2023, 11:00 a.m. – 11:05 a.m. CEST

The presentation is available on the Agenus website at View Source

References

1 . D’Angelo SP, et al. Lancet Oncol. 2018;19
2. Chen JL, et al. J Clin Oncol. 2020;38(15)_suppl:11511-11511
3. Wagner MJ, et al. J Immunother Cancer. 2021;9:e002990.

About Botensilimab

Botensilimab is an investigational multifunctional anti-CTLA-4 immune activator designed to boost both innate and adaptive anti-tumor immune responses. Its novel design leverages mechanisms of action to extend immunotherapy benefits to "cold" tumors which generally respond poorly to standard of care or are refractory to conventional PD-1/CTLA-4 therapies and other investigational therapies. Botensilimab augments immune responses across a wide range of tumor types by priming and activating T cells, downregulating intratumoral regulatory T cells, activating myeloid cells and inducing long-term memory responses.

Approximately 600 patients have been treated with botensilimab in phase 1 and phase 2 clinical trials. Botensilimab alone, or in combination with Agenus’ investigational anti-PD-1, balstilimab, has shown clinical responses across nine metastatic, late-line cancers. For more information about botensilimab trials, visit www.clinicaltrials.gov with the identifiers NCT03860272, NCT05608044, NCT05630183, and NCT05529316.

On October 21, 2023 The Janssen Pharmaceutical Companies of Johnson & Johnson reported results from the Phase 2 randomized, open-label THOR-2 study evaluating BALVERSA versus investigator choice of intravesical chemotherapy in patients with high-risk non-muscle-invasive bladder cancer (HR-NMIBC) and select fibroblast growth factor receptor (FGFR) alterations which recurred after Bacillus Calmette-Guérin (BCG) therapy (Press release, Johnson & Johnson, OCT 21, 2023, View Source [SID1234636189]). Data from Cohort 1 of the study were featured today in a Proffered Paper Late-Breaking Session (Abstract #LBA102) at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) 2023 Congress taking place October 20-24 in Madrid, Spain, and simultaneously published in Annals of Oncology.1,2

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Of the 73 patients included in Cohort 1, 49 were randomized to BALVERSA and 24 were randomized to chemotherapy. Oral erdafitinib reduced the risk of recurrence of disease or death by 72 percent compared with intravesical chemotherapy in patients with high-risk resected papillary Ta/T1 NMIBC harboring FGFR mutations or fusions with recurrence after BCG treatment and who refused or were ineligible for radical cystectomy.

With a median follow-up of 13.4 months at the data cutoff, median recurrence-free survival (RFS) was not met in patients who received BALVERSA and was 11.6 months for patients who received chemotherapy (Hazard Ratio [HR]=0.28; 95 percent Confidence Interval [CI], 0.13-0.62; nominal p=0.0008). The six-month RFS in patients randomized to BALVERSA was 96 percent compared to 73 percent in those assigned to chemotherapy. The 12-month RFS in patients assigned to BALVERSA was 77 percent compared to 41 percent in patients who received chemotherapy.

Grade 3 or 4 serious treatment-related adverse events (TRAEs) were observed in fifteen patients (31 percent) who received BALVERSA and one patient (4 percent) randomized to chemotherapy. Fourteen patients (29 percent) assigned to BALVERSA and zero patients who received intravesical chemotherapy had TRAEs that lead to discontinuation of treatment. Central serous retinopathy occurred in 19 patients (39 percent) who received BALVERSA and resolved in 11 patients (58 percent).

"Patients with NMIBC who experience disease recurrence after BCG treatment have limited treatment options, and those eligible patients with FGFR alterations who received erdafitinib in the THOR-2 trial had far fewer recurrences against patients treated by the current standard of care," said James W.F. Catto*, Ph.D., Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK and presenting author of the study. "Our findings underscore the importance of detecting certain genetic biomarkers to identify patients who may benefit from treatment with a targeted therapy like erdafitinib."

"Janssen’s ongoing development of BALVERSA reinforces our commitment to bringing targeted, precision medicines to patients with FGFR-driven bladder cancer," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. "These results support the importance of testing for FGFR in early-stage bladder cancer and potential benefit with BALVERSA in patients with high-risk non-muscle-invasive bladder cancer where disease progression and poor outcomes are common."

