On December 12, 2024 Tanner Pharma, a global provider of specialty medicine access solutions, reported a collaboration with Agenus, a leading immuno-oncology company, to provide expanded access to botensilimab (BOT) and balstilimab (BAL) (Press release, Tanner Pharma Group, DEC 12, 2024, View Source [SID1234649096]). Through a Named Patient Program (NPP), this initiative offers patients with microsatellite stable colorectal cancer (MSS CRC) and other advanced solid tumors the opportunity to access BOT/BAL based on supporting clinical evidence and medical need.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

Tanner Pharma will manage access to BOT/BAL for patients in geographies that allow named patient access to investigational medicines. The NPP ensures that patients, in consultation with their physicians, can access BOT/BAL even before regulatory approval, adhering to all ethical and compliance standards.

BOT and BAL are investigational immunotherapies designed to target challenging cancers, including MSS CRC and other tumors historically resistant to immune-based treatments. Clinical outcomes have demonstrated complete pathological responses in neoadjuvant MSS colon cancer patients and durable tumor responses across multiple cancer types. These results establish BOT/BAL as a treatment option with the potential to redefine standards of care for patients with difficult-to-treat cancers.

On December 12, 2024 PDC*line Pharma, a clinical-stage biotech company developing a new class of immunotherapies for cancers, reported the primary results of its phase I/II clinical trial for PDC*lung01, an innovative off-the-shelf therapeutic cancer vaccine, at the ESMO (Free ESMO Whitepaper)-IO 2024 conference (Press release, PDC Line Pharma, DEC 12, 2024, View Source [SID1234649095]). PDC*lung01, when combined with pembrolizumab, demonstrated significant clinical benefits for stage IV Non-Small Cell Lung Cancer (NSCLC) patients with PD-L1 ≥ 50%, along with a mild safety profile.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"PDC*lung01 in combination with anti-PD-1 showed a very promising and durable response as well as a significant immune response with indications of a relationship with clinical outcome in cohort B2. The data suggest that this combination could offer a clinically meaningful tumor response in stage IV NSCLC patients, along with a compelling safety profile," said Prof Johan Vansteenkiste, emeritus professor in respiratory oncology at KU Leuven in Belgium and chair of the Data and Safety Monitoring Board.

The phase I/II trial (PDC-LUNG-101, NCT03970746) evaluated the safety, tolerability, immunogenicity, and preliminary clinical activity of PDC*lung01 in NSCLC patients. The trial included 67 HLA-A02:01-positive NSCLC patients across five European countries. Patients received six weekly doses of PDC*lung01 through subcutaneous and intravenous administration. It assessed the vaccine in two doses both as a single agent (cohorts A1, A2 for stage II & IIIa NSCLC) and in combination with pembrolizumab (cohorts B1, B2 for stage IV NSCLC). Key clinical activity parameters, such as ORR and PFS, were analyzed in the B1 and B2 cohorts, with primary results reported from the high-dose, B2 cohort. With a database cut-off date on July 18, 2024, the patients’ median follow-up was 19.5 months (95% CI 13.8-25.6).

Highlights: View Source

Immune Response:

56% of patients exhibited tumor antigen-specific CD8+ T-cell responses, with measurable expansions of anti-tumor CD8+ T-cells observed in some cases, up to 2.3% of total CD8+T-cells.

A significant correlation was observed between the amplitude of antigen-specific CD8+ T-cell responses and PFS.
Efficacy:

In the high-dose (B2) cohort consisting of 42 evaluable patients, PDC*lung01 combined with pembrolizumab achieved a confirmed objective response rate (ORR) of 55% (80% CI 43.7%; 65.4%), surpassing the trial’s predefined success criteria (15% absolute increase compared to 39% for external comparator KEYNOTE-042). The Best Overall Response (BOR) according to RECIST 1.1 included 23 confirmed Partial Response (55%) and 12 Stable Disease (29%).

