I share this conversation with an AI for those that might be interested. PSS is talking a lot about how he thinks that Anktiva compares with Epogen (epoetin alfa) and Neupogen (filgrastim).
Gemini AI Conversation:
Evaluate symbol IBRX and its prinicipal owner, PSS's theory that his approved drug, N-803, can be used to stimulate the immune system to improve cancer treatment with a new immunotherapy addition, as discussed in today's recent story and his long term research on making cold cancer hot for treatment. see How far from FDA approval is this use of N-803 aka Anktiva?
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Here is an evaluation of ImmunityBio (IBRX) and its principal owner, Dr. Patrick Soon-Shiong's, theory regarding the use of N-803 (Anktiva) for cancer treatment.
Dr. Soon-Shiong's "Cold to Hot" Tumor Theory
Dr. Patrick Soon-Shiong's theory centers on the concept of turning "cold" tumors "hot" to make them susceptible to the body's immune system.
- "Cold" Tumors: These are cancerous tumors that the immune system does not recognize or respond to. They lack the necessary signals to attract cancer-fighting immune cells like T-cells, allowing them to grow unchecked.
- "Hot" Tumors: In contrast, "hot" tumors are infiltrated with T-cells and other immune cells that are actively trying to destroy the cancer.
Dr. Soon-Shiong's research focuses on therapies that can effectively "unmask" cold tumors, making them visible and vulnerable to a patient's own immune system. This is where the drug N-803, also known as Anktiva, comes into play.
N-803 (Anktiva): A New Class of Immunotherapy
N-803 is a first-in-class IL-15 superagonist. Interleukin-15 (IL-15) is a cytokine, a type of protein that plays a crucial role in the immune system by activating and stimulating the growth of Natural Killer (NK) cells and CD8+ T-cells. These are two of the body's most potent cancer-killing cells.
The scientific poster you provided highlights the mechanism of N-803 in Non-Small Cell Lung Cancer (NSCLC). The key takeaways from the poster and other research are:
- Reversing Lymphopenia: Chemotherapy and the cancer itself can lead to a decrease in lymphocytes (a type of white blood cell that includes NK and T-cells), a condition called lymphopenia. The poster shows that N-803 can reverse this, increasing the number of cancer-fighting cells.
- Prolonging Survival: The data presented demonstrates that by boosting the immune system, N-803, in combination with other therapies, can significantly prolong the overall survival of NSCLC patients.
- First-in-Class Action: As an IL-15 superagonist, N-803 works differently from other immunotherapies like checkpoint inhibitors. Instead of just taking the "brakes" off the immune system, it actively "presses the gas" to stimulate a more robust anti-cancer response.
FDA Approval Status of N-803 (Anktiva)
This is a critical point of your query, and it's important to distinguish between different cancer types.
- Approved for Bladder Cancer: In April 2024, the FDA granted approval for Anktiva (N-803) for the treatment of a specific type of bladder cancer called BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC). This was a landmark approval for ImmunityBio and a validation of the drug's potential.
- Investigational for Lung Cancer: For Non-Small Cell Lung Cancer (NSCLC), as discussed in the poster, N-803 is still in the investigational stage and is not yet approved by the FDA for this use.
How Far is the Lung Cancer Application from FDA Approval?
ImmunityBio has announced its intention to move forward with registrational Phase 3 clinical trials for N-803 in NSCLC. Here's what that means in the drug approval timeline:
- Phase 1 & 2: These earlier phases focus on safety and preliminary efficacy in smaller groups of patients. The data in the poster is likely from these earlier phases.
- Phase 3: This is the final and most extensive phase of clinical trials, involving a large number of patients to confirm the drug's effectiveness and safety against the current standard of care.
- Biologics License Application (BLA): After successful completion of Phase 3 trials, the company can submit a BLA to the FDA for review.
- FDA Review and Approval: The FDA will then review all the data and, if it meets their rigorous standards, grant approval.