About THOR-2

THOR 2 (NCT04172675) is a Phase 2 randomized, open-label study evaluating BALVERSA versus investigator choice of intravesical chemotherapy in participants with NMIBC who recurred after BCG therapy. Patients are categorized to one of three cohorts based on their disease presentation: patients with HR-NMIBC and a papillary tumour only, where early cancer cells are still confined within the innermost layer of the bladder lining (Cohort 1), patients with HR-NMIBC presenting as carcinoma in situ (CIS) with or without a concurrent papillary tumour (Cohort 2), or patients with intermediate-risk NMIBC presenting with papillary disease only (Cohort 3). Patients in Cohort 1 are randomized to receive either BALVERSA or chemotherapy (mitomycin C or gemcitabine) in a 2:1 ratio and all patients in Cohorts 2 and 3 will receive BALVERSA. The Cohort 1 primary endpoint is RFS; secondary endpoints include RFS at six- and 12-months, time to progression, overall survival, plasma concentration of BALVERSA and number of patients with adverse events. The study consists of screening period, treatment phase, follow-up phase and long-term extension phase.

About BALVERSA

BALVERSA (erdafitinib) is a once-daily, oral FGFR kinase inhibitor that received accelerated approval in 2019 for the treatment of adults with locally advanced or metastatic urothelial carcinoma (mUC) which has susceptible FGFR3 or FGFR2 genetic alterations and who have progressed during or following at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Patients are selected for therapy based on an FDA-approved companion diagnostic for BALVERSA. Information on FDA-approved tests for the detection of FGFR genetic alterations in urothelial cancer is available at: View Source

In addition to the Phase 2 THOR-2 study, BALVERSA is being studied in the Phase 3 THOR (NCT03390504) study comparing BALVERSA in two cohorts; BALVERSA versus standard of care chemotherapy (investigators choice of docetaxel or vinflunine) after at least one line of treatment including an anti-programmed death (ligand) 1 (PD-[L]1) agent (Cohort 1); and BALVERSA compared to pembrolizumab after one prior treatment not containing an anti-PD-(L)1 agent (Cohort 2) in patients with metastatic or unresectable urothelial carcinoma, with selected FGFR genetic alterations, who showed disease progression during or after one or two prior lines of treatment.4,5

In August 2023, Janssen submitted a Supplemental New Drug Application to the U.S. Food and Drug Administration seeking the full approval of BALVERSA based upon data from Cohort 1 Phase 3 THOR study. The Company also submitted a marketing authorization application to the European Medicines Agency in September 2023.

In 2008, Janssen Pharmaceutica NV entered into an exclusive worldwide license and collaboration agreement with Astex Pharmaceuticals to develop and commercialize BALVERSA.

For more information, visit www.BALVERSA.com.

About High-Risk Non-Muscle-Invasive Bladder Cancer

High-risk non-muscle-invasive bladder cancer (HR-NMIBC) is a type of non-invasive bladder cancer that is more likely to recur or spread beyond the lining of the bladder, called the urothelium, and progress to invasive bladder cancer compared to low-risk NMIBC.6,7 HR-NMIBC makes up 15–44 percent of patients with NMIBC and is characterized by a high-grade, large tumor size, presence of multiple tumors, and CIS. Radical cystectomy is currently recommended for NMIBC patients who fail BCG therapy, with over 90 percent cancer-specific survival if performed before muscle-invasive progression.8,9 Given that NMIBC typically affects older patients, many may be unwilling or unfit to undergo radical cystectomy.10 The high rates of recurrence and progression can pose significant morbidity and distress for these patients.9,11

BALVERSA IMPORTANT SAFETY INFORMATION12

WARNINGS AND PRECAUTIONS

Ocular Disorders – BALVERSA can cause ocular disorders, including central serous retinopathy/retinal pigment epithelial detachment (CSR/RPED) resulting in visual field defect.

CSR/RPED was reported in 25% of patients treated with BALVERSA, with a median time to first onset of 50 days. Grade 3 CSR/RPED, involving central field of vision, was reported in 3% of patients. CSR/RPED resolved in 13% of patients and was ongoing in 13% of patients at the study cutoff. CSR/RPED led to dose interruptions and reductions in 9% and 14% of patients, respectively, and 3% of patients discontinued BALVERSA. Dry eye symptoms occurred in 28% of patients during treatment with BALVERSA and were Grade 3 in 6% of patients. All patients should receive dry eye prophylaxis with ocular demulcents as needed.

Perform monthly ophthalmological examinations during the first 4 months of treatment and every 3 months afterwards, and urgently at any time for visual symptoms. Ophthalmological examination should include assessment of visual acuity, slit lamp examination, fundoscopy, and optical coherence tomography. Withhold BALVERSA when CSR occurs and permanently discontinue if it does not resolve within 4 weeks or if Grade 4 in severity. For ocular adverse reactions, follow the dose modification guidelines [see Dosage and Administration (2.3)].