Median progression-free survival (mPFS) was 8.9 months, a 36% improvement (2.4 months longer) compared to pembrolizumab alone (KEYNOTE-042).

The Disease Control Rate (DCR) was 76% (80% CI: 83.8, 65.4) and Clinical Benefit Rate (CBR) was 64%. The 9-month PFS rate was 50% (80% CI 39.1%; 60.9%). Median duration of response and median overall survival were not reached.
Safety:

In 48 patients who received at least one dose of PDC*lung01 in the B2 cohort, PDC*lung01 exhibited a mild safety profile. Most treatment-emergent adverse events (TEAEs) were grades 1-2, with only one grade 4-related TEAE reported.

Only 2% of related TEAEs led to discontinuation, compared to 9.1% for pembrolizumab alone in the KEYNOTE-042 study.
Further data from the trial will become available at the end of 2025, once all patients have reached two years of follow-up. Based on these very encouraging findings, PDC*line Pharma is preparing a randomized phase IIb study in untreated stage IV NSCLC (and PD-L1 ≥50%) in combination with pembrolizumab, with initiation planned in 2026.

"We are thrilled by these promising results, which position PDC*lung01 as the first cancer vaccine of its kind tested in metastatic NSCLC with high PD-L1 expression. Its unique mechanism of action and favorable safety profile make it an excellent complement to pembrolizumab and other existing or emerging therapies for this patient population. Moreover, our off-the-shelf technology has significant potential for expansion into other clinical settings and indications. Our upcoming randomized Phase IIb trial is a critical step toward confirming clinical proof of concept and fostering collaborations with industrial partners to bring our innovative technology to market," said Eric Halioua, CEO of PDC*line Pharma.

About PDC*lung01:

PDC*lung01 is an off-the-shelf cancer vaccine composed of irradiated human Plasmacytoid Dendritic Cells (PDC*line) loaded with peptides derived from key tumor antigens (NY-ESO-1, MAGE-A3, MAGE-A4, Multi-MAGE-A, MUC1, Survivin, Melan-A). These professional antigen-presenting cells prime and boost cytotoxic CD8+ T-cells, making the vaccine synergistic with checkpoint inhibitors like pembrolizumab.

On December 12, 2024 TerSera Therapeutics LLC reported the presentation of new real-world analyses on the use of goserelin 3.6 mg and goserelin 10.8 mg in premenopausal women with breast cancer (Press release, TerSera Therapeutics, DEC 12, 2024, View Source [SID1234649094]). These data were presented in a poster session at the 2024 San Antonio Breast Cancer Symposium, held December 10-13 in San Antonio, TX.1 A copy of the poster is available here.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHas) is an essential component of therapy for a large proportion of pre- or perimenopausal women with hormone-sensitive breast cancer"

Post this
This was a retrospective, observational, non-inferiority study using structured, de-identified, patient-level data and curated progress notes from U.S. electronic medical record (EMR) data from the ConcertAI Patient360 Breast Cancer Dataset. The objective of this study was to compare real-world treatment outcomes among breast cancer patients treated with goserelin 3.6 mg and 10.8 mg.

The primary outcome was the real-world event-free survival (rwEFS) rate at 12 months to assess the non-inferiority of the goserelin 10.8 mg dose given every 12 weeks vs. the 3.6 mg dose given every 4 weeks. The 12-month rwEFS rates for goserelin 3.6 mg and goserelin 10.8 mg, respectively, were 76.6% vs. 79.2% (treatment difference: 2.7% [95% CI: -1.8%, 7.0%]) which supports the non-inferiority of goserelin 10.8 mg to goserelin 3.6 mg at the prespecified -15% margin based on previously published oncology trials. In evaluating time to discontinuation, this study also found that more patients remained on goserelin 10.8 mg than 3.6 mg at years 1 and 2 post treatment initiation (51.2% vs. 39.6% and 32.4% vs. 23.1%, respectively), supporting previously published data in a separate real-world evidence analysis of breast cancer patients receiving goserelin 10.8 mg.2

"Ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHas) is an essential component of therapy for a large proportion of pre- or perimenopausal women with hormone-sensitive breast cancer," said Kelly E. McCann, M.D., Ph.D., assistant clinical professor of medicine at the UCLA Health David Geffen School of Medicine. "ZOLADEX 3.6 mg given every 4 weeks is the only FDA-approved GnRHa for women with breast cancer. Our data suggests that the 10.8 mg dose given every 12 weeks may also be an effective option."