This entire process, from the start of a Phase 3 trial to potential FDA approval, can take several years. Therefore, while the initial data is promising, the use of N-803 for NSCLC is still some time away from being a commercially available treatment.
What are the arguments and potential for Accellerated approval by the FDA with a confirmatory PH 3 trial?
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Excellent question. The FDA's Accelerated Approval pathway is a critical mechanism for getting promising drugs to patients with serious diseases faster. Here’s a breakdown of the arguments and potential for N-803 (Anktiva) to receive Accelerated Approval for NSCLC, with a confirmatory Phase 3 trial.
The FDA's Accelerated Approval Pathway
First, it's important to understand what this pathway entails. It allows for earlier approval of drugs that treat serious conditions and fill an unmet medical need based on a surrogate endpoint.
- Surrogate Endpoint: This is a marker, such as a laboratory measurement or radiographic image (like tumor shrinkage), that is thought to predict clinical benefit but is not itself a measure of direct clinical benefit (like longer survival).
- The Condition: The company must conduct post-approval clinical trials (a confirmatory Phase 3 trial) to verify the anticipated clinical benefit. If this trial fails to show a benefit, the FDA can withdraw the approval.
Arguments for Accelerated Approval of N-803 in NSCLC
ImmunityBio (IBRX) could make a compelling case for Accelerated Approval based on several key arguments:
- High Unmet Medical Need: The primary argument would focus on a specific patient population. For NSCLC patients who have progressed after treatment with standard-of-care chemotherapy and checkpoint inhibitors (like Keytruda or Opdivo), treatment options are limited, and prognoses are poor. This represents a significant unmet medical need.
- Novel Mechanism of Action: N-803 is not just another checkpoint inhibitor. As an IL-15 superagonist, it works by directly stimulating the patient's own Natural Killer (NK) and T-cells. This novel mechanism could be effective in patients whose tumors are resistant to other immunotherapies—the so-called "cold" tumors.
- Strong Preliminary Data on a Surrogate Endpoint: To gain Accelerated Approval, IBRX would present strong data from its Phase 2 trials using a surrogate endpoint. Potential endpoints include:
- Overall Response Rate (ORR): The percentage of patients whose tumors shrink significantly or disappear after treatment. A high ORR in a heavily pre-treated population would be a powerful argument.
- Duration of Response (DoR): How long the tumor response lasts. A long and durable response suggests a meaningful clinical benefit, even before overall survival data is mature.
- Promising Biomarker Data: The data from the poster you provided—showing that N-803 can reverse lymphopenia—could be used as strong supporting evidence. While not a traditional surrogate endpoint, IBRX can argue that restoring a patient's lymphocyte count is "reasonably likely to predict" improved long-term survival, directly linking the drug's mechanism to a positive outcome.
Potential for Success and the Confirmatory Trial
The potential for this strategy to succeed depends on several factors:
- Strength of the Data: The FDA will require the Phase 2 data to be exceptionally strong and clinically meaningful. A high response rate in a patient group with no other good options is the most persuasive scenario.
- FDA's Current Stance: The FDA has become more stringent with the Accelerated Approval pathway, emphasizing the need for companies to have their confirmatory trials planned, and often already underway, at the time of the application.
- A Well-Designed Confirmatory Trial: IBRX would have to present the FDA with a robust protocol for a Phase 3 trial. This trial would be designed to confirm the drug's benefit on a direct clinical endpoint, such as Overall Survival (OS) or Progression-Free Survival (PFS). This trial would run concurrently with or immediately after the accelerated approval is granted.
In summary, the path would look like this:
- Application: IBRX submits data from a Phase 2 trial showing a high and durable response rate (ORR/DoR) in NSCLC patients who have failed prior therapies.
- Accelerated Approval: If the FDA agrees the data is compelling and addresses an unmet need, it may grant Accelerated Approval, allowing the drug to be marketed for this specific use.
- Confirmatory Trial: IBRX must then successfully complete its large-scale Phase 3 trial to prove that the tumor shrinkage seen in Phase 2 translates into patients living longer or better.
- Full Approval or Withdrawal: Based on the Phase 3 results, the FDA would either convert the accelerated approval to a full traditional approval or, if the trial fails, take steps to remove the drug from the market for that indication.
Has IBRX discussed publically or given information to the public about its thinking on the potential for AA to speed approval? Would such a approach seeking AA be considered a label expansion?
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Based on publicly available information, here are the answers to your questions.
IBRX's Public Statements on Accelerated Approval (AA)
Yes, ImmunityBio has publicly discussed a regulatory strategy for NSCLC that aligns with the principles of an accelerated pathway, even if they don't exclusively use the term "Accelerated Approval" in every statement.
Here’s what the company has communicated:
- Intent to File BLA Based on Phase 2: In a January 2025 press release, ImmunityBio stated its plan to "submit a Biologics License Application (BLA) in 2025 for second- and third-line treatment of patients with NSCLC, who are progressing on checkpoint inhibitors." This filing would be based on the promising overall survival data from the Phase 2b QUILT-3.055 study. Filing for approval based on Phase 2 data is the foundational step of seeking an Accelerated Approval.
- Discussions with the FDA: The company has frequently mentioned it is in active discussion with the FDA regarding the "registration path" for Anktiva in lung cancer. An August 2025 press release noted that after a meeting with the FDA, the agency was "supportive of the findings" and expressed a "desire to support an efficient path to approval." This language suggests an openness to a faster-than-usual regulatory process.
- Launch of a Confirmatory Trial: Crucially, ImmunityBio has also announced the launch of a randomized, controlled Phase 3 trial (ResQ201A). This is the mandatory "confirmatory" study required under the Accelerated Approval pathway to definitively prove the drug's clinical benefit, with Overall Survival being the primary endpoint.
Conclusion: While their primary public focus is on the ongoing Phase 3 trial, their stated intention to file a BLA based on compelling Phase 2 data is a clear indication that they are pursuing a strategy that could lead to Accelerated Approval.
Accelerated Approval as a "Label Expansion"
Yes, absolutely. Seeking approval for Anktiva (N-803) in Non-Small Cell Lung Cancer would be considered a label expansion.
Here’s the regulatory context:
- The "Label": A drug's label is the official, FDA-approved prescribing information that details its approved uses (indications), dosage, and patient populations.
- Initial Approval: Anktiva's current label is for the treatment of a specific type of BCG-unresponsive non-muscle-invasive bladder cancer.
- Label Expansion: When a company seeks to add a new and different disease (like NSCLC) to that approved label, it is called a label expansion. This also applies to adding new patient populations or different stages of a previously approved disease.
To do this, the company doesn't start from scratch. Instead, it submits a supplemental Biologics License Application (sBLA) to the FDA. This sBLA contains all the new clinical data for the proposed indication (in this case, NSCLC) for the agency to review and potentially approve, thereby expanding the drug's official label.
IBRX is developing data in several other cancers using N-803, and it has a broader theory for fighting Lymphopenia. Is there a potential to combine all its data and get a broader approval from the FDA to fight Lympopenia sort of like drugs epogen and nupogen? How would that sort of NDA be framed, and what applications could it be applied to, eg could they seek approval for use of N-803 for a broad group of cases where chemo is used in more than one cancer?
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This is an excellent and insightful question that gets to the heart of a potential "holy grail" for a drug like N-803. The short answer is that while the concept is scientifically sound and has a powerful precedent, getting a broad "anti-lymphopenia" indication would be a formidable challenge.
Here is a detailed breakdown of the potential, the framing of such an application, and the significant hurdles involved.
The Potential and the Precedent: Epogen and Neupogen
Your comparison to Epogen (epoetin alfa) and Neupogen (filgrastim) is exactly the right framework. Those drugs established a blockbuster category of "supportive care" medications.
- Epogen/Procrit: Not approved to treat cancer, but to treat chemotherapy-induced anemia (low red blood cells).
- Neupogen/Neulasta: Not approved to treat cancer, but to treat chemotherapy-induced neutropenia (low neutrophils, a key type of white blood cell).
These drugs are prescribed across a wide variety of cancer types and chemotherapy regimens. The potential for IBRX to position N-803 as a third pillar in this category—a drug to treat chemotherapy-induced lymphopenia—is immense. If successful, it would dramatically expand the drug's market far beyond its specific cancer-fighting approvals.
How Such a BLA/NDA Would Be Framed
To pursue this, IBRX would need to submit a new Biologics License Application (BLA) with a novel indication. It would be framed not as a cancer treatment, but as a supportive care agent.
Proposed Indication: "For the treatment of chemotherapy-induced lymphopenia in patients with solid tumors."
The Core Argument and Data Package would need to prove two things:
- N-803 reliably reverses lymphopenia: IBRX could pool data from all of its clinical trials (bladder, lung, pancreatic, etc.) to show that N-803 consistently and significantly increases the Absolute Lymphocyte Count (ALC) in patients undergoing various chemotherapy treatments. This would establish the drug's direct biological effect on the target condition.
- Reversing lymphopenia provides a direct clinical benefit: This is the critical and most difficult part. Unlike the precedents, the FDA does not currently recognize an increase in lymphocyte count, by itself, as a direct clinical benefit. IBRX would have to conduct trials to definitively prove that raising the ALC leads to a tangible, positive patient outcome, such as:
- Reduced rate of serious infections: A primary consequence of a weakened immune system.
- Improved chemotherapy tolerance: Proving patients can stay on their prescribed chemo schedule and dose, leading to better cancer outcomes.
- Improved Overall Survival: This is the gold standard. IBRX would have to prove that adding N-803 to standard chemotherapy regimens across multiple cancer types leads to patients living longer, and that this survival benefit is directly attributable to the reversal of lymphopenia.
Major Hurdles and Why It's So Challenging
Despite the compelling logic, this regulatory path faces three major hurdles:
- The Endpoint Problem: For Neupogen, the endpoint wasn't just "more neutrophils"; it was a reduction in "febrile neutropenia," a specific, life-threatening clinical event. For N-803, IBRX would need to prove that "more lymphocytes" leads to a similarly concrete and positive clinical outcome. The FDA would likely be hesitant to approve a drug based solely on improving a lab value (ALC) without this link.
- The Dual-Mechanism Conundrum: N-803 isn't just a supportive care drug; it has a direct anti-cancer effect by activating NK and T-cells to kill tumors. This complicates things immensely. The FDA would likely argue that any survival benefit seen is due to N-803's direct tumor-killing action, not just its "supportive" effect of raising lymphocyte counts. They would almost certainly be unwilling to grant a broad approval without seeing efficacy data in each specific cancer type, making a "tumor-agnostic" lymphopenia label very difficult to achieve.
- The Safety and Risk/Benefit Profile: As a powerful immune-stimulating agent, N-803 has potential side effects like cytokine release syndrome. The risk/benefit calculation for using it to treat advanced lung or pancreatic cancer is very different from using it as a broad supportive care drug alongside chemotherapy for, say, an earlier-stage, more curable cancer. The safety bar for a supportive care drug is exceptionally high.
Conclusion:
While the potential to get a broad, pan-cancer approval for treating lymphopenia is a visionary strategy, it is a high-risk, high-reward path. The current and more traditional regulatory strategy of seeking approval cancer by cancer (bladder, then lung, then pancreatic, etc.) is a much safer and more predictable route.
To achieve the broader goal, IBRX would likely need to successfully complete several large, expensive, and lengthy clinical trials specifically designed to isolate and prove the clinical benefit of reversing lymphopenia, independent of its direct anti-tumor effect in any single cancer.