Hyperphosphatemia and Soft Tissue Mineralization – BALVERSA can cause hyperphosphatemia leading to soft tissue mineralization, cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification. Increases in phosphate levels are a pharmacodynamic effect of BALVERSA [see Pharmacodynamics (12.2)]. Hyperphosphatemia was reported as an adverse reaction in 76% of patients treated with BALVERSA. The median onset time for any grade event of hyperphosphatemia was 20 days (range: 8–116) after initiating BALVERSA. Thirty-two percent of patients received phosphate binders during treatment with BALVERSA. Cutaneous calcinosis, non-uremic calciphylaxis and vascular calcification have been observed in 0.3% of patients treated with BALVERSA.

Monitor for hyperphosphatemia throughout treatment. In all patients, restrict phosphate intake to 600-800 mg daily. If serum phosphate is above 7.0 mg/dL, consider adding an oral phosphate binder until serum phosphate level returns to <5.5 mg/dL. Withhold, dose reduce, or permanently discontinue BALVERSA based on duration and severity of hyperphosphatemia [see Dosage and Administration (2.3), Table 2: Dose Modifications for Adverse Reactions].

Embryo-Fetal Toxicity – Based on the mechanism of action and findings in animal reproduction studies, BALVERSA can cause fetal harm when administered to a pregnant woman. In a rat embryo-fetal toxicity study, erdafitinib was embryotoxic and teratogenic at exposures less than the human exposures at all doses studied. Advise pregnant women of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with BALVERSA and for one month after the last dose [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

Most common adverse reactions including laboratory abnormalities ≥20%:

Phosphate increased (76%), stomatitis (56%), fatigue (54%), creatinine increased (52%), diarrhea (47%), dry mouth (45%), nail disorder (45%), alanine aminotransferase increased (41%), alkaline phosphatase increased (41%), sodium decreased (40%), decreased appetite (38%), albumin decreased (37%), dysgeusia (37%), hemoglobin decreased (35%), dry skin (34%), aspartate aminotransferase increased (30%), magnesium decreased (30%), dry eye (28%), alopecia (26%), palmar-plantar erythrodysesthesia syndrome (26%), constipation (28%), phosphate decreased (24%), abdominal pain (23%), calcium increased (22%), nausea (21%), and musculoskeletal pain (20%). The most common Grade 3 or greater adverse reactions (>1%) were stomatitis (9%), nail dystrophy*, palmar-plantar erythrodysesthesia syndrome (6%), paronychia (3%), nail disorder (10%), keratitis†, and hyperphosphatemia (1%).

*Included within nail disorder. †Included within dry eye.

An adverse reaction with a fatal outcome in 1% of patients was acute myocardial infarction.
Serious adverse reactions occurred in 41% of patients, including eye disorders (10%).
Permanent discontinuation due to an adverse reaction occurred in 13% of patients. The most frequent reasons for permanent discontinuation included eye disorders (6%).
Dosage interruptions occurred in 68% of patients. The most frequent adverse reactions requiring dosage interruption included hyperphosphatemia (24%), stomatitis (17%), eye disorders (17%), and palmar-plantar erythrodysesthesia syndrome (8%).
Dose reductions occurred in 53% of patients. The most frequent adverse reactions for dose reductions included eye disorders (23%), stomatitis (15%), hyperphosphatemia (7%), palmar-plantar erythrodysesthesia syndrome (7%), paronychia (7%), and nail dystrophy (6%).
Drug Interactions

Moderate CYP2C9 or strong CYP3A4 Inhibitors: Consider alternative agents or monitor closely for adverse reactions. (7.1)
Strong CYP2C9 or CYP3A4 inducers: Avoid concomitant use with BALVERSA. (7.1)
Moderate CYP2C9 or CYP3A4 inducers: Increase BALVERSA dose up to 9 mg. (7.1)
Serum phosphate level-altering agents: Avoid concomitant use with agents that can alter serum phosphate levels before the initial dose modification period. (2.3, 7.1)
CYP3A4 substrates: Avoid concomitant use with sensitive CYP3A4 substrates with narrow therapeutic indices. (7.2)
OCT2 substrates: Consider alternative agents or consider reducing the dose of OCT2 substrates based on tolerability. (7.2)
P-gp substrates: Separate BALVERSA administration by at least 6 hours before or after administration of P-gp substrates with narrow therapeutic indices. (7.2)
Use in Specific Populations

Lactation – Because of the potential for serious adverse reactions from erdafitinib in a breastfed child, advise lactating women not to breastfeed during treatment with BALVERSA and for one month following the last dose.