U.S. INDICATIONS

ZOLADEX 3.6 mg and ZOLADEX 10.8 mg are indicated for:

Management of locally confined Stage T2b-T4 (Stage B2-C) carcinoma of the prostate in combination with flutamide. Treatment with ZOLADEX and flutamide should start 8 weeks prior to initiating radiation therapy and continue during radiation therapy.
Palliative treatment of advanced carcinoma of the prostate.
ZOLADEX 3.6 mg is also indicated for:

Management of endometriosis, including pain relief and reduction of endometriotic lesions for the duration of therapy. Experience with ZOLADEX for the management of endometriosis has been limited to women 18 years of age and older treated for 6 months.
Use as an endometrial-thinning agent prior to endometrial ablation for dysfunctional uterine bleeding.
Palliative treatment of advanced breast cancer in pre- and perimenopausal women.
IMPORTANT SAFETY INFORMATION

Anaphylactic reactions to ZOLADEX have been reported in the medical literature. ZOLADEX is contraindicated in patients with a known hypersensitivity to GnRH, GnRH agonist analogues, or any of the components in ZOLADEX.

ZOLADEX is contraindicated during pregnancy unless used for palliative treatment of advanced breast cancer. ZOLADEX can cause fetal harm when administered to a pregnant woman. If used during pregnancy, the patient should be apprised of the potential hazard to the fetus. There is an increased risk for pregnancy loss due to expected hormonal changes that occur with ZOLADEX treatment. ZOLADEX should not be given to women with undiagnosed abnormal vaginal bleeding.

Pregnancy must be excluded for use in benign gynecological conditions. Women should be advised against becoming pregnant while taking ZOLADEX. Effective nonhormonal contraception must be used by all premenopausal women during ZOLADEX therapy and for 12 weeks following discontinuation of therapy.

Transient worsening of tumor symptoms, or the occurrence of additional signs and symptoms of breast cancer, may occasionally develop during the first few weeks of treatment. Some patients may experience a temporary increase in bone pain. Monitor patients at risk for complications of tumor flare.

Hyperglycemia and an increased risk of developing diabetes or worsening of glycemic control in patients with diabetes have been reported in men receiving GnRH agonists like ZOLADEX. Monitor blood glucose levels and glycosylated hemoglobin (HbA1c) periodically and manage according to current clinical practice.

Increased risk of developing myocardial infarction, sudden cardiac death and stroke has been reported in association with use of GnRH agonists like ZOLADEX in men. Patients receiving a GnRH agonist should be monitored for symptoms and signs suggestive of development of cardiovascular disease and be managed according to current clinical practice.

Hypercalcemia has been reported in some breast cancer patients with bone metastases after starting treatment with ZOLADEX. If hypercalcemia does occur, appropriate treatment measures should be initiated.

Hypersensitivity, antibody formation and acute anaphylactic reactions have been reported with GnRH agonist analogues.

ZOLADEX may cause an increase in cervical resistance. Therefore, caution is recommended when dilating the cervix for endometrial ablation.

GnRH agonists may prolong the QT/QTc interval. Providers should consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients with congenital long QT syndrome, congestive heart failure, frequent electrolyte abnormalities, and in patients taking drugs known to prolong the QT interval. Electrolyte abnormalities should be corrected. Consider periodic monitoring of electrocardiograms and electrolytes.

Injection site injury and vascular injury including pain, hematoma, hemorrhage and hemorrhagic shock, requiring blood transfusions and surgical intervention, have been reported with ZOLADEX. Extra care should be taken when administering ZOLADEX to patients with low BMI and/or to patients receiving full dose anticoagulation.

Depression may occur or worsen in women receiving GnRH agonists.

Treatment with ZOLADEX may be associated with a reduction in bone mineral density over the course of treatment. Data suggest a possibility of partial reversibility. In women, current available data suggest that recovery of bone loss occurs on cessation of therapy in the majority of patients.

In women, the most frequently reported adverse reactions were related to hypoestrogenism. The adverse reaction profile was similar for women treated for breast cancer, dysfunctional uterine bleeding, and endometriosis.

The most commonly reported adverse reactions with ZOLADEX in clinical trials for endometriosis were: hot flashes (96%), vaginitis (75%), headache (75%), decreased libido (61%), emotional lability (60%), depression (54%), sweating (45%), acne (42%), breast atrophy (33%), seborrhea (26%), and peripheral edema (21%).

The most commonly reported adverse reactions with ZOLADEX in clinical trials for endometrial thinning were: vasodilation/hot flashes (57%), headache (32%), sweating (16%), and abdominal pain (11%).

The most commonly reported adverse reactions with ZOLADEX in breast cancer clinical trials were hot flashes (70%), decreased libido (47.7%), tumor flare (23%), nausea (11%), edema (5%), and malaise/fatigue/lethargy (5%). Injection site reactions were reported in less than 1% of patients.

For ZOLADEX 3.6 mg: Hot flashes (62%), sexual dysfunction (21%), decreased erections (18%), lower urinary tract symptoms (13%), lethargy (8%), pain (worsened in the first 30 days) (8%), edema (7%), upper respiratory infection (7%), rash (6%), and sweating (6%).

For ZOLADEX 10.8 mg: Hot flashes (64%), pain (general) (14%), gynecomastia (8%), pelvic pain (6%), and bone pain (6%).

In the locally advanced carcinoma of the prostate clinical trial, additional adverse event data were collected for the combination therapy with radiation group during both the hormonal treatment and hormonal treatment plus radiation phases of this study. Adverse experiences (incidence >5%) in both phases of this study were hot flashes (46%), diarrhea (40%), nausea (9%), and skin rash (8%). Treatment with ZOLADEX and flutamide did not add substantially to the toxicity of radiation treatment alone.

Please see Full Prescribing Information for ZOLADEX 3.6 mg and ZOLADEX 10.8 mg.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit fda.gov/safety/medwatch or call 1-800-FDA-1088. You can also contact TerSera Therapeutics at 1-844-334-4035 or [email protected].

About HR-positive breast cancer

Breast cancer is the second most commonly diagnosed cancer and one of the leading causes of cancer-related deaths worldwide.3 In the United States, over 310,000 women will be diagnosed with breast cancer this year; 40,000 will be under the age of 50.4 Approximately 75% of diagnosed cases in women under age 50 are considered to be hormone positive (HR+) breast cancer. Compared to older women, young women generally face more aggressive cancers and lower survival rates.5-7 Recent studies have shown that breast cancer before age 40 differs biologically from the cancer faced by older women.6,7

About ZOLADEX (goserelin implant)

ZOLADEX is an injectable luteinizing hormone-releasing hormone agonist (LHRHa) used to treat prostate cancer, breast cancer, and certain benign gynecological disorders. First approved in the U.S. in 1989, ZOLADEX is available as a 3.6 mg implant dosed every 28 days or as a 10.8 mg implant dosed every 12 weeks. Worldwide, ZOLADEX 3.6 mg is approved for use in breast cancer in 125 countries. ZOLADEX 10.8 mg is approved for use in breast cancer in over 60 countries.

