On March 16, 2024 GSK plc (LSE/NYSE: GSK) reported statistically significant and clinically meaningful overall survival (OS) results from Part 1 and progression-free survival (PFS) results from Part 2 of the RUBY/ENGOT-EN6/GOG3031/NSGO phase III trial in adult patients with primary advanced or recurrent endometrial cancer. These data were presented today in a late-breaking plenary session at the Society of Gynecologic Oncology 2024 Annual Meeting on Women’s Cancer (16-18 March) (Press release, GlaxoSmithKline, MAR 16, 2024, View Source [SID1234641216]).

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The goal of the RUBY phase III trial programme is to evaluate which patients with primary advanced or recurrent endometrial cancer could potentially benefit from treatment with Jemperli (dostarlimab) plus chemotherapy, with or without the addition of Zejula (niraparib) maintenance. Part 1 of the RUBY phase III trial is investigating dostarlimab plus standard-of-care chemotherapy (carboplatin-paclitaxel) followed by dostarlimab compared to chemotherapy plus placebo followed by placebo. Part 2 of the RUBY phase III trial is evaluating dostarlimab plus standard-of-care chemotherapy, followed by dostarlimab plus niraparib as maintenance therapy compared to chemotherapy plus placebo followed by placebo. The safety and tolerability profiles of dostarlimab plus carboplatin-paclitaxel and dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib were generally consistent with the known safety profiles of the individual medicines.

Previous data showed a statistically significant and clinically meaningful improvement in PFS with Jemperli plus chemotherapy versus chemotherapy alone in frontline mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer. These data led to regulatory approvals for this patient population in the US, EU and certain other countries. Data presented today show additional potential benefit of dostarlimab plus chemotherapy, with or without the addition of niraparib, in the overall population of patients with primary advanced or recurrent endometrial cancer, including patients with mismatch repair proficient (MMRp)/microsatellite stable (MSS) tumours, for which there are currently no approved immuno-therapy-based regimens.

Hesham Abdullah, Senior Vice President, Global Head Oncology, R&D, GSK said: "The positive data presented today further show how dostarlimab-based regimens could benefit a broader set of patients with endometrial cancer. The results we’ve seen to date comprise the growing body of evidence supporting the role of dostarlimab as the backbone of our immuno-oncology development programme. Our goal is to continue to identify ways to use dostarlimab alone and in combination with other therapies to help improve outcomes for patients with limited treatment options."

RUBY Part 1: a statistically significant and clinically meaningful improvement in OS was observed for dostarlimab plus chemotherapy versus placebo plus chemotherapy, meeting a primary endpoint of the study.
Dostarlimab plus chemotherapy versus chemotherapy alone showed:

In the overall population:

a statistically significant reduction in the risk of death by 31% (Hazard Ratio [HR]: 0.69; [95% CI: 0.539–0.890])
a clinically meaningful improvement of 16.4 months in median OS (44.6 months vs 28.2 months)
In a prespecified exploratory analysis of the MMRp/MSS population:

a clinically meaningful trend in reduced risk of death by 21% (HR: 0.79; [95% CI: 0.602–1.044])
a clinically meaningful improvement of seven months in median OS (34.0 months vs 27.0 months)
Full OS summaries are shown below.

dostarlimab +
carboplatin-paclitaxel

placebo +
carboplatin-paclitaxel

Overall population, Number (N)

245

249

OS, HR (95% CI)

0.69 (0.539–0.890)

P-value1

0.002

OS, median (95% CI), mo.

44.6 (32.6–NR)

28.2 (22.1–35.6)

dMMR/MSI-H population2, N

53

65

OS, HR (95% CI)

0.32 (0.166–0.629)

OS, median3 (95% CI), mo.

NR (NR–NR)

31.4 (20.3–NR)

MMRp/MSS2, N

192

184

OS, HR (95% CI)

0.79 (0.602–1.044)

OS, median (95% CI), mo.

34.0 (28.6–NR)

27.0 (21.5–35.6)

1One-sided p-value based on stratified log-rank test.
2Exploratory analyses of OS in dMMR/MSI-H and OS in MMRp/MSS populations were pre-specified with no planned hypothesis testing.
3Although the median OS was not reached, at 30 months the estimated reduction in the risk of death was 82.8% for patients who received dostarlimab plus chemotherapy vs. 54.1% for patients who received chemotherapy alone.

Matthew Powell, MD, Division of Gynecologic Oncology, Washington University School of Medicine,
and US principal investigator of the RUBY trial said: "RUBY Part 1 is the first clinical trial to show a statistically significant and clinically meaningful improvement in overall survival for an immuno-oncology therapy in combination with chemotherapy in the overall population of patients with primary advanced or recurrent endometrial cancer. As a clinician, I celebrate the results of the RUBY Part 1 trial presented today, which show how dostarlimab added to chemotherapy could potentially benefit a broader set of patients with this type of cancer."

In RUBY Part 1, grade 3 or higher and serious treatment-emergent adverse events (AEs) were approximately 12% higher in the dostarlimab plus carboplatin-paclitaxel arm (treatment arm) compared with the placebo plus carboplatin-paclitaxel arm (control arm). The nature and types of immune-related AEs in the dostarlimab plus chemotherapy safety profile were consistent with the mechanism of action of dostarlimab and similar to those reported for other PD-(L)1 inhibitors. In the trial, 40.7% of participants in the treatment arm and 16.3% of participants in the control arm had immune-related AEs assessed by the investigator as related to dostarlimab or placebo, respectively. Discontinuation of dostarlimab or placebo due to a treatment-emergent AE occurred in 19.1% of patients in the treatment arm and 8.1% of patients in the control arm.