Please see the full Prescribing Information for BALVERSA.

On October 21, 2023 Astrazeneca reported that Positive results from the primary analysis of the DUO-E Phase III trial showed that Imfinzi (durvalumab) plus platinum-based chemotherapy, followed by either Imfinzi monotherapy or Imfinzi plus Lynparza (olaparib), both demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to chemotherapy alone in the overall trial population of patients with newly diagnosed advanced or recurrent endometrial cancer (Press release, AstraZeneca, OCT 21, 2023, View Source [SID1234636188]).

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These results will be presented today in a proffered paper session at the 2023 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Madrid, Spain (Presentation #LBA41) and simultaneously published online in the Journal of Clinical Oncology.

In the overall trial population, results showed that treatment with Imfinzi plus chemotherapy followed by Imfinzi plus Lynparza (Imfinzi plus Lynparza Arm) and treatment with Imfinzi plus chemotherapy followed by Imfinzi monotherapy (Imfinzi Arm) demonstrated a reduction in the risk of disease progression or death, by 45% (hazard ratio [HR] 0.55; 95% confidence interval [CI] 0.43-0.69; p<0.0001) and 29% (HR 0.71; 95% CI 0.57-0.89; p=0.003), respectively, versus chemotherapy alone (Control Arm). Median PFS was 15.1 months in the Imfinzi plus Lynparza Arm and 9.6 months in the Control Arm.

Mismatch repair (MMR) status is a biomarker of interest in endometrial cancer, therefore a prespecified exploratory subgroup analysis by MMR status was conducted in DUO-E. Results from the analysis of mismatch repair proficient (pMMR) patients showed a reduction in the risk of disease progression or death in both the Imfinzi plus Lynparza and the Imfinzi Arms, by 43% (HR 0.57; 95% CI 0.44-0.73) and 23% (HR 0.77; 95% CI 0.60-0.97), respectively, versus the Control Arm. Median PFS was 15 months in the Imfinzi plus Lynparza Arm and 9.7 months in the Control Arm.

Results from the analysis of mismatch repair deficient (dMMR) patients showed a similar reduction in the risk of disease progression or death in both the Imfinzi plus Lynparza and the Imfinzi Arms, by 59% (HR 0.41; 95% CI 0.21-0.75) and 58% (HR 0.42; 95% CI 0.22-0.80), respectively, versus the Control Arm.

Interim overall survival (OS) data showed a favourable trend for both treatment regimens in the overall population.

Shannon N. Westin, Professor of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, and principal investigator of the trial, said, "These findings showcase, for the first time, the potential of combining immunotherapy with a PARP inhibitor to deliver significant clinical improvements for these patients. These DUO-E data may offer oncologists novel avenues to enhance outcomes for endometrial cancer patients."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said, "The treatment options for most patients with advanced endometrial cancer are limited, especially for those with mismatch repair proficiency, and have not changed for many years. We are delighted that these DUO-E data show meaningful clinical improvements for patients when Imfinzi and Lynparza are combined or when Imfinzi is added alone. We look forward to discussing these data with global regulatory authorities and bringing these important new treatment approaches to patients as soon as possible."

PD-L1 is a known biomarker for Imfinzi in other indications and a prespecified analysis based on PD-L1 status showed, in the PD-L1 positive population, that treatment reduced the risk of disease progression or death by 58% (HR 0.42; 95% CI 0.31-0.57) and 37% (HR 0.63; 95% CI 0.48-0.83) in the Imfinzi plus Lynparza and the Imfinzi Arms, respectively, versus the Control Arm. Median PFS was 20.8 months in the Imfinzi plus Lynparza Arm and 9.5 months in the Control Arm.

In the PD-L1 negative population, treatment reduced the risk of disease progression or death by 20% (HR 0.80; 95% CI 0.55-1.16) and 11% (HR 0.89; 95% CI 0.59-1.34) in the Imfinzi plus Lynparza and the Imfinzi Arms, respectively, versus the Control Arm.