On December 12, 2024 Agendia, Inc., reported it will be presenting new data highlighting MammaPrint and BluePrint utility in guiding treatment decisions for patients with early-stage breast cancer (Press release, Agendia, DEC 12, 2024, View Source [SID1234649093]). The findings will be presented in two spotlight presentations and two posters at the San Antonio Breast Cancer Symposium 2024 (SABCS), on Wednesday, December 11th and Thursday, December 12th.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

One poster spotlight, titled "Association of MammaPrint with gene expression pathways predictive of resistance to cyclin-dependent kinase inhibition," presented by Adam Brufsky, MD, PhD, Professor and Associate Chief of Hematology and Oncology at UPMC Hillman Cancer Center, examined 5,657 patients with early-stage HR+HER2- tumors enrolled in the ongoing prospective, observational FLEX Trial (NCT03053193). The analysis evaluated the correlation between MammaPrint and gene expression patterns associated with Retinoblastoma (Rb) loss-of-function and CDK4 independent cellular proliferation to identify which MammaPrint Risk categories may be resistant to CDK4/6 inhibition.

A linear correlation was observed between increasing MammaPrint Risk and increasing Rb loss-of-function gene expression, suggesting that MammaPrint High 2 tumors have the highest probability of CDK4/6 resistance. Additionally, MammaPrint High 2 tumors were most likely to exhibit high cell proliferation independent of CDK4 activity (43.0%), in comparison to Ultra Low (0.1%), Low (0.5%), and High 1 (1.8%) tumors (p < 0.001). These data provide the first evidence for the utility of a commercially available signature to potentially predict resistance to CDK4/6 inhibition and help patients receive more targeted and individualized therapies.

The second poster spotlight, titled "MammaPrint and BluePrint Predict Pathological Response to Neoadjuvant Chemotherapy in Patients with HR+HER2- Early-Stage Breast Cancer Enrolled in FLEX," presented by Joyce O’Shaughnessy, MD, National Principal Investigator of the FLEX Study, Director, Breast Cancer Research, Baylor University Medical Center, Texas Oncology and the Sarah Cannon Research Institute in Dallas, TX, evaluated MammaPrint and BluePrint in predicting pathological response to neoadjuvant chemotherapy among 457 HR+HER2- breast cancer patients enrolled in FLEX.

Rates of Pathological Response (PR), including pathological Complete Response (pCR) and minimal residual cancer burden (RCB-I), were highest in High 2 Basal (43.4%) and Luminal B (21.4%) tumors, with High 2 tumors overall showing better PR rates (32.7%) compared to High 1 tumors (9.5%). Multivariate analysis indicated that only MammaPrint High 2 was significantly associated with likelihood of PR, after adjusting for clinical confounders. Overall, MammaPrint and BluePrint proved effective in predicting neoadjuvant chemosensitivity in HR+HER2- breast cancer, which may enable downstaging and improve overall outcomes.

"The findings from these two studies highlight the ability of genomic testing using MammaPrint and BluePrint to predict patient response to therapies like chemotherapy, and may be able to predict benefit from CDK4/6 inhibitors," said Dr. O’Shaughnessy. "The ongoing data that continues to be generated through FLEX is building evidence that these tests may help unlock optimal treatment plans based on the patient’s tumor biology."

Abstracts Accepted as Posters

Neoadjuvant Chemotherapy for T3 Tumors in the Era of Precision Medicine – Biology is Still King (Rahman, R., et al.)
A pooled analysis was conducted on 404 clinical T3 breast cancer patients from the NBRST, FLEX, and MINT trials undergoing neoadjuvant chemotherapy. MammaPrint (MP) and BluePrint (BP) subtyping showed higher pathological complete response (pCR) rates across all MP High Risk subtype tumors (Basal (32.5%, HER2 53.7%, Luminal B 8.6%) compared to MP Low Risk Luminal A subtype tumors (0% pCR). Menopausal status, nodal status, and grade were not significant predictors of pCR response. High Risk tumors had significantly higher pCR rates, suggesting MammaPrint Low Risk, cT3 tumors are unlikely to achieve pCR to neoadjuvant chemotherapy, suggesting these patients may avoid neoadjuvant chemotherapy despite their large tumor size.