GSK expects US Food and Drug Administration regulatory submission acceptance based on RUBY Part 1 data for an expanded indication in the overall population in the first half of this year.

RUBY Part 2: addition of niraparib to dostarlimab in maintenance setting significantly improved PFS in first-line primary advanced or recurrent endometrial cancer compared to chemotherapy alone, meeting the primary endpoint of the trial.
Dostarlimab plus chemotherapy followed by dostarlimab plus niraparib compared to placebo plus chemotherapy followed by placebo showed:

In the overall population:

a statistically significant reduction in the risk of disease progression or death by 40% (HR: 0.60 [95% CI: 0.43–0.82])
a clinically meaningful improvement of 6.2 months in median PFS (14.5 months vs 8.3 months)
In the MMRp/MSS population:

a statistically significant reduction in the risk of disease progression or death by 37% (HR: 0.63 [95% CI: 0.44–0.91])
a clinically meaningful improvement of 6.0 months in median PFS (14.3 months vs 8.3 months)
Dr Mansoor Raza Mirza, Chief Oncologist, Copenhagen University Hospital, Denmark, and RUBY principal investigator said: "In RUBY Part 2, we observed that the use of dostarlimab in combination with niraparib in the maintenance therapy setting further improved progression-free survival versus placebo for patients with primary advanced or recurrent endometrial cancer. These findings are particularly important for patients who have MMRp/MSS tumours as the data help build on the initial benefit observed with an immuno-oncology plus chemotherapy regimen, reflecting the potential for the addition of niraparib maintenance to address unmet medical need for these patients."

In RUBY Part 2, grade 3 or higher and serious treatment-emergent AEs were approximately 36% and 24% higher, respectively, in the dostarlimab plus chemotherapy followed by dostarlimab plus niraparib arm (treatment arm) compared with the placebo plus chemotherapy followed by placebo arm (control arm). In the trial, 36.6% of participants in the treatment arm and 6.3% of participants in the control arm had immune-related AEs assessed by the investigator as related to dostarlimab or placebo, respectively. No cases of myelodysplastic syndrome/acute myeloid leukaemia were reported; other secondary primary malignancies occurred in 1 patient each in both treatment arms. Discontinuation of dostarlimab or placebo due to a TEAE occurred in 24.1% of patients in the treatment arm and 5.2% of patients in the control arm. Discontinuation of niraparib or placebo due to a treatment-emergent AE occurred in 15.7% of patients in the treatment arm and 4.2% of patients in the control arm.

About endometrial cancer
Endometrial cancer is found in the inner lining of the uterus, known as the endometrium. Endometrial cancer is the most common gynaecologic cancer in developed countries, with approximately 417,000 new cases reported each year worldwide1, and incidence rates are expected to rise by almost 40% between 2020 and 2040.2,3 Approximately 15-20% of patients with endometrial cancer will be diagnosed with advanced disease at the time of diagnosis.4

About RUBY
RUBY is a two-part global, randomised, double-blind, multicentre phase III trial of patients with primary advanced or recurrent endometrial cancer. Part 1 is evaluating dostarlimab plus carboplatin-paclitaxel followed by dostarlimab versus carboplatin-paclitaxel plus placebo followed by placebo. Part 2 is evaluating dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib versus placebo plus carboplatin-paclitaxel followed by placebo.

In Part 1, the dual-primary endpoints are investigator-assessed PFS based on the Response Evaluation Criteria in Solid Tumours v1.1 and OS. The statistical analysis plan included pre-specified analyses of PFS in the dMMR/MSI-H and overall populations and OS in the overall population. Pre-specified exploratory analyses of PFS and OS in the MMRp/MSS population and OS in the dMMR/MSI-H populations were also performed. RUBY Part 1 included a broad population, including histologies often excluded from clinical trials and had approximately 10% of patients with carcinosarcoma and 20% with serous carcinoma.

In Part 2, the primary endpoint is investigator-assessed PFS in the overall population, followed by PFS in the MMRp/MSS population, and OS in the overall population is a key secondary endpoint. Additional secondary endpoints in Part 1 and Part 2 include PFS per blinded independent central review, PFS2, overall response rate, duration of response, disease control rate, patient-reported outcomes, and safety and tolerability.

RUBY is part of an international collaboration between the European Network of Gynaecological Oncological Trial groups (ENGOT), a research network of the European Society of Gynaecological Oncology (ESGO) that consists of 22 trial groups from 31 European countries that perform cooperative clinical trials, and the GOG Foundation, a non-profit organisation dedicated to transforming the standard of care in gynaecologic oncology.