The safety and tolerability profiles of both regimens (Imfinzi plus Lynparza Arm and Imfinzi Arm) were broadly consistent with those observed in prior clinical trials and the known profiles of the individual medicines.1,2

The most common adverse events (AEs) (affecting 20% or more of patients) reported in the Imfinzi plus Lynparza Arm during the overall study were anaemia (62%), nausea (55%), fatigue and asthenia (54%), alopecia (51%), neutropenia (42%), constipation (33%), thrombo-cytopenia (30%), diarrhoea (28%), vomiting (26%), peripheral neuropathy (25%), peripheral sensory neuropathy (25%), arthralgia (24%), decreased appetite (23%), leukopenia (20%) and urinary tract infection (20%).

The most common AEs reported in the Imfinzi Arm during the overall study were alopecia (50%), anaemia (48%), fatigue and asthenia (43%), nausea (41%), neutropenia (36%), diarrhoea (31%), arthralgia (30%), thrombo-cytopenia (28%), constipation (27%), peripheral neuropathy (26%), peripheral sensory neuropathy (26%) and vomiting (21%).

Notes

Endometrial cancer
Endometrial cancer is a highly heterogeneous disease that originates in the tissue lining of the uterus and is most common in women who have already been through the menopause, with the average age at diagnosis being over 60 years old.3-5 It is the 6th most common cancer in women worldwide.6 Incidence and mortality of endometrial cancer are expected to increase by approximately 46% and 62% respectively (from 417,400 cases and 97,400 deaths in 2020 to 608,130 cases and 157,813 deaths) in 2040.6,7

The majority of patients with endometrial cancer are diagnosed at an early stage of disease where the cancer is confined to the uterus. They are typically treated with surgery and/or radiation and the 5-year survival rate is high (approximately 95%). Patients with advanced disease (Stage III-IV) usually have a much poorer prognosis, with the 5-year survival rate falling to around 20-30%. The standard of care for advanced endometrial cancer has traditionally been limited to chemotherapy.5,8,9,10,11,12 There is a high unmet need for novel treatment options and strategies that can improve long-term outcomes in advanced or recurring endometrial cancer.10,13

DUO-E
The DUO-E trial (GOG 3041/ENGOT-EN10) is a three-arm, randomised, double-blind, placebo-controlled, multicentre Phase III trial of 1st-line Imfinzi (durvalumab) plus platinum-based chemotherapy (carboplatin and paclitaxel) followed by either Imfinzi monotherapy or Imfinzi plus Lynparza (olaparib) as maintenance therapy versus platinum-based chemotherapy alone as a treatment for patients with newly diagnosed advanced or recurrent endometrial cancer.

The DUO-E trial randomised 699 patients with newly diagnosed advanced or recurrent epithelial endometrial carcinoma to receive either Imfinzi (1120mg) or placebo, given every three weeks in addition to standard-of-care platinum-based chemotherapy. After 4-6 cycles of chemotherapy, patients (whose disease had not progressed) then received either Imfinzi (1500mg) or placebo every four weeks as maintenance, plus 300mg Lynparza (300mg BID [2x150mg tablets, twice a day]) or placebo until disease progression.

The dual primary endpoint was progression-free survival (PFS) of each treatment arm versus standard of care. Key secondary endpoints included overall survival (OS), safety and tolerability. Mismatch repair status, recurrence status and geographic location were stratification factors. Mismatch repair deficient (dMMR) status reflects an inability to correct DNA replication errors and therefore results in an increased risk of cancer, while mismatch repair proficient (pMMR) status indicates when DNA repair pathways remain intact and where the mismatch repair pathway is active and functional.14,15 The trial was sponsored independently by AstraZeneca and conducted in 253 study locations across 22 countries including the US, Europe, South America and Asia.

For more information about the trial please visit ClinicalTrials.gov.

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 non-small cell lung cancer (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 indications in lung cancer, Imfinzi also is approved in combination with chemotherapy (gemcitabine plus cisplatin) in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma 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.

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination-related (HRR) genes, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as new hormonal agents [NHAs]).

Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.

Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA mutation (gBRCAm), HER2-negative metastatic breast cancer (in the EU and Japan, this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan, this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) when chemotherapy is not clinically indicated (EU only) and for BRCAm mCRPC (US and Japan); and as monotherapy for HRR gene-mutated mCRPC in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCA-mutated mCRPC as well as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.

Lynparza is being jointly developed and commercialised by AstraZeneca and MSD, both as a monotherapy and in combination with other potential medicines. Independently, the companies are developing and will commercialise Lynparza in combination with their respective PD-L1 and PD-1 medicines, Imfinzi (durvalumab) and Keytruda (pembrolizumab). Lynparza has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

On October 21, 2023 Astrazeneca reported results from a prespecified exploratory analysis of the FLAURA2 Phase III trial showed Tagrisso (osimertinib) with the addition of chemotherapy demonstrated a 42% improvement in central nervous system (CNS) progression-free survival (PFS), compared to Tagrisso alone for patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) and brain metastases at baseline, reprsenting 40% of patients in the trial, as assessed by blinded independent central review (BICR) (Press release, AstraZeneca, OCT 21, 2023, View Source [SID1234636187]).

