CEL-SCI Highlights Biological Rationale for the Use of Multikine in the Confirmatory Registration Head and Neck Cancer Study
CEL-SCI (NYSE American: CVM) has received FDA approval for a 212-patient confirmatory registration study of Multikine in head and neck cancer treatment. The study focuses on patients who showed a 73% survival rate with Multikine versus 45% in control groups during the prior Phase 3 study.
The study will target newly diagnosed locally advanced primary (stage III and IVa) head and neck cancer patients with no lymph node involvement and low PD-L1 tumor expression. Multikine demonstrated significant tumor regression in just three weeks of pre-surgical therapy, with five complete regressions observed in the Phase 3 study.
The selection criteria for the confirmatory study is supported by strong statistical significance (p=0.0015) in a large subgroup of 114 patients, and aligns with Multikine's biological mechanism of action.
CEL-SCI (NYSE American: CVM) ha ricevuto l'approvazione della FDA per uno studio registrativo di conferma su 212 pazienti riguardante il trattamento del cancro testa-collo con Multikine. Lo studio si concentra sui pazienti che hanno mostrato un tasso di sopravvivenza del 73% con Multikine rispetto al 45% nei gruppi di controllo durante il precedente studio di Fase 3.
Lo studio mirerà a pazienti con diagnosi recente di cancro alla testa e al collo localmente avanzato primario (stadio III e IVa) senza coinvolgimento dei linfonodi e con bassa espressione del tumore PD-L1. Multikine ha dimostrato una significativa regressione tumorale già dopo tre settimane di terapia prechirurgica, con cinque regressioni complete osservate nello studio di Fase 3.
I criteri di selezione per lo studio di conferma sono supportati da una forte significatività statistica (p=0.0015) in un ampio sottogruppo di 114 pazienti e sono in linea con il meccanismo biologico d'azione di Multikine.
CEL-SCI (NYSE American: CVM) ha recibido la aprobación de la FDA para un estudio de registro confirmatorio de 212 pacientes sobre el tratamiento del cáncer de cabeza y cuello con Multikine. El estudio se centra en pacientes que mostraron una tasa de supervivencia del 73% con Multikine frente al 45% en los grupos de control durante el anterior estudio de Fase 3.
El estudio se dirigirá a pacientes recién diagnosticados con cáncer de cabeza y cuello primario localmente avanzado (etapa III y IVa) sin afectación de los ganglios linfáticos y con baja expresión tumoral de PD-L1. Multikine demostró una regresión tumoral significativa en solo tres semanas de terapia prequirúrgica, con cinco regresiones completas observadas en el estudio de Fase 3.
Los criterios de selección para el estudio de confirmación están respaldados por una fuerte significación estadística (p=0.0015) en un gran subgrupo de 114 pacientes, y se alinean con el mecanismo biológico de acción de Multikine.
CEL-SCI (NYSE American: CVM)는 두경부 암 치료를 위한 Multikine의 212명 환자를 대상으로 하는 확인 등록 연구에 대해 FDA 승인을 받았습니다. 이 연구는 이전 3상 연구에서 Multikine 사용 시 73%의 생존율, 대조군에서 45%의 생존율을 보인 환자들에 중점을 둡니다.
이번 연구는 림프절 관여가 없고 PD-L1 종양 발현이 낮은 새로 진단된 국소 진행성 종양(3기 및 4a기) 두경부 암 환자를 대상으로 할 것입니다. Multikine은 수술 전 치료 3주 만에 상당한 종양 퇴행을 보여주었으며, 3상 연구에서 5건의 완전 퇴행이 관찰되었습니다.
확인 연구의 선택 기준은 114명의 대규모 하위 그룹에서 강력한 통계적 유의성(p=0.0015)을 기반으로 하며, Multikine의 생리학적 작용 메커니즘과 일치합니다.
CEL-SCI (NYSE American: CVM) a reçu l'approbation de la FDA pour une étude enregistrant 212 patients dans le cadre d'une étude de confirmation du Multikine dans le traitement des cancers de la tête et du cou. L'étude se concentre sur les patients ayant présenté un taux de survie de 73% avec Multikine contre 45% dans les groupes de contrôle lors de l'étude de Phase 3 précédente.
L'étude ciblera des patients récemment diagnostiqués avec un cancer localement avancé de la tête et du cou (stades III et IVa) sans implication ganglionnaire et avec une faible expression tumorale de PD-L1. Multikine a montré une régression tumorale significative en seulement trois semaines de thérapie préchirurgicale, avec cinq régressions complètes observées dans l'étude de Phase 3.
Les critères de sélection pour l'étude de confirmation sont soutenus par une forte signification statistique (p=0.0015) dans un grand sous-groupe de 114 patients, et s'alignent avec le mécanisme d'action biologique de Multikine.
CEL-SCI (NYSE American: CVM) hat die Genehmigung der FDA für eine Bestätigungsstudie mit 212 Patienten zum Einsatz von Multikine bei der Behandlung von Kopf- und Halskrebs erhalten. Die Studie konzentriert sich auf Patienten, die in der vorherigen Phase-3-Studie eine Überlebensrate von 73% mit Multikine im Vergleich zu 45% in den Kontrollgruppen aufwiesen.
Die Studie wird neu diagnostizierte Patienten mit lokal fortgeschrittenem primärem (Stadium III und IVa) Kopf- und Halstumor ohne Lymphknotenbefall und mit geringer PD-L1-Tumorexpression anvisieren. Multikine zeigte bereits nach nur drei Wochen der präoperativen Therapie eine signifikante Tumorrückbildung, mit fünf vollständigen Rückbildungen, die in der Phase-3-Studie beobachtet wurden.
Die Auswahlkriterien für die Bestätigungsstudie sind durch eine starke statistische Signifikanz (p=0.0015) in einer großen Untergruppe von 114 Patienten untermauert und stimmen mit dem biologischen Wirkmechanismus von Multikine überein.
- FDA approved confirmatory registration study for 212 patients
- 73% survival rate with Multikine vs 45% in control group
- Significant tumor regression achieved in just 3 weeks
- Strong statistical significance (p=0.0015) in 114-patient subgroup
- Five complete tumor regressions observed in Phase 3 study
- Phase 3 study missed primary endpoint of 10% improvement in overall survival
- No survival benefit observed in patients who received chemotherapy post-surgery (approximately 50% of patients)
Insights
This announcement details the biological rationale behind CEL-SCI's confirmatory registration study for Multikine in head and neck cancer, representing a significant development. The key highlights include: 73% vs 45% survival rate in the target population, with a strong statistical significance (p=0.0015) and hazard ratio of 0.35. The study will focus on 212 patients with specific criteria: newly diagnosed locally advanced primary head and neck cancer, no lymph node involvement and low PD-L1 tumor expression.
The pre-surgical tumor regression data and biological mechanism of action provide compelling evidence for Multikine's efficacy. The selection criteria are well-supported by scientific rationale, addressing common criticisms of subgroup analyses through pre-specified protocols and strong statistical significance. The focus on patients with intact immune systems pre-surgery aligns with the immunotherapy's mechanism of action.
This development is strategically significant for CEL-SCI, potentially positioning Multikine as a first-line treatment in head and neck cancer. With a market cap of just
- 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)
“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
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 (
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
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.
View source version on businesswire.com: https://www.businesswire.com/news/home/20241212453035/en/
Gavin de Windt
CEL-SCI Corporation
(703) 506-9460
Source: CEL-SCI Corporation
FAQ
What were the survival rates for Multikine in CVM's Phase 3 head and neck cancer trial?
How long does it take to see tumor regression with CVM's Multikine treatment?
What is the size of CVM's new confirmatory registration study for Multikine?
What are the patient selection criteria for CVM's new Multikine study?
What statistical significance did CVM's Multikine show in the target subgroup?