About Jemperli (dostarlimab)
Jemperli is a programmed death receptor-1 (PD-1)-blocking antibody that binds to the PD-1 receptor and blocks its interaction with the PD-1 ligands PD-L1 and PD-L2.5

In the US, Jemperli is indicated in combination with carboplatin and paclitaxel, followed by Jemperli as a single agent for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is dMMR, as determined by a US FDA-approved test, or MSI-H, and as a single agent for adult patients with dMMR recurrent or advanced endometrial cancer, as determined by a US FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and are not candidates for curative surgery or radiation. The supplemental Biologics License Application supporting the newly approved indication in combination with carboplatin and paclitaxel for dMMR/MSI-H primary advanced or recurrent endometrial cancer received Breakthrough Therapy designation and Priority Review from the US FDA.

Jemperli is also indicated in the US for patients with dMMR recurrent or advanced solid tumours, as determined by a US FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. The latter indication is approved in the US under accelerated approval based on tumour response rate and durability of response. Continued approval for this indication in solid tumours may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Jemperli was discovered by AnaptysBio, Inc. and licensed to TESARO, Inc., under a collaboration and exclusive license agreement signed in March 2014. Under this agreement, GSK is responsible for the ongoing research, development, commercialisation, and manufacturing of Jemperli, and cobolimab (GSK4069889), a TIM-3 antagonist.

Important Information for Jemperli in the EU
Indication 
Jemperli is indicated:

in combination with carboplatin-paclitaxel, for the treatment of adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer and who are candidates for systemic therapy;
as monotherapy for treating adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.
Refer to the Jemperli EMA Reference Information for a full list of adverse events and the complete important safety information in the EU.

About Zejula (niraparib)
Zejula is an oral, once-daily poly (ADP-ribose) polymerase (PARP) inhibitor indicated in the US for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy; and for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy and who have been selected based on a US FDA-approved companion diagnostic for Zejula.

Important Information for Zejula in the EU 
Indication
Zejula is indicated:

as monotherapy for the maintenance treatment of adult patients with advanced epithelial (FIGO Stages III and IV) high-grade ovarian, fallopian tube or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy.
as monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy.
Refer to the Zejula EMA Reference Information for a full list of adverse events and the complete important safety information in the EU.

On March 15, 2024 Legend Biotech Corporation (NASDAQ: LEGN) (Legend Biotech), a global leader in cell therapy, reported that the U.S. Food and Drug Administration (FDA) Oncologic Drugs Advisory Committee (ODAC) recommended CARVYKTI (ciltacabtagene autoleucel, cilta-cel) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD) and are refractory to lenalidomide (Press release, Legend Biotech, MAR 15, 2024, View Source [SID1234641215]). The positive recommendation follows the committee’s evaluation of efficacy and safety data from the Phase 3 CARTITUDE-4 study. The committee voted unanimously in favor of CARVYKTI (11 to 0) finding the risk-benefit assessment of cilta-cel for the proposed indication as favorable. A supplemental Biologics License Application (sBLA) supported by the CARTITUDE-4 study is currently under review by the FDA with a target Prescription Drug User Fee Act (PDUFA) date of April 5, 2024.

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"The advisory committee’s positive recommendation for CARVYKTI brings us one step closer to helping more patients fighting relapsed and refractory multiple myeloma," said Ying Huang, Ph.D., Chief Executive Officer of Legend Biotech. "We are committed to improving the lives of patients with multiple myeloma, and we’re excited by the prospect of bringing our innovative therapy to patients earlier in the course of their disease."

The committee reviewed results from the CARTITUDE-4 study (NCT04181827), the first randomized Phase 3 study evaluating the efficacy and safety of CARVYKTI versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in the treatment of patients with relapsed and lenalidomide-refractory multiple myeloma who have received one to three prior lines of therapy.1

Outcomes from the Phase 3 CARTITUDE-4 study were first presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting. These study results also supported the recent European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) positive opinion for CARVYKTI in adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent (IMiD), have demonstrated disease progression on the last therapy and are refractory to lenalidomide.

The ODAC is assembled upon request from the FDA to review and evaluate safety and efficacy data of human drug products for use in the treatment of oncologic diseases. The committee provides non-binding recommendations based on its evaluation; final decisions on approval of the drug are made by the FDA.

CARVYKTI INDICATIONS AND USAGE

CARVYKTI (ciltacabtagene autoleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma, after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

IMPORTANT SAFETY INFORMATION

WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, PROLONGED and RECURRENT CYTOPENIA, and SECONDARY HEMATOLOGICAL MALIGNANCIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with CARVYKTI. Do not administer CARVYKTI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), which may be fatal or life-threatening, occurred following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with CARVYKTI. Provide supportive care and/or corticosteroids as needed.

Parkinsonism and Guillain-Barré syndrome and their associated complications resulting in fatal or life-threatening reactions have occurred following treatment with CARVYKTI.

Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS), including fatal and life-threatening reactions, occurred in patients following treatment with CARVYKTI. HLH/MAS can occur with CRS or neurologic toxicities.

Prolonged and/or recurrent cytopenias with bleeding and infection and requirement for stem cell transplantation for hematopoietic recovery occurred following treatment with CARVYKTI.

Secondary hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia, have occurred following treatment with CARVYKTI.

CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS Program.

WARNINGS AND PRECAUTIONS

CYTOKINE RELEASE SYNDROME (CRS) including fatal or life-threatening reactions, occurred following treatment with CARVYKTI in 95% (92/97) of patients receiving ciltacabtagene autoleucel. Grade 3 or higher CRS (2019 ASTCT grade) occurred in 5% (5/97) of patients, with Grade 5 CRS reported in 1 patient. The median time to onset of CRS was 7 days (range: 1-12 days). The most common manifestations of CRS included pyrexia (100%), hypotension (43%), increased aspartate aminotransferase (AST) (22%), chills (15%), increased alanine aminotransferase (ALT) (14%) and sinus tachycardia (11%). Grade 3 or higher events associated with CRS included increased AST and ALT, hyperbilirubinemia, hypotension, pyrexia, hypoxia, respiratory failure, acute kidney injury, disseminated intravascular coagulation and hemorrhage, HLH/MAS, angina pectoris, supraventricular and ventricular tachycardia, malaise, myalgias, increased C-reactive protein, ferritin, blood alkaline phosphatase and gamma-glutamyl transferase.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. One patient with CRS and suspected HLH/MAS developed a fatal retroperitoneal hemorrhage in the setting of thrombocytopenia, coagulopathy, and anticoagulation in another ongoing study of CARVYKTI.

Sixty-nine of 97 (71%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of ciltacabtagene autoleucel. Forty-four (45%) patients received only tocilizumab, of whom 33 (34%) received a single dose and 11 (11%) received more than one dose; 24 patients (25%) received tocilizumab and a corticosteroid, and one patient (1%) received only corticosteroids. Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.

Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMS-certified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids.

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

NEUROLOGIC TOXICITIES, which may be severe, life-threatening, or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included ICANS, neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré Syndrome, immune mediated myelitis, peripheral neuropathies, and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.

Overall, one or more subtypes of neurologic toxicity described below occurred following ciltacabtagene autoleucel in 26% (25/97) of patients, of which 11% (11/97) of patients experienced Grade 3 or higher events. These subtypes of neurologic toxicities were also observed in two ongoing studies.

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS): Patients may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS. ICANS occurred in 23% (22/97) of patients receiving ciltacabtagene autoleucel including Grade 3 or 4 events in 3% (3/97) and Grade 5 (fatal) events in 2% (2/97). The median time to onset of ICANS was 8 days (range 1-28 days). All 22 patients with ICANS had CRS. The most frequent (≥5%) manifestation of ICANS included encephalopathy (23%), aphasia (8%) and headache (6%).

Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Parkinsonism: Of the 25 patients in the CARTITUDE-1 study experiencing any neurotoxicity, six male patients had neurologic toxicity with several signs and symptoms of parkinsonism, distinct from immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicity with parkinsonism has been reported in other ongoing trials of ciltacabtagene autoleucel. Patients had parkinsonian and non-parkinsonian symptoms that included tremor, bradykinesia, involuntary movements, stereotypy, loss of spontaneous movements, masked facies, apathy, flat affect, fatigue, rigidity, psychomotor retardation, micrographia, dysgraphia, apraxia, lethargy, confusion, somnolence, loss of consciousness, delayed reflexes, hyperreflexia, memory loss, difficulty swallowing, bowel incontinence, falls, stooped posture, shuffling gait, muscle weakness and wasting, motor dysfunction, motor and sensory loss, akinetic mutism, and frontal lobe release signs. The median onset of parkinsonism in the 6 patients in CARTITUDE-1 was 64 days (range 14-914 days) from infusion of ciltacabtagene autoleucel.

Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease, for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.

Guillain-Barré Syndrome: A fatal outcome following Guillain-Barré Syndrome (GBS) has occurred in another ongoing study of ciltacabtagene autoleucel despite treatment with intravenous immunoglobulin (IVIG). Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances and polyradiculoneuritis.

Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulin and plasma exchange, depending on severity of GBS.

Immune Mediated Myelitis: Grade 3 myelitis has occurred 25 days following treatment in another ongoing study. Symptoms reported included hypoesthesia of the lower extremities and the lower abdomen with impaired sphincter control. Symptoms improved with the use of corticosteroids and intravenous immune globulin. Myelitis was ongoing at the time of death from other cause.

Peripheral Neuropathy: Seven patients in CARTITUDE-1 developed peripheral neuropathy. These neuropathies presented as sensory, motor, or sensorimotor neuropathies. Median time of onset of symptoms was 66 days (range 4-914 days), median duration of peripheral neuropathies was 138 days (range 2-692 days) including those with ongoing neuropathy. Patients who experienced peripheral neuropathy also experienced cranial nerve palsies or GBS in other ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of peripheral neuropathies.

Cranial Nerve Palsies: Three patients (3.1%) experienced cranial nerve palsies in CARTITUDE-1. All three patients had 7th cranial nerve palsy; one patient had 5th cranial nerve palsy as well. Median time to onset was 26 days (range 21-101 days) following infusion of ciltacabtagene autoleucel. Occurrence of 3rd and 6th cranial nerve palsy, bilateral 7th cranial nerve palsy, worsening of cranial nerve palsy after improvement, and occurrence of peripheral neuropathy in patients with cranial nerve palsy have also been reported in ongoing trials of ciltacabtagene autoleucel. Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)/MACROPHAGE ACTIVATION SYNDROME (MAS): Fatal HLH occurred in one patient (1%), 99 days after ciltacabtagene autoleucel. The HLH event was preceded by prolonged CRS lasting 97 days. The manifestations of HLH/MAS include hypotension, hypoxia with diffuse alveolar damage, coagulopathy, cytopenia, and multi-organ dysfunction, including renal dysfunction.

One patient with Grade 4 HLH/MAS developed fatal intracerebral and gastrointestinal hemorrhage in the setting of coagulopathy and thrombocytopenia 12 days after treatment in another ongoing study. Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematological parameters in patients with HLH/MAS and transfuse per institutional guidelines.

HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.

CARVYKTI REMS: Because of the risk of CRS and neurologic toxicities, CARVYKTI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the CARVYKTI REMS.

Further information is available at View Source or 1-844-672-0067.

PROLONGED AND RECURRENT CYTOPENIAS: Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion. One patient underwent autologous stem cell therapy for hematopoietic reconstitution due to prolonged thrombocytopenia.

In CARTITUDE-1, 30% (29/97) of patients experienced prolonged Grade 3 or 4 neutropenia and 41% (40/97) of patients experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Day 30 following ciltacabtagene autoleucel infusion.

Recurrent Grade 3 or 4 neutropenia, thrombocytopenia, lymphopenia, and anemia were seen in 63% (61/97), 19% (18/97), 60% (58/97), and 37% (36/97) after recovery from initial Grade 3 or 4 cytopenia following infusion. After Day 60 following ciltacabtagene autoleucel infusion, 31%, 12% and 6% of patients had a recurrence of Grade 3 or higher lymphopenia, neutropenia, and thrombocytopenia, respectively, after initial recovery of their Grade 3 or 4 cytopenia. Eighty-seven percent (84/97) of patients had one, two, or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Eight and 12 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.

Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.

INFECTIONS: CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after CARVYKTI infusion.

Infections (all grades) occurred in 57 (59%) patients. Grade 3 or 4 infections occurred in 21% (20/97) of patients; Grade 3 or 4 infections with an unspecified pathogen occurred in 15%, viral infections in 7%, bacterial infections in 1%, and fungal infections in 1% of patients. Overall, 5 patients had Grade 5 infections: lung abscess (n=1), sepsis (n=3) and pneumonia (n=1).

Grade 5 infections reported in other studies include bronchopulmonary aspergillosis, pneumocystis jirovecii pneumonia, and CMV colitis (with HSV-1 hepatitis). Another patient developed mycotic aneurysm due to cerebral aspergillosis and died of subarachnoid hemorrhage.

Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines. Febrile neutropenia was observed in 10% of patients after ciltacabtagene autoleucel infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care, as medically indicated.

In a randomized controlled study of relapsed or refractory multiple myeloma (CARTITUDE-4), patients treated with ciltacabtagene autoleucel had an increased rate of fatal COVID-19 infections compared to the standard therapy arm. Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19.

Viral Reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia. Perform screening for Cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV), or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing. Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.

HYPOGAMMAGLOBULINEMIA was reported as an adverse event in 12% (12/97) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 92% (89/97) of patients. Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Use of Live Vaccines: The safety of immunization with live viral vaccines during or following CARVYKTI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during CARVYKTI treatment, and until immune recovery following treatment with CARVYKTI.

HYPERSENSITIVITY REACTIONS have occurred in 5% (5/97) of patients following ciltacabtagene autoleucel infusion. Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage appropriately according to the severity of the hypersensitivity reaction.

SECONDARY MALIGNANCIES: Patients treated with CARVYKTI may develop secondary malignancies. Myeloid neoplasms (five cases of myelodysplastic syndrome, three cases of acute myeloid leukemia and two cases of myelodysplastic syndrome followed by acute myeloid leukemia) occurred in 10% (10/97) of patients in CARTITUDE-1 study following treatment with CARVYKTI. The median time to onset of myeloid neoplasms was 485 days (range: 162 to 1040 days) after treatment with CARVYKTI. Nine of these 10 patients died following the development of myeloid neoplasms; four of the 10 cases of myeloid neoplasm occurred after initiation of subsequent antimyeloma therapy. Cases of myelodysplastic syndrome and acute myeloid leukemia have also been reported in the post marketing setting. Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc., at 1-800-526-7736 for reporting and to obtain instructions on collection of patient samples.

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES: Due to the potential for neurologic events, including altered mental status, seizures, neurocognitive decline, or neuropathy, patients are at risk for altered or decreased consciousness or coordination in the 8 weeks following CARVYKTI infusion. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery during this initial period, and in the event of new onset of any neurologic toxicities.

ADVERSE REACTIONS

The most common non-laboratory adverse reactions (incidence greater than 20%) are pyrexia, cytokine release syndrome, hypogammaglobulinemia, hypotension, musculoskeletal pain, fatigue, infections of unspecified pathogen, cough, chills, diarrhea, nausea, encephalopathy, decreased appetite, upper respiratory tract infection, headache, tachycardia, dizziness, dyspnea, edema, viral infections, coagulopathy, constipation, and vomiting. The most common laboratory adverse reactions (incidence greater than or equal to 50%) include thrombocytopenia, neutropenia, anemia, aminotransferase elevation, and hypoalbuminemia.

Please read full Prescribing Information, including Boxed Warning, for CARVYKTI.