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These results were presented today in an oral presentation at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress in Madrid, Spain (abstract #LBA68).

In this group of patients, Tagrisso with the addition of chemotherapy reduced the risk of CNS disease progression or death by 42% compared to Tagrisso alone (based on a hazard ratio [HR] of 0.58; 95% confidence interval [CI] 0.33-1.01) as assessed by BICR. With two years of follow-up, 74% of patients treated with Tagrisso plus chemotherapy had not experienced CNS disease progression or death versus 54% of patients treated with Tagrisso monotherapy. Results also showed a higher proportion of patients demonstrated CNS complete response (CR) with Tagrisso plus chemotherapy (59%) versus Tagrisso alone (43%).

David Planchard, MD, PhD, thoracic oncologist at Gustave Roussy Institute of Oncology and principal investigator for the trial, said: "Osimertinib has a proven ability to cross the blood-brain barrier and improve outcomes for patients with lung cancer and central nervous system metastases, who often face a poorer prognosis than patients whose disease has not spread to the brain. In FLAURA2, the addition of chemotherapy to osimertinib led to a complete response and the disappearance of these tumours in the brain, in more than half of these patients."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "In this trial, patients with brain metastases at baseline saw a meaningful benefit with the FLAURA2 regimen, offering hope for patients whose cancer has spread to the brain. These data build on the recent positive progression-free survival results from FLAURA2, further reinforcing Tagrisso as the backbone therapy in EGFR-mutated non-small cell lung cancer."

The safety profile of Tagrisso with the addition of chemotherapy was generally manageable and consistent with the established profiles of the individual medicines. Adverse event (AEs) rates were higher in the Tagrisso plus chemotherapy arm, driven by well-characterised chemotherapy-related AEs. Tagrisso discontinuation rates were low in both arms of the trial (11% for the Tagrisso plus chemotherapy arm and 6% for the monotherapy arm).

In the Tagrisso plus chemotherapy arm, patients remained on Tagrisso for a median duration of 22.3 months, while patients had a median exposure to platinum-based chemotherapy of 2.8 months and a median exposure to pemetrexed of 8.3 months.

Summary of results: FLAURA2 CNS efficacyi

Tagrisso plus chemotherapy

(n=118)

Tagrisso monotherapy

(n=104)

PFS HR (95% CI)

0.58 (0.33-1.01)

Median PFS (months; 95% CI)

30.2 (28.4-NCii)

27.6 (22.1-NC)

CNS objective response rate, n (%)

86 (73)

72 (69)

CR, n (%)

70 (59)

45 (43)

Median CNS duration of response (in months; 95% CI)

NRiii (23.8-NC)

26.2 (19.4-NC)

i The data cut-off date was 3 April, 2023.
ii NC, non-calculable
iii NR, not reached

Earlier this month, Tagrisso with the addition of chemotherapy was granted Priority Review by the Food and Drug Administration (FDA) for the 1st-line treatment of adult patients with locally advanced or metastatic EGFRm NSCLC based on positive PFS data from the FLAURA2 Phase III trial recently presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer. In August 2023, Tagrisso with the addition of chemotherapy also received Breakthrough Therapy Designation from the FDA in this setting.

Notes

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer.2 The majority of all NSCLC patients are diagnosed with advanced disease.3

Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.4

FLAURA2
FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg once daily oral tablets in combination with chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5) every three weeks for four cycles, followed by Tagrisso with pemetrexed maintenance every three weeks.

The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of overall survival (OS).

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against CNS metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 700,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

Tagrisso is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. These include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage (IB, II and IIIA) EGFRm NSCLC, where Tagrisso recently demonstrated a statistically significant and clinically meaningful OS benefit.

There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve survival in both early-stage disease in the ADAURA Phase III trial and late-stage disease in the FLAURA Phase III trial.

AstraZeneca also has several ongoing Phase III trials focused on earlier stages of lung cancer, including a trial in the Stage IA2-IA3 adjuvant resectable setting (ADAURA2), in the neoadjuvant setting (NeoADAURA), and in the Stage III locally advanced unresectable setting (LAURA).

The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines.