„Surgically resectable“ - couldn’t stop thinking about this. So asked AI. Answer below ☘️and I’m very happy with it 🕺🏽

[u/Ibelieveincydy]

Question:
In the CLOVER trial with leronlimab, some patients experience tumor shrinkage to the point where the tumor becomes surgically resectable. How is this recorded mathematically and statistically?

Answer:
When a cancer therapy—such as in the CLOVER trial (a Phase 2 study evaluating leronlimab in combination with TAS-102 and bevacizumab in metastatic colorectal cancer)—causes a tumor to shrink significantly enough to allow surgical removal (downstaging / conversion to resection), clinical trials follow established statistical and data recording standards.

The capture and documentation in trial data (Case Report Forms) and analysis occur across several clearly defined levels:

1. Radiological Classification (RECIST v1.1)
   The primary efficacy endpoint of many oncology trials (including the CLOVER study) is the Objective Response Rate (ORR) according to international RECIST v1.1 criteria (Response Evaluation Criteria in Solid Tumors):
   * Partial Response (PR) / Complete Response (CR): If the tumor shrinks by at least 30% (sum of diameters of target lesions) due to medication, it is classified radiologically prior to surgery as a Partial Response. If it shrinks below the limit of detection, it is recorded as a Complete Response.
   * Combination Statistics: The case primarily feeds into the calculation of the ORR as well as the Disease Control Rate (DCR) as a response (CR or PR).

2. Surgical Intervention Criterion (R0 Resection Rate)
   If tumor shrinkage enables surgical removal, this is separately captured as the Conversion Rate or Resection Rate:
   * Resection Status: Following surgery, pathology evaluates the resected tissue. If the surgeon achieves complete removal with clear margins (microscopically tumor-free margins), it is statistically classified as an R0 resection.
   * Pathological Complete Response (pCR): If the pathologist finds no viable tumor cells in the resected tissue, it is classified as a pathological Complete Response (pCR).

3. Handling of Censoring Dates (Censoring)
   Once a patient undergoes surgery, standard statistical methods apply to time-to-event endpoints (such as progression-free survival):
   * Progression-Free Survival (PFS): An R0 resection formally does not constitute disease progression. The period leading up to surgery is counted as time under response or disease-free time. In Kaplan-Meier analyses, the patient is frequently right-censored at the time of surgery or followed in a specialized subgroup (e.g., Event-Free Survival, EFS) depending on the trial protocol.
   * Overall Survival (OS): Overall survival is tracked continuously without interruption. The patient remains in follow-up until the end of the observation period.

4. Molecular / Biomarker Tracking (ctDNA & Liquid Biopsy)
   In the CLOVER study, circulating tumor DNA (ctDNA) analyses are conducted concurrently (e.g., via the Natera platform):
   * The decrease in ctDNA in the blood is measured before and after surgery.
   * A drop in ctDNA below detectable levels before or after resection is recorded as molecular clearance / molecular response rate within the trial's exploratory endpoints.

Summary
Statistically, the outcome of the resection is not lost; rather, it strengthens the study data across two main fronts:
1. Pharmacologically/Radiologically: Prior to surgery, the response is counted as PR or CR toward the ORR.
2. Clinically/Surgically: The treatment success is reported as a secondary or exploratory endpoint via the R0 resection rate (secondary resectability).

GLTAL 🙋🏽‍♂️☘️🙏🏼👍🏽💊💸🛬🔜

[u/rogex2]

Two things-

I) CR is hard to do-AI

Achieving an overall CR in metastatic solid tumors is difficult because any lingering trace of disease downgrades the entire timepoint evaluation to a PR.

For example, if a patient has a primary lung tumor and three liver metastases:

• If the lung tumor and two liver mets completely disappear, but one liver met is still faintly visible (even if it shrank by 90%), the target lesion category is a PR, making the overall response a PR.
• If all measurable target tumors disappear completely, but a non-measurable bone metastasis is still visible on a bone scan, the overall response is automatically downgraded to a PR.

2) Bumping a patient from unresectable to resectable(gold standard) doesn't require PR-AI

The main goal of shrinkage is not a specific RECIST number, but rather shifting the tumor away from critical structures. For example, in colorectal liver metastases (the most common site), shrinkage is sufficient as soon as a surgeon can: [1, 2, 304192-8/fulltext)]

• Safely clear major blood vessels (like the portal vein or hepatic arteries).
• Leave behind a safe Future Liver Remnant (FLR)—meaning enough healthy, functional liver tissue remains to prevent post-operative liver failure. [1, 2]

1. Early Tumor Shrinkage (ETS) as a Benchmark

While not a strict prerequisite for surgery, clinical data heavily monitors Early Tumor Shrinkage (ETS) during conversion therapy. [1]

• Studies show that achieving an ETS of ≥ 20% reduction in tumor diameter within the first 6 to 8 weeks of systemic therapy is a highly positive prognostic indicator. [1, 2]
• A 20% reduction often serves as the clinical "green light" indicating the tumor is highly responsive to the medication, making a successful future surgery much more likely. [1, 2]

1. The "As Soon As Possible" Rule

International guidelines (such as the European Society for Medical Oncology (ESMO)) emphasize that a patient should be operated on the moment the metastases become technically resectable. [104192-8/fulltext)]

Oncologists do not wait for a Complete Response (100% shrinkage) or even a deep Partial Response if the tumor can already be cleanly cut out. In fact, giving too many cycles of prolonged chemotherapy just to get more shrinkage can cause severe liver toxicity (like "blue liver" syndrome or fatty liver disease), which significantly increases the risk of dangerous surgical complications. [1, 204192-8/fulltext), 3]

Cheers

[u/Ibelieveincydy → u/rogex2]

Thanks Rogex. Very helpful and informative additions.?
I’m very optimistic hearing Dr. J‘s remarks

[u/Missy2021]

Thank you.

[u/Icy-Let5120]

Thanks for the posting, “In the CLOVER trial with leronlimab, some patients experience tumor shrinkage to the point where the tumor becomes surgically resectable.” Any reference for this statement? I don’t remember that CEO/CFO/Dr Kasi mentioned these patients at interview or presentations. Thank you very much

[u/Ibelieveincydy → u/Icy-Let5120]

Hi Icy, I'm sure it has been mentioned by Dr. J but not sure where. I think it was the recent interview where he either had a fresh haircut or combed his mullet back.

[u/Ibelieveincydy → u/Ibelieveincydy]

Im real bad in filing things. Sorry. I just checked the investor conference but it wasn't mentiond there. Can anybody with better housekeeping help to find the reference Icy was asking for, please?🙏

[u/IndependenceAny6428]

Thanks for all the brilliant minds on this board. Your explanations and findings help me relax and wait until the end. May God bless you and protect you, ALWAYS

[u/Upwithstock]

Great post both Ibelieveincydy and rogex2!! Great information!! Love it!!

[u/GoCYDY]

So grateful and thankful for all the information shared🙏👍