ABOUT CARVYKTI (CILTACABTAGENE AUTOLEUCEL; CILTA-CEL)

Ciltacabtagene autoleucel is a BCMA-directed, genetically modified autologous T-cell immunotherapy, which involves reprogramming a patient’s own T-cells with a transgene encoding a chimeric antigen receptor (CAR) that identifies and eliminates cells that express BCMA. The cilta-cel CAR protein features two BCMA-targeting single domain antibodies designed to confer high avidity against human BCMA. Upon binding to BCMA-expressing cells, the CAR promotes T-cell activation, expansion, and elimination of target cells.2

In December 2017, Legend Biotech entered into an exclusive worldwide license and collaboration agreement with Janssen Biotech, Inc. (Janssen), a Johnson & Johnson company, to develop and commercialize cilta-cel. In February 2022, cilta-cel was approved by the U.S. Food and Drug Administration (FDA) under the brand name CARVYKTI for the treatment of adults with relapsed or refractory multiple myeloma. In May 2022, the European Commission (EC) granted conditional marketing authorization of CARVYKTI for the treatment of adults with relapsed and refractory multiple myeloma. In September 2022, Japan’s Ministry of Health, Labour and Welfare (MHLW) approved CARVYKTI. Cilta-cel was granted Breakthrough Therapy Designation in the U.S. in December 2019 and in China in August 2020. In addition, cilta-cel received a PRIority MEdicines (PRIME) designation from the European Commission in April 2019. Cilta-cel also received Orphan Drug Designation from the U.S. FDA in February 2019, from the European Commission in February 2020, and from the Pharmaceuticals and Medicinal Devices Agency (PMDA) in Japan in June 2020. In March 2022, the European Medicines Agency’s Committee for Orphan Medicinal Products recommended by consensus that the orphan designation for cilta-cel be maintained on the basis of clinical data demonstrating improved and sustained complete response rates following treatment.

ABOUT CARTITUDE-4

CARTITUDE-4 (NCT04181827) is an ongoing, international, randomized, open-label Phase 3 study evaluating the efficacy and safety of cilta-cel versus pomalidomide, bortezomib and dexamethasone (PVd) or daratumumab, pomalidomide and dexamethasone (DPd) in adult patients with relapsed and lenalidomide-refractory multiple myeloma who received one to three prior lines of therapy, including a PI and an IMiD. The primary endpoint of the study was progression-free survival.3

ABOUT MULTIPLE MYELOMA

Multiple myeloma is an incurable blood cancer that starts in the bone marrow and is characterized by an excessive proliferation of plasma cells.4 In 2024, it is estimated that more than 35,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.5 While some patients with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone problems, low blood counts, calcium elevation, kidney problems or infections.

On March 15, 2024 Calidi Biotherapeutics Inc. (NYSE American: CLDI) ("Calidi"), a clinical-stage biotechnology company developing a new generation of targeted immunotherapies, reported its fourth quarter and full-year 2023 operating and financial results and reviewed recent business highlights (Press release, Calidi Biotherapeutics, MAR 15, 2024, View Source [SID1234641214]).

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"Calidi continues to make great progress across our development programs while continuing to innovate and expand our industry-leading position in cell-based immunotherapies," said Allan Camaisa, CEO and Chairman of the Board of Calidi Biotherapeutics. "We anticipate reporting an interim clinical update from our Phase 1 trial evaluating CLD-101 in high-grade glioma patients in collaboration with City of Hope in the second quarter of this year assuming we are successful in raising additional capital, and we were thrilled to recently strengthen our collaboration with City of Hope to evaluate CLD-101 for the treatment of ovarian cancer with the support of CIRM. In addition, we were proud to recently unveil our potentially paradigm-shifting advance in the treatment of advanced solid tumors, including lung cancer and metastatic disease, that required a systemic application, through our RTNova systemic delivery approach."

Fourth Quarter 2023 and Recent Corporate Developments

City of Hope, a leader in cancer research and treatment, was awarded $5.3 million to further support preclinical translational studies, product manufacturing (using Calidi’s next generation manufacturing process) and clinical trial design for ovarian cancer using Calidi’s licensed oncolytic virotherapy product, CLD-101. CLD-101 is a cutting-edge therapeutic candidate in Calidi’s NeuroNova program, comprising tumor-tropic neural stem cells (NSCs) that deliver an oncolytic adenovirus – CRAd-S-pk7 – selectively to tumor sites.
Publicly announced novel systemic enveloped oncolytic virotherapy program, RTNova (CLD-400), targeting advanced solid tumors, including advanced metastatic disease. The new program builds upon Calidi’s experience using stem cells to protect oncolytic viruses from inactivation by the patient’s immune system allowing for easier administration, increased cost-effectiveness, and the ability to reach a broad patient population.
Appointed Antonio Chiocca, M.D., Ph.D., David T. Curiel, M.D., Ph.D., and Burt L. Nabors, M.D., to the company’s Scientific and Medical Advisory Board. These physician scientists bring a deep expertise in oncology, hailing from top cancer research institutions and facilities.
Announced the appointment of David LaPré to the company’s Board of Directors. Mr. LaPré brings significant experience in technical operations strategy and execution in the pharmaceutical industry.
Received patent covering novel SuperNova technology platform (CLD-201) composed of adipose-derived mesenchymal stem cells loaded with oncolytic vaccinia virus. This patent strengthens the company’s robust intellectual property portfolio as Calidi plans to initiate a clinical trial in the second half of 2024. Calidi has shown preclinically the potential of SuperNova to shield the viral payload from the immune system allowing for its delivery to tumor sites.
Upcoming Anticipated Milestones

1H 2024: Interim clinical update from CLD-101 Phase 1 trial in collaboration with City of Hope for recurrent high-grade glioma patients
1H 2024: First patient dosed in CLD-101 Phase 1 trial in collaboration with Northwestern University for newly diagnosed high-grade glioma patients
2H 2024: First patient dosed in CLD-201 Phase 1 trial
Fourth Quarter 2023 Financial Results

The company reported a net loss of $8.2 million, or $0.23 per share, for the three months ended December 31, 2023, compared to a net loss of $7.8 million, or $0.90 per share, for the same period in 2022.