FLEX: A Real-World Evidence, Full Transcriptome Study in 30,000 Patients with Early-Stage Breast Cancer (Maganini, R., et al.)
The FLEX Study, a large, multi-center, real-world evidence, whole transcriptome, observational breast cancer study (NCT03053193), has grown substantially since its launch in April 2017. With more than 17,000 patients enrolled across 100 sites in the US and around the world, FLEX includes over 40 sub-studies in several topics. Participants are of all racial and ethnic backgrounds with stage I, II, or III early-stage breast cancer, aiming for a representative data set. The study has produced more than 10 clinical evidence pieces on diversity and includes 1,377 self-identified Black, 530 Latin American/Hispanic, and 353 Asian and Pacific Islanders, making FLEX the most diverse study on EBC patients to date.

"These data significantly enhance our understanding of MammaPrint and BluePrint’s growing clinical applications," said William Audeh, MD, MS, Chief Medical Officer at Agendia. "Our findings reinforce the importance of precision medicine, as it allows us to tailor treatment strategies, including neoadjuvant chemotherapy consideration, incorporating immunotherapies, and potentially sparing patients from the harms of unnecessary chemotherapy. As we continue to gather data from studies like FLEX, we are solidifying the role of these genomic assays in guiding personalized treatment decisions for breast cancer patients."

About Agendia

On December 12, 2024 CEL-SCI Corporation (NYSE American: CVM) reported strong biological rationale for the use of Multikine in the confirmatory registration head and neck cancer study (Press release, Cel-Sci, DEC 12, 2024, View Source [SID1234649092]). This study of 212 newly diagnosed locally advanced, resectable head and neck cancer patients was given the go-ahead as a confirmatory registration study by FDA and will focus on those patients who showed a 73% survival with Multikine vs. a 45% for the control patients not treated with Multikine in the prior Phase 3 study.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"I am hopeful that this report will help investors understand why we believe that we have developed a potentially very effective and safe new medicine for newly diagnosed head and neck cancer, a horrible disease with very few treatment options. Our goal is to make the first cancer treatment more successful by activating an anti-tumor immune response BEFORE surgery, radiotherapy and chemotherapy weaken the immune system," said Geert Kersten, Chief Executive Officer of CEL-SCI Corporation.

Multikine (Leukocyte Interleukin, Injection)* is an immunotherapy intended for use in treating cancer. CEL-SCI has long hypothesized that to achieve maximum stimulation of a patient’s immune system, it is best to administer an immunotherapy as a neo-adjuvant (pre-surgical) therapy, prior to standard of care treatments, when the immune system is still intact. Multikine Phase 2 studies showed significant tumor regression resulting from Multikine treatment in just three-weeks of neoadjuvant therapy with no excess toxicity beyond the standard of care. Following these positive results, CEL-SCI conducted a 928-patient randomized controlled Phase 3 clinical trial to confirm Multikine’s ability to cause tumor regressions prior to surgery, confirm its safety profile and ultimately longer overall survival versus the standard of care.

The Phase 3 study missed the primary endpoint of 10% improvement in overall survival (OS) in the ITT population (all patients in the study) but showed a 46.5-month (almost 4 years) OS benefit vs control (101.7 months vs. 55.2 months) in the patients who received Multikine followed by surgery and radiotherapy. In the other group of about 50% of patients who had chemotherapy added to radiotherapy after surgery, there was no survival benefit. Because the decision to administer chemotherapy is made after surgery, CEL-SCI had to develop selection criteria that would identify at screening those patients who would be most likely to benefit from Multikine neoadjuvant (pre-surgery) treatment. After this analysis was done and the evidence collected, CEL-SCI presented these selection criteria to FDA. The agency accepted these selection criteria and gave CEL-SCI the go-ahead to conduct a 212-patient confirmatory registration study in the patient population defined by the selection criteria. The study will include patients with newly diagnosed locally advanced primary (disease stage III and IVa) head and neck cancer presenting with: No lymph node involvement (N0) (determined via PET imaging) and having low PD-L1 tumor expression (determined via biopsy).

There are many factors that support going ahead with the confirmatory registration study, including the following:

Multikine was shown to be highly active in the full Phase 3 study population, leading to significant rates of tumor regression, including 5 complete regressions, before surgery, following just 3 weeks of Multikine treatment. Refer to slide 31 in the corporate slide presentation posted on the Company’s website. In this advanced disease stage, tumors do not shrink spontaneously, and the control group in the study had no reported pre-surgical tumor regressions. Therefore, the regressions had to be due to Multikine.
Pre-surgical tumor regressions were confirmed by pathology at surgery, where biological evidence of Multikine’s activity, inducing cellular infiltration of anti-tumor immune cells, could be seen at the tumor microenvironment.
Pre-surgical tumor regressions were also seen in prior published Phase 2 studies, further supporting the validity of the Phase 3 results showing Multikine’s anti-cancer activity.
The pre-surgical tumor regressions forecasted increased long-term survival benefit in responders. That is, subjects who had tumor regressions lived longer than those who did not. Refer to slide 20 of the corporate slide presentation for these data in the full study population.
In the target population selected for the confirmatory study the rate of pre-surgical tumor regressions was substantially higher than what was seen in the full Phase 3 population. Refer to slide 21 of the corporate slide presentation. This shows that the selected population is highly likely to show a significant survival prolongation in the confirmatory registration study.
CEL-SCI addresses some criticisms that are often levelled against any subgroup analysis. These criticisms are often applied dogmatically without considering specific facts.

Strong statistical significance
Criticism: Clinical trials are typically designed to detect effects in the overall population, not within subgroups. Analyzing smaller subgroups reduces the sample size, which decreases statistical power and increases the likelihood of false positives (Type I error) or false negatives (Type II error).
Response: the selected group from the Phase 3 study is large. It includes 114 Intention-to-Treat (ITT) patients, leading to results with strong statistical significance (p=0.0015). Refer to slide 16 of the corporate slide presentation. The hazard ratio of 0.35 (less than 1 is beneficial) and its statistical 95% confidence interval upper limit of 0.66 are below the 0.7 usually needed for approval. The Kaplan-Myer survival curve shows a clear survival benefit for Multikine-treated patients over control at all times during the 5-year follow-up of the Phase 3 study.
Multiple comparisons require a higher level of significance
Criticism: When multiple subgroups are analyzed, the probability of finding a significant result by chance increases. This can lead to spurious findings.
Response: The subgroup analysis by risk was pre-specified in the original Phase 3 protocol, so these results do not arise from a post hoc search for pockets of favorable results after the fact. It should be noted that at the time of Phase 3 study initiation PD-L1 was not available. However, as the study progressed, the statistical analysis plan (SAP) was updated to specify analysis by cellular markers including tumor PD-L1. The SAP also stated: "For each biomarker (including the pre-defined ratio and differences), proportional hazard models for OS, LRC, and PFS will be run first for just stage, location, lower biomarker cutoff, higher biomarker cutoff, and treatment as covariates; the models will be repeated by adding treatment interactions with stage, location, and the biomarker cutoffs". Moreover, the statistical strength of these results is very strong. For example, it is universally accepted that a p-value of less than 0.05 denotes a statistically significant result. When multiple subgroups are analyzed, however, the threshold for significance becomes much stricter, i.e., a need for a lower p-value to show statistical significance. The data meet these stricter standards because the p-value is only 0.0015, which is much better than a p-value of 0.05.
Are the results post hoc or not?
Criticism: Subgroup analyses are often conducted after the trial is completed and not pre-specified in the protocol or the SAP. This exploratory nature increases the risk of data dredging or p-hacking, where investigators may unintentionally focus on results that appear significant by chance.
Response: The subgroup analyses in the Phase 3 study were pre-specified in the original protocol including analysis of cellular markers; for markers not available at the time of study initiation, analysis by these markers was pre-specified in the SAP (signed and issued prior to database lock).
Is there a biological basis for the results?
Criticism: Subgroup analyses can show positive results in populations that have no biological connection to the outcome. A famous example is the ISIS-2 trial where researchers, somewhat jokingly, analyzed results by zodiac sign and found seemingly negative effects of aspirin on people born under Gemini or Libra, highlighting the pitfalls of analyzing data in extremely small subgroups.
Response: The results in the selected subgroup are based on factors that tie directly to Multikine’s mechanism of action. They therefore have a strong biological rationale that explains why this particular group should be expected to do well with Multikine pre-surgery treatment. In other words, we did not select patients based on factors, like the zodiac, that bear no relation to Multikine. Rather, the selection criteria for the patient population is supported by Multikine’s biological mechanism of action.
Were the treatment and control groups well balanced?
Criticism: Subgroup effects may not truly reflect differences in treatment but rather random variation in patient characteristics. It can be difficult to distinguish genuine treatment effects from noise without a strong biological rationale.
Response: The baseline and demographics of the two comparator groups in the confirmatory registration study are well balanced. There was a small disadvantage to Multikine because the Multikine treated group had a higher percentage of sicker stage IVa patients, but the Multikine arm still showed a highly significant overall survival advantage versus control. Refer to slide 35 of the corporate slide presentation.
There is a strong biological rationale for the selection criteria that help identify the patients who best respond to Multikine