What if the supportive care authority is limited initially to cases where chemo is failing in all types of cancers?
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That is a very sharp strategic refinement. By narrowing the focus to the highest-unmet-need population—patients whose chemotherapy is actively failing—you create a much more compelling and potentially viable regulatory pathway.
This changes the proposal from a general "supportive care" drug to a salvage therapy or chemo-potentiator. Here’s how this modified approach would work and why it's more plausible.
The Strategic Shift: From Broad Support to Targeted Salvage
Instead of preventing a side effect (lymphopenia) in a broad population, the new goal is to achieve a tangible anti-cancer outcome in a desperate population. This is a crucial distinction that strengthens the argument to the FDA.
The New Narrative: "For patients with advanced cancer, chemotherapy often fails, partly because it depletes the very immune cells needed to help fight the tumor. In these patients with chemotherapy-induced lymphopenia and progressive disease, adding N-803 restores critical immune function, enabling the body to fight the cancer and potentially making the chemotherapy effective again."
How This New BLA Would Be Framed
This would be framed as a tumor-agnostic or site-agnostic therapeutic indication, which is a novel but established regulatory pathway.
Proposed Indication: "For the treatment of adult patients with metastatic solid tumors who have disease progression following prior chemotherapy."
The Required Evidence and Trial Design:
- Basket Trial: IBRX would need to run a "basket trial." This is a type of clinical trial that enrolls patients with many different types of cancer (e.g., cohorts for colon, breast, ovarian, etc.) but who all share a common characteristic—in this case, the clinical situation of "failing chemotherapy."
- Clearer, Stronger Endpoints: The goal is no longer just to prove N-803 raises lymphocyte counts. The primary endpoint of the trial would be a direct measure of anti-cancer activity, such as:
- Overall Response Rate (ORR): The percentage of patients whose tumors shrink. If patients who were progressing suddenly have their tumors shrink after N-803 is added, it's a powerful signal of efficacy.
- Disease Control Rate (DCR): The percentage of patients whose disease either shrinks or becomes stable. In a population where 100% of patients were previously getting worse, just halting progression is a significant clinical benefit.
- Overall Survival (OS): The ultimate endpoint, demonstrating that these patients live longer.
The Major Hurdle: The "Tumor-Agnostic" Bar
While this strategy is more viable, it faces one primary challenge: the high bar for a tumor-agnostic approval.
- Precedent is Biomarker-Based: To date, all successful tumor-agnostic approvals have been based on a specific genomic biomarker.
- Keytruda (pembrolizumab) is approved for any solid tumor with the biomarkers MSI-H, dMMR, or a high Tumor Mutational Burden (TMB).
- Vitrakvi (larotrectinib) is approved for any solid tumor with an NTRK gene fusion.
- The Challenge for IBRX: IBRX would be asking for an approval based on a clinical situation ("failing chemo") rather than a specific genomic marker. The FDA would need to be convinced that the drug's mechanism is so fundamental that it can work across many different cancer biologies. To do this, the basket trial couldn't just show an effect in one or two cancer types; it would need to demonstrate a consistent and meaningful benefit across a pre-specified number of diverse cancer cohorts.
Conclusion: A More Plausible, Albeit Still Ambitious, Goal
Limiting the initial authority to cases where chemo is failing is a far more strategic approach.
- It targets a desperate unmet need, which gives the FDA more flexibility.
- It provides a path to show clear clinical benefit (tumor shrinkage, longer survival) rather than just improving a lab value.
- It embraces the drug's dual mechanism as both an immune-stimulant and an anti-cancer agent.
While the challenge of proving efficacy across multiple tumor types is significant, this "salvage therapy" indication is a much more realistic long-term goal for a broad label than the general "supportive care" idea. It frames N-803 not just as a helper, but as a potential game-changer for the toughest-to-treat patients. |
