Excellent work, Sherlock, so I asked Gemini to break down how your post relates to Leronlimab.
This is an insightful comparison based on the available preliminary data, highlighting the differences in observed efficacy signals between Leronlimab and IBI363 in metastatic Colorectal Cancer (mCRC), particularly considering the small sample sizes for Leronlimab's initial data.Here's an explanation of how your points about IBI363 relate to Leronlimab:1. Overall Response Rate (ORR) Comparison (Small Sample)IBI363 (Monotherapy): ORR of 1$13.6\%$ in a trial of 22 patients.2 This represents $\approx 3$ responses.Leronlimab (Compassionate Use/Basket Trial): ORR of $60\%$ ($3$ out of $5$ mCRC patients).The Relation: Your analysis correctly points out that, based on these very limited early numbers, Leronlimab's ORR looks significantly more favorable than IBI363's, even when IBI363 is compared against the Standard of Care (SOC) ORR of $6.1\%$. The key caveat, as you note, is the very small sample size ($N=5$ vs $N=22$) for Leronlimab's $60\%$ ORR, which came from a compassionate use/basket study.Confirmation of Leronlimab ORR: Recent data from CytoDyn's compassionate use study of leronlimab in mCRC indeed reported that 3$3$ out of 4$5$ patients experienced at least a partial response, including one complete response (CR), supporting your 5$60\%$ ORR figure in that specific small cohort.6 This early data is the basis for CytoDyn's ongoing Phase II trial.2. Overall Survival (OS) and Metastasis ControlIBI363 (Monotherapy): Median Overall Survival (OS) was 7$14$ months for patients with liver metastases and 8$17$ months for those without.9 The overall median OS for IBI363 monotherapy in late-line mCRC was reported as 10$16.1$ months (11$N=68$).12Leronlimab: You stated you didn't have the OS numbers, but a recent presentation on the 5 mCRC patients from the basket/compassionate use study reported a median OS of $15.5$ months with a follow-up of $20.1$ months. Critically, one patient with liver metastasis who received leronlimab with chemotherapy remained alive with no evidence of disease for almost 5 years.13The Relation:Leronlimab's preliminary OS of $15.5$ months in a very small, heavily pre-treated cohort is comparable to the $16.1$ months reported for the larger IBI363 monotherapy cohort.The idea that Leronlimab's strength is controlling metastasis aligns with its mechanism as a CCR5 antagonist, as CCR5 signaling is implicated in metastasis. The long-term survival and CR observed in the single patient with liver metastasis further supports the potential for controlling metastatic disease, though more data is needed.143. Combination Therapy NumbersIBI363 + Bevacizumab: ORR is $15\%$ in all metastatic patients ($N=73$), rising to $31\%$ in metastatic patients without liver metastases.Leronlimab: Your current Phase II trial for mCRC is evaluating Leronlimab in combination with Trifluridine/Tipiracil (TAS-102) and Bevacizumab.15 It is an open-label, randomized study (16$N \approx 60$) looking at two doses of leronlimab (17$350$ mg vs 18$700$ mg).19The Relation:The IBI363 combination data sets a bar: 20$15.1\%$ ORR in metastatic patients.21The ongoing Leronlimab trial is also using a combination (with 22$TAS-102$ and Bevacizumab), making it a more relevant comparison to the IBI363 + Bevacizumab data than the monotherapy-like compassionate use data.23 The expectation is that the $60\%$ ORR from the small monotherapy/basket trial will likely not hold in a larger, more rigorous Phase II combination study, but a result superior to the IBI363 combination ORR of $15\%$ would be highly positive.4. Immuno-Oncology Combination (ICI)Leronlimab and ICIs: The rationale for pairing Leronlimab with an Immune Checkpoint Inhibitor (ICI) like a PD-1 blocker is strong. Data in Triple-Negative Breast Cancer (TNBC) suggested that leronlimab may act as a "priming" agent by increasing PD-L1 expression, potentially turning "cold" tumors "hot."24 This is a key part of the "backbone immuno-oncology treatment" hypothesis. In one small TNBC cohort, 25$5/5$ patients who showed increased PD-L1 and received an ICI remain alive.26IBI363: IBI363 is itself a first-in-class PD-1/IL-2 27$\alpha$-bias bispecific antibody fusion protein.28 It already has an immuno-oncology component (PD-1 blockade and IL-2 signaling) built into the monotherapy.The Relation:Leronlimab's potential lies in its ability to enhance the effect of existing ICIs in CCR5-positive solid tumors by addressing the tumor microenvironment (e.g., controlling metastasis, modulating the immune landscape).IBI363 is an ICI-type drug. Your hypothesis is that the combination of Leronlimab with an established ICI could yield a "quite substantial" benefit, a prediction rooted in the proposed mechanism of action and the TNBC data.In summary, the preliminary, small-sample Leronlimab mCRC data ($60\%$ ORR, $15.5$ months OS) is highly encouraging when compared to the initial IBI363 data ($13.6\%$ ORR, $16.1$ months OS). The true test will be the results of Leronlimab's ongoing Phase II combination trial in a larger, randomized setting.
This is an insightful comparison based on the available preliminary data, highlighting the differences in observed efficacy signals between Leronlimab and IBI363 in metastatic Colorectal Cancer (mCRC), particularly considering the small sample sizes for Leronlimab's initial data.Here's an explanation of how your points about IBI363 relate to Leronlimab:1. Overall Response Rate (ORR) Comparison (Small Sample)IBI363 (Monotherapy): ORR of 1$13.6\%$ in a trial of 22 patients.2 This represents $\approx 3$ responses.Leronlimab (Compassionate Use/Basket Trial): ORR of $60\%$ ($3$ out of $5$ mCRC patients).The Relation: Your analysis correctly points out that, based on these very limited early numbers, Leronlimab's ORR looks significantly more favorable than IBI363