Here's a question I've had that I don't think I ha
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Posted On: 10/03/2025 5:57:39 PM
Here's a question I've had that I don't think I have seen addressed on this board -
What is the success rate of checkpoint inhibitors against various types of cancers?
I put the question to ChatGPT and got an answer that seems to indicate that checkpoint inhibitors are not as effective as I would have thought - 5% to less than 50% usually. Only in Hodgkin Lymphoma did it get as high as 60-75%.
One answer I got for TNBC was - if there was not expression of PD-L1 by the breast tumor, don't even try a checkpoint inhibitor!
Yet from Cytodyn's experience, limited as it is, a combo of Leronlimab and a CI got an almost perfect response, in mTNBC no less!
So to my mind that result shows that, sure, Leronlimab can upregulate PD-L1 to increase the effectiveness of a CI but the real value is in restoring a person's immune system back to near normal or homeostasis. Obviously, though, the immune system will not return to homeostasis until the tumor or any other morbidity in the body that a health immune system would normally deal with is done.
So here is ChatGPT's answer to my original question -
It varies a lot by cancer type, by the specific checkpoint drug (anti-PD-1/PD-L1 alone vs combined with anti-CTLA-4), by whether it’s used first-line or after other treatments, and by biomarkers (PD-L1, MSI-H/TMB, etc.). Below I summarize typical **objective response rates (ORR)** and a few key outcomes for the major tumor types.
### How to read these numbers
* **ORR (objective response rate)** = percent of patients with tumor shrinkage (complete + partial responses).
* **Durability / survival** matters too: many responders on checkpoint inhibitors have long-lasting remissions, so a modest ORR can still produce meaningful long-term benefit.
* Numbers below are approximate ranges from clinical trials or meta-analyses; real-world and trial-to-trial differences (patient selection, prior therapy, PD-L1 or MSI status, combination vs single agent) change them substantially.
---
## Typical response ranges by cancer type (approximate ORR)
* **Melanoma (advanced)** — *single-agent anti-PD-1*: ORR ≈ **30–45%**; *combo anti-PD-1 + anti-CTLA-4* (nivolumab + ipilimumab) can give higher ORRs and much-improved long-term survival (many trials show durable 5–10 year survival in a sizable minority).
* **Non-small cell lung cancer (NSCLC)** — depends on PD-L1 and regimen:
* *High PD-L1 (≥50%) pembrolizumab monotherapy*: ORR ≈ **40–45%** in first line.
* *PD-1/PD-L1 + chemotherapy* in first line: ORR often **~45–50%** (compared with ~20% with chemo alone in some trials).
* **Renal cell carcinoma (RCC)** — *single agent anti-PD-1* ORR ≈ **20–30%**; *combination (eg nivolumab + ipilimumab or PD-1 + VEGF TKI)* ORRs commonly **~30–45%**, with meaningful improvements in survival in many studies.
* **Urothelial (bladder) cancer** — single-agent PD-1/PD-L1 in platinum-refractory disease: ORR ≈ **15–25%** (higher in PD-L1+ tumors); pooled analyses give average ORR ≈ 20%.
* **Classical Hodgkin lymphoma** — among the highest: anti-PD-1 in relapsed/refractory disease → ORR **~65–75%** in pivotal studies, with many durable responses.
* **MSI-high / dMMR solid tumors (tumor-agnostic indication)** — pembrolizumab in MSI-H/dMMR tumors: ORR **~30–40%** across many different tumor types, and responses are often durable (this is the basis for tissue-agnostic approvals). Some cohorts (non-CRC) show higher ORRs.
* **Triple-negative breast cancer (TNBC)** — single-agent activity is modest; **best results when combined with chemotherapy** for PD-L1+ tumors. In KEYNOTE-355 (pembro+chemo) the combination produced improved PFS/OS and higher response rates vs chemo alone (ORR varies by trial/PD-L1 cutoffs; combinations may produce ORRs in the 40–50% range in selected PD-L1+ patients).
* **Head & neck squamous cell carcinoma (HNSCC)** — single-agent anti-PD-1 in the recurrent/metastatic setting: **ORR ~13–18%** overall, higher in PD-L1+ subsets; combinations/earlier use improve outcomes.
* **Merkel cell carcinoma, cutaneous squamous cell carcinoma** — these skin cancers are relatively sensitive to PD-1 blockade; ORRs are often **~30–60%** depending on setting/trial, with many durable responses (these are among the tumor types where immunotherapy is particularly active).
---
## Big-picture takeaways
1. **Wide range:** ORRs span from single-digit/teens (some chemo-resistant cancers) to **>60%** (Hodgkin lymphoma, some virus-associated or high-TMB/MSI tumors).
2. **Biomarkers matter:** PD-L1 expression, MSI/dMMR status, tumor mutational burden, and other features strongly influence the chance of response. Trials often show higher ORR in PD-L1+ or MSI-H patients.
3. **Combinations usually raise response rates** (PD-1 + CTLA-4, or PD-1 + chemo or targeted therapy) but can increase toxicity. Many recent approvals are for combination regimens in specific indications.
4. **Durability is the key clinical advantage**: a subset of responders experience long, durable remissions and improved long-term survival compared with prior standard therapies.
---
If you want, I can:
* produce a **compact table** showing approximate ORR ranges (by cancer + single agent vs combos) for the tumor types above.
Definitions
MSI (Microsatellite Instability):
A genetic feature where short, repeated DNA sequences (microsatellites) become unstable due to defects in DNA mismatch repair.
MSI-high (MSI-H) tumors accumulate mutations → more neoantigens → better recognized by the immune system.
dMMR (Deficient Mismatch Repair):
Refers to the loss of function in mismatch repair genes (e.g., MLH1, MSH2, MSH6, PMS2).
dMMR leads to MSI-H.
Both terms are often used together: “MSI-H/dMMR” identifies tumors highly responsive to checkpoint blockade (FDA tissue-agnostic approval for pembrolizumab was based on this).
What is the success rate of checkpoint inhibitors against various types of cancers?
I put the question to ChatGPT and got an answer that seems to indicate that checkpoint inhibitors are not as effective as I would have thought - 5% to less than 50% usually. Only in Hodgkin Lymphoma did it get as high as 60-75%.
One answer I got for TNBC was - if there was not expression of PD-L1 by the breast tumor, don't even try a checkpoint inhibitor!
Yet from Cytodyn's experience, limited as it is, a combo of Leronlimab and a CI got an almost perfect response, in mTNBC no less!
So to my mind that result shows that, sure, Leronlimab can upregulate PD-L1 to increase the effectiveness of a CI but the real value is in restoring a person's immune system back to near normal or homeostasis. Obviously, though, the immune system will not return to homeostasis until the tumor or any other morbidity in the body that a health immune system would normally deal with is done.
So here is ChatGPT's answer to my original question -
It varies a lot by cancer type, by the specific checkpoint drug (anti-PD-1/PD-L1 alone vs combined with anti-CTLA-4), by whether it’s used first-line or after other treatments, and by biomarkers (PD-L1, MSI-H/TMB, etc.). Below I summarize typical **objective response rates (ORR)** and a few key outcomes for the major tumor types.
### How to read these numbers
* **ORR (objective response rate)** = percent of patients with tumor shrinkage (complete + partial responses).
* **Durability / survival** matters too: many responders on checkpoint inhibitors have long-lasting remissions, so a modest ORR can still produce meaningful long-term benefit.
* Numbers below are approximate ranges from clinical trials or meta-analyses; real-world and trial-to-trial differences (patient selection, prior therapy, PD-L1 or MSI status, combination vs single agent) change them substantially.
---
## Typical response ranges by cancer type (approximate ORR)
* **Melanoma (advanced)** — *single-agent anti-PD-1*: ORR ≈ **30–45%**; *combo anti-PD-1 + anti-CTLA-4* (nivolumab + ipilimumab) can give higher ORRs and much-improved long-term survival (many trials show durable 5–10 year survival in a sizable minority).
