CVM: Target Population Comes Into Relief
NYSE:CVM
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Multikine Clinical Data
CEL-SCI Corporation (NYSE:CVM) has continued to generate data and analysis related to its IT-MATTERS trial - a Phase III study evaluating Multikine in advanced primary squamous cell carcinoma of the oral cavity and soft palate. Since our previous update a month ago, CEL-SCI has continued to prepare its manufacturing facility for commercial scale production and has released new data, further refining the target population that benefits from the pre-surgery administration of the leukocyte interleukin injection.
In the most recent poster presentation at European Society for Medical Oncology (ESMO), CEL-SCI further identified downstaging of disease after Multikine therapy as a predictor of better survival. Combined with the selection criteria that can be identified upon diagnosis, including no involvement of disease in the lymph nodes, no extracapsular spread of the tumor and low PD-L1 expression, CEL-SCI has identified a population that may support regulatory approval in multiple jurisdictions.
What Is Surgical Downstaging and Upstaging?
Surgical downstaging and upstaging reflect changes in the stage of a cancer, and in the context of this poster, from before surgery to after surgery, based on what is found during the surgery. Cancer stages are a way to measure cancer’s spread based on tumor size, invasion of nearby tissue, spread to lymph nodes and metastasis. The stage ranges from I to IV indicating less severe to more severe disease.
Downstaging occurs when the stage is lowered after surgery compared to before. For instance, a cancer that was thought to be stage III before surgery, but re-evaluated at stage II after surgery is an example of downstaging. Some reasons for downstaging include:
➢ Imaging tests before surgery overestimated the extent of the tumor. The surgeon finds the tumor is not as advanced as thought;
➢ Neoadjuvant therapy (chemo/radiation or agent such as Multikine given before surgery) was effective and shrank the tumor more than expected.
Upstaging is when evaluation of the stage increases after surgery. If a cancer was thought to be stage II before the surgical procedure, but more extensive disease is later found to support stage III, this represents upstaging. Reasons for upstaging include:
➢ Imaging tests before surgery underestimated the extent of the tumor. More disease is found during surgery;
➢ There was undetected regional lymph node spread or microscopic metastatic disease not seen on scans before surgery.
Therefore, downstaging results from a post-surgical assessment that cancer is less extensive than expected. This is in contrast to upstaging which indicates more advanced disease and typically has a worse prognosis.
ESMO Poster Presentation
CEL-SCI presented data from the IT-MATTERS clinical trial at the European Society of Medical Oncology (ESMO) Congress in Spain on October 22, 2023. The presented poster was accompanied by a press release which explained the details presented at the conference and detailed the finalization of the selection criteria for the target population and CEL-SCI next steps. CEL-SCI has identified a population that is particularly responsive to Multikine which can be identified upon diagnosis. This includes patients with no involvement of disease in the lymph nodes, no extracapsular spread of the tumor and low PD-L1 tumor expression.
Lack of spread to the lymph nodes indicates less severe disease and that the cancer is more contained. When cancer spreads to lymph nodes, it increases the risk that cancer cells will then spread further through the body through the bloodstream or lymphatic system and metastasize. Extracapsular spread (ECS) is another indicator that cancer has spread outside its origin and occurs when cancer cells expand beyond the capsule of a lymph node. The capsule of a lymph node is a thin layer of tissue that surrounds the node and helps to keep the cancer cells inside. When cancer cells spread beyond the capsule, it is called ECS. ECS is a serious finding because it indicates that the cancer is more likely to spread to other parts of the body.
PD-L1 is programmed death-ligand 1 and appears on the surface of some cancer cells to erroneously communicate to immune cells that the cancer cell is harmless. In circumstances where there is high PD-L1 expression, a checkpoint inhibitor such as Keytruda may improve tumor response and contribute to a higher probability of survival as it can block the receptor which allows the cancer cell to hide. Low PD-L1 expressing cancers do not respond well to checkpoint inhibitors, leaving an unmet need. CEL-SCI’s data show that Multikine works well in this population of low PD-L1 expressers and could potentially address this void.
CEL-SCI identifies multiple factors that support its efforts to seek marketing authorization. This includes data supporting Multikine’s use in patients with low PD-L1 expression, which was approximately 70% of the IT-MATTERS study population, the ability to identify patients that can respond to the therapy upon diagnosis and a significant increase in 5-year overall survival in the target group from 45% for control patients who did not receive Multikine to 73% for Multikine-treated patients.
Under a previous heading earlier in this report we discussed upstaging and downstaging following surgery and some of the reasons behind a change in estimating cancer stage. The ESMO poster refers to pre-surgery changes in stage as it relates to Multikine-treated patients who were downstaged following surgery. These patients had much better survival in the IT-MATTERS study measured with a high degree of statistical significance (p < 0.0002). The study showed that patients with disease downstaging survived longer than those who were not downstaged and that there was a 35% rate of pre-surgical downstaging in study subjects who met the above mentioned selection criteria when treated with Multikine. Additional detail related to the overall population in the trial and changes in staging are provided in the following exhibit. Note that upstaging is about the same for Combined LI and SOC, whereas there is an almost 9 percentage point difference in favor of Multikine for downstaging (21.5% vs. 13.0%).
When we examine the Kaplan-Meier curve for intent to treat Multikine patients comparing those who were downstaged, upstaged and remained at the same stage, we can see the wide separation in the curves.
CEO Shareholder Letter
Several CEL-SCI posters have been presented at conferences sponsored by the European Society for Medical Oncology (ESMO) and the American Head and Neck Cancer Society (AHNS) among other scientific conferences. In parallel with their release, CEL-SCI CEO Geert Kersten has published a shareholder letter emphasizing some of the differentiating characteristics of Multikine that have emerged after further analysis of the IT-MATTERS clinical data. He lists several factors that enable physicians to identify patients that respond to Multikine 28.4 percentage points better than the control group, which is a greater than 60% improvement. Survival is improved in cases where there is:
➢ Low PD-L1 protein receptor expression
➢ Low risk assessment
➢ No extracapsular spread
➢ No lymph node invasion (N0)
For patients with these characteristics at diagnosis, risk of death fell from 55% to 27% at the five year mark in the IT-MATTERS trial. Other metrics related to this population are the hazard ratio, presurgical response (PSR) and presurgical downstaging (PSD). The hazard ratio of 0.35 indicates that deaths occurred at 35% of the rate in the Multikine arm as in the control arm. 13% of Multikine patients compared to 0% control patients exhibited a PSR while 35% of Multikine patients and 13% of control patients showed a PSD. Mr. Kersten puts these elements together and intends to seek immediate approval based on the efficacy and safety of Multikine and the unmet need for squamous cell carcinoma of the head and neck (SCCHN).
CEL-SCI intends to present this new data to regulatory agencies including Health Canada, the FDA, the MHRA and the EMA. It believes that the strongly supportive data will merit submission using a conditional approval pathway, which would not require a new trial before approval. Management thinks that it will be clear whether or not this is an option as soon as January 2024.
Manufacturing Facility
Commissioning of the Multikine manufacturing facility is substantially complete as reported in an October 19th press release. CEL-SCI is commissioning and qualifying the facility’s utilities, systems, and equipment in alignment with guidelines for the International Society for Pharmaceutical Engineering (ISPE) and the International Conference for Harmonization (ICH). The facility will be subject to regulatory review prior to the granting of a commercial manufacturing license and marketing clearance for Multikine. Details related to the commissioning of the facility will be included in the company’s biologic licensing application (BLA).
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1. Cel-Sci’s 2023 ESMO Poster Graphic.
2. Cel-Sci’s 2023 ESMO Poster Graphic.
3. Cel-Sci’s 2023 ESMO Poster Graphic.
4. CEL-SCI Shareholder Letter, October 25, 2023
