CEL-SCI Highlights Biological Rationale for the Use of Multikine in the Confirmatory Registration Head and Neck Cancer Study

• Multikine is the first cancer immunotherapy to show pre-surgical tumor regression in head and neck cancer in just 3 weeks - confirmed by pathology at surgery
• Factors supporting the go-ahead for the 212-person registration study in the target population include:
  • Multikine led to significant rates of tumor regression
  • Pre-surgical tumor regressions were confirmed at surgery and forecast survival benefit
  • Target population is likely to show significant survival prolongation in the confirmatory study
• Confirmatory study target population selection is based on:
  • Strong statistical significance in a large subgroup of 114 patients
  • Subgroup analysis was pre-defined in the statistical analysis plan (SAP)
  • Strong biological rationale for the results based on Multikine’s mechanism of action (MOA)

VIENNA, Va.--(BUSINESS WIRE)--$CVM #Multikine--CEL-SCI Corporation (NYSE American: CVM) today highlights strong biological rationale for the use of Multikine in the confirmatory registration head and neck cancer study. 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.

“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:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.

1. Strong statistical significance
   1. 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).
   2. 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.
2. Multiple comparisons require a higher level of significance
   1. Criticism: When multiple subgroups are analyzed, the probability of finding a significant result by chance increases. This can lead to spurious findings.
   2. 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.
3. Are the results post hoc or not?
   1. 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.
   2. 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).
4. Is there a biological basis for the results?
   1. 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.
   2. 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.
5. Were the treatment and control groups well balanced?
   1. 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.
   2. 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.

About CEL-SCI Corporation

CEL-SCI believes that boosting a patient’s immune system while it is still intact should provide the greatest possible impact on survival. Multikine is designed to help the immune system “target” the tumor at a time when the immune system is still relatively intact and thereby thought to be better able to mount an attack on the tumor.

Multikine (Leukocyte Interleukin, Injection), a true first-line cancer therapy, has been dosed in over 740 patients and received Orphan Drug designation from the FDA for neoadjuvant therapy in patients with squamous cell carcinoma (cancer) of the head and neck. Based on the very strong data from the completed randomized controlled Phase 3 study, the FDA concurred with CEL-SCI’s target patient selection criteria and gave the go-ahead to conduct a small, focused, confirmatory Registration Study which will enroll 212 patients. CEL-SCI will enroll newly diagnosed locally advanced primary treatment naïve resectable head and neck cancer patients with no lymph node involvement (determined via PET scan) and with low PD-L1 tumor expression (determined via biopsy), representing about 100,000 patients annually.

The Company has operations in Vienna, Virginia, and near/in Baltimore, Maryland.

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. When used in this press release, the words “intends,” “believes,” “anticipated,” “plans” and “expects,” and similar expressions, are intended to identify forward-looking statements. Such statements are subject to risks and uncertainties that could cause actual results to differ materially from those projected. Factors that could cause or contribute to such differences include an inability to duplicate the clinical results demonstrated in clinical studies, timely development of any potential products that can be shown to be safe and effective, receiving necessary regulatory approvals, difficulties in manufacturing any of the Company’s potential products, inability to raise the necessary capital and the risk factors set forth from time to time in CEL-SCI’s filings with the Securities and Exchange Commission, including but not limited to its report on Form 10-K for the year ended September 30, 2023. The Company undertakes no obligation to publicly release the result of any revision to these forward-looking statements which may be made to reflect the events or circumstances after the date hereof or to reflect the occurrence of unanticipated events.

* Multikine (Leukocyte Interleukin, Injection) is the trademark that CEL-SCI has registered for this investigational therapy. This proprietary name is subject to FDA review in connection with the Company’s future anticipated regulatory submission for approval. Multikine has not been licensed or approved for sale, barter or exchange by the FDA or any other regulatory agency. Similarly, its safety or efficacy has not been established for any use.

Contacts

Gavin de Windt
CEL-SCI Corporation
(703) 506-9460