* **Non-small cell lung cancer (NSCLC)** — depends on PD-L1 and regimen:
* *High PD-L1 (≥50%) pembrolizumab monotherapy*: ORR ≈ **40–45%** in first line.
* *PD-1/PD-L1 + chemotherapy* in first line: ORR often **~45–50%** (compared with ~20% with chemo alone in some trials).
* **Renal cell carcinoma (RCC)** — *single agent anti-PD-1* ORR ≈ **20–30%**; *combination (eg nivolumab + ipilimumab or PD-1 + VEGF TKI)* ORRs commonly **~30–45%**, with meaningful improvements in survival in many studies.
* **Urothelial (bladder) cancer** — single-agent PD-1/PD-L1 in platinum-refractory disease: ORR ≈ **15–25%** (higher in PD-L1+ tumors); pooled analyses give average ORR ≈ 20%.
* **Classical Hodgkin lymphoma** — among the highest: anti-PD-1 in relapsed/refractory disease → ORR **~65–75%** in pivotal studies, with many durable responses.
* **MSI-high / dMMR solid tumors (tumor-agnostic indication)** — pembrolizumab in MSI-H/dMMR tumors: ORR **~30–40%** across many different tumor types, and responses are often durable (this is the basis for tissue-agnostic approvals). Some cohorts (non-CRC) show higher ORRs.
* **Triple-negative breast cancer (TNBC)** — single-agent activity is modest; **best results when combined with chemotherapy** for PD-L1+ tumors. In KEYNOTE-355 (pembro+chemo) the combination produced improved PFS/OS and higher response rates vs chemo alone (ORR varies by trial/PD-L1 cutoffs; combinations may produce ORRs in the 40–50% range in selected PD-L1+ patients).
* **Head & neck squamous cell carcinoma (HNSCC)** — single-agent anti-PD-1 in the recurrent/metastatic setting: **ORR ~13–18%** overall, higher in PD-L1+ subsets; combinations/earlier use improve outcomes.
* **Merkel cell carcinoma, cutaneous squamous cell carcinoma** — these skin cancers are relatively sensitive to PD-1 blockade; ORRs are often **~30–60%** depending on setting/trial, with many durable responses (these are among the tumor types where immunotherapy is particularly active).
---
## Big-picture takeaways
1. **Wide range:** ORRs span from single-digit/teens (some chemo-resistant cancers) to **>60%** (Hodgkin lymphoma, some virus-associated or high-TMB/MSI tumors).
2. **Biomarkers matter:** PD-L1 expression, MSI/dMMR status, tumor mutational burden, and other features strongly influence the chance of response. Trials often show higher ORR in PD-L1+ or MSI-H patients.
3. **Combinations usually raise response rates** (PD-1 + CTLA-4, or PD-1 + chemo or targeted therapy) but can increase toxicity. Many recent approvals are for combination regimens in specific indications.
4. **Durability is the key clinical advantage**: a subset of responders experience long, durable remissions and improved long-term survival compared with prior standard therapies.
---
If you want, I can:
* produce a **compact table** showing approximate ORR ranges (by cancer + single agent vs combos) for the tumor types above.
Definitions
MSI (Microsatellite Instability):
A genetic feature where short, repeated DNA sequences (microsatellites) become unstable due to defects in DNA mismatch repair.
MSI-high (MSI-H) tumors accumulate mutations → more neoantigens → better recognized by the immune system.
dMMR (Deficient Mismatch Repair):
Refers to the loss of function in mismatch repair genes (e.g., MLH1, MSH2, MSH6, PMS2).
dMMR leads to MSI-H.
Both terms are often used together: “MSI-H/dMMR” identifies tumors highly responsive to checkpoint blockade (FDA tissue-agnostic approval for pembrolizumab was based on this).
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