The confirmatory registration study will be conducted in patients with newly diagnosed locally advanced primary (disease stage III and IVa) head and neck cancer, presenting with:

no lymph node involvement (N0) (determined via PET imaging) and
low PD-L1 tumor expression (determined via biopsy).
There are three biological factors supporting this population definition. First, it is widely recognized that the timing of surgery is an important factor for patients depending on their tumor burden. Secondly, Multikine’s mechanism of action will result in greater therapeutic effect in patients with intact local immune architecture and lower-disease burden. Thirdly, tumors with low PD-L1 expression (having lower defenses to anti-tumor immune cellular attack) should be more susceptible to the cellular immune attack incited by Multikine. Together, this gives a biological basis for how the effect of Multikine will vary across the locally advanced head and neck cancer population in the neoadjuvant setting, provides biological rationale and supports the selection criteria.

This biological basis is evidenced by the Phase 3 clinical trial results, which showed a higher rate of pre-surgical responses among subjects with lower disease burden. Pre-specified histopathology and immunohistochemistry performed blinded to the study confirmed a similar heterogeneity of Multikine’s effect on the tumor microenvironment, as well as Multikine’s greater effect in subjects with low PD-L1 tumor expression (TPS < 10, which included TPS = 0 to <10) vs those with higher PD-L1 tumor expression (TPS ≥ 10).

These outcomes were expected in view of Multikine’s biological mechanism of action. Specifically, because the timing of surgery is important to individual patients depending on their tumor burden and lymph node involvement, it was expected that the three-week delay of surgery necessary for the administration of Multikine would mostly negatively affect subjects with higher disease burden, while subjects with lower disease burden at entry may have a better chance of benefiting from Multikine administration. Additionally, because Multikine relies on activating the patient’s local antitumor immune response, it should be expected that Multikine will have greater effect in patients with an intact local immune architecture and increased immune competency, lower-disease burden, and the anti-tumor cellular immune response incited by Multikine will have an increased anti-tumor effect in tumors with lower PD-L1 tumor expression (where tumor defenses to, and ability to hide from, the immune system are reduced).

When these criteria were retrospectively applied to subjects in the Phase 3 study by selecting those with N0 and low PD-L1 tumor expression, the results of this analysis showed a 5-year OS advantage over control (73% vs 45%), unstratified log rank p=0.0015, and a hazard ratio of 0.35 [0.18, 0.66], Wald 0.0012, as shown on slide 16 in the corporate slide presentation.