Research and development expenses were $4.0 million for the three months ended December 31, 2023, compared to $2.3 million for the comparable period in 2022, respectively.

General and administrative expenses were $5.9 million for the three months ended December 31, 2023, compared to $2.4 million for the comparable period in 2022, respectively.

Full Year 2023 Financial Results

The company reported a net loss of $29.2 million, or $1.73 per share, for the year ended December 31, 2023, compared to a net loss of $25.4 million, or $2.99 per share, for the year ended December 31, 2022.

Research and development expenses were $13.0 million for the year ended December 31, 2023, compared to $7.3 million for the year ended December 31, 2022, respectively.

General and administrative expenses were $16.0 million for the year ended December 31, 2023, compared to $15.9 million for the year ended December 31, 2022, respectively.

The company had approximately $1.9 million in cash and $0.2 million in restricted cash as of December 31, 2023, compared to $0.4 million in cash and $0.2 million in restricted cash as of December 31, 2022.

On March 15, 2024 ImmVira reported that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for oncolytic virus product MVR-T3011 IT (intratumoral injection) for the treatment of recurrent or metastatic head and neck squamous cell cancer with disease progression after platinum-based chemotherapy and at least one prior line of anti-PD1/PDL1 therapy (Press release, Immvira, MAR 15, 2024, View Source [SID1234641211]). Fast track designation is intended to facilitate the development and expedite the review of drugs targeting serious conditions with unmet medical needs.

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The Fast Track designation was sought based on the promising potential of MVR-T3011 IT to meet the unmet medical needs associated with HNSCC. Supporting evidence for this request was derived from Phase I/II trials conducted in both the United States and China, focusing on evaluating the efficacy, safety, and durability of response in patients with HNSCC.

HNSCC has become a growing public health concern, with increases in incidence rates as of 2023 statistics. Approximately 32% of patients face recurrence after curative therapy, and 3-10% present with metastatic disease at the time of diagnosis, emphasizing the aggressive nature and severity of this cancer. While immune checkpoint inhibitors such as PD-1/PD-L1 blockers have transformed HNSCC treatment, their benefits are confined to a modest 15-20% of patients. This treatment gap underscores the critical need for innovative therapies. Clinical data indicates that MVR-T3011 IT demonstrated the potential to overcome immunosuppression, and delivered favorable outcomes in terms of tumor shrinkage and control in patients who failed ICI treatments.

"Attaining Fast Track designation from the FDA marks a pivotal milestone and underscores MVR-T3011 IT’s capacity to address the substantial unmet needs of HNSCC patients," said Grace Guoying Zhou, Chairwoman and CEO of ImmVira. "We are encouraged by the FDA’s decision as it reflects the need for FDA approved and widely available treatments for these patients. This designation will allow us to work closely with the FDA to quickly advance MVR-T3011 IT, to make a meaningful difference for patients who require new treatment options."

About MVR-T3011

MVR-T3011, ImmVira’s proprietary 3-in-1 oHSV, is a novel genetic engineered oHSV which aims to achieve the most favorable profile of attenuated HSV-1 with replication potency in tumor cells and highly restricted replication in normal cells. Its incorporation of two latest and well-validated exogenous genes, PD-1 antibody and IL-12, further enhances immune responses in the tumor microenvironment.

On March 15, 2024 Qilu Pharmaceutical reported the Phase II clinical trial results for iparomlimab and tuvonralimab (QL1706) in an oral presentation (Press release, Qilu Pharmaceutical, MAR 15, 2024, View Source [SID1234641210]). This trial, known as DUBHE-C-206, recruited patients with recurrent or metastatic cervical cancer who failed first-line standard treatments. The findings were presented by Professor Jihong Liu from the Sun Yat-sen University Cancer Center in China.

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Study Background and Design

Cervical cancer is one of the most prevalent malignancies among women and a leading cause of cancer-related death. For those who have failed the first-line standard therapy, the currently available treatment options are inadequate. The objective response rate (ORR) for pembrolizumab was 12.2%, with an ORR of 0% in the PD-L1-negative population[1]. Additionally, the median progression-free survival (PFS) and median overall survival (OS) were reported to be 2.1 months and 9.4 months, respectively. Similarly, cemiplimab showed an ORR of 16.4%, with a median PFS of 2.8 months and a median OS of 12.0 months[2]. This highlights the unmet need for effective and safe clinical treatments for patients with cervical cancer who failed first-line therapy. By targeting and inhibiting two immune checkpoint pathways (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), Qilu Pharmaceutical’s proprietary drug QL1706 has shown a favorable safety profile and preliminary efficacy in patients with cervical cancer in early studies. The DUBHE-C-206 study aimed to evaluate the efficacy and safety of QL1706 in patients with recurrent or metastatic cervical cancer.

This study was a multi-center, single-arm, open-label phase II clinical trial which enrolled patients with recurrent or metastatic cervical cancer who failed first-line platinum-based chemotherapy (with or without bevacizumab) and without prior immunotherapy. Participants received QL1706 at a dose of 5.0 mg/kg once every three weeks (Q3W). The primary endpoint of the trial was the ORR as assessed by an Independent Evaluation Committee (IRC). Secondary endpoints included the ORR as evaluated by investigators, duration of response (DoR) and disease control rate (DCR) as assessed by both IRC and investigators, PFS, 6-month and 12-month PFS rates, OS, 12-month OS rate, as well as safety, pharmacokinetics, and immunogenicity.

Study Results

As of April 28, 2023, the study had enrolled 148 patients with a median age of 53.0 years, including 132 (89.2%) diagnosed with squamous cell carcinoma. Of these participants, 109 (73.6%) had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 1. Additionally, 105 (70.9%) patients had a combined positive score (CPS) of ≥1, while 43 (29.1%) had a CPS of <1. Notably, 39.9% of the participants had been treated with bevacizumab, and 37.2% had received second-line and subsequent therapy. The median follow-up duration of the study was 11.0 months.

In terms of efficacy, the ORR as assessed by IRC was 33.8% (95% CI: 26.2%-42.0%), and the DCR reached 64.9% (95% CI: 56.6%-72.5%). The median PFS was 5.4 months (95% CI: 3.9-6.9), with 6-month and 12-month PFS rates of 45.0% and 16.1%, respectively. The median OS had not been reached, with 6-month and 12-month OS rates standing at 83.9% and 65.4%, respectively. In subgroup analyses, the ORR for patients with a CPS of ≥1 was 37.1%, compared to 25.6% for those with a CPS of <1. Furthermore, the ORR for patients who had previously received bevacizumab was 28.8%, whereas it was 37.1% for those who had not undergone such treatment.

Regarding safety, among all the participants, 104 (70.3%) experienced treatment-related adverse events (TRAEs), with the most common being hypothyroidism (20.9%) and hyperthyroidism (18.9%). TRAEs of grade 3 or higher were observed in 36 individuals (24.3%), with anemia (4.1%), increased gamma-glutamyl transferase (GGT) (2.7%), and increased lipase level (2.7%) being the most frequently reported. Three patients (2.0%) discontinued treatment due to TRAEs. There were no reported deaths resulting from TRAEs. In the study, 65 participants (43.9%) experienced immune-related adverse events (irAEs), with grade 3 or higher irAEs reported in 21 (14.2%).

In conclusion, QL1706 has shown promising efficacy and acceptable safety profile in patients with recurrent or metastatic cervical cancer who failed first-line standard therapy, regardless of their PD-L1 expression. This positions QL1706 as a more effective and safer therapeutic option for patients with cervical cancer whose disease progressed after first-line standard therapy. A phase III clinical trial is currently in progress, evaluating the use of QL1706 in combination with chemotherapy (with or without bevacizumab) as a first-line treatment option.

Prof. Liu from the Sun Yat-sen University Cancer Center commented, "The findings from the DUBHE-C-206 study offer new evidence to support the use of dual immunotherapy in the second- and late-line treatment of recurrent or metastatic advanced cervical cancer (ACC). They also affirm QL1706’s potential as a promising new treatment option for ACC patients. The study’s results have shown the efficacy benefits of QL1706 across the whole ACC patient population while demonstrating its considerable safety advantages. These findings suggest that QL1706 has the potential to significantly enhance the quality of life for patients and provide superior clinical benefits. We eagerly anticipate the outcomes of the Phase 3 trial for QL1706, which is now in progress to assess the efficacy and safety of QL1706 in combination with chemotherapy, with or without bevacizumab, as a first-line treatment for recurrent or metastatic ACC."

Professor Hanmei Lou from Zhejiang Cancer Hospital stated, "For ACC patients who have failed first-line therapy, the available treatment options are still limited and exhibit unsatisfactory efficacy, highlighting substantial unmet clinical needs. The efficacy and safety data from the DUBHE-C-206 study are promising. Compared with the previously reported combination therapy involving PD-1 and CTLA-4 inhibitors, QL1706 has demonstrated reduced toxicity and offers notable advantages in both safety and efficacy. This further supports the use of dual immunotherapy for the treatment of recurrent or metastatic ACC. Consequently, the data from the DUBHE-C-206 study holds significant clinical value and implications."

Ms Xiaoyan Kang, Executive Deputy General Manager of Qilu Pharmaceutical’s Clinical Research & Development Center and Chief Medical Officer (CMO) for Oncology, explained, "QL1706 represents the world’s first dual-functional MabPair antibody targeting both PD-1 and CTLA-4 pathways. Data from several clinical studies of this novel drug have been released. The inclusion of the latest clinical trial results in the oral presentation at the ESGO conference underscores the international academic community’s interest in and recognition of the clinical potential of this novel product. Currently, multiple Phase III clinical trials involving QL1706 are in progress, covering various disease indications. Going forward, we plan to further accelerate the clinical development of QL1706 to ensure that this treatment can reach and benefit patients as soon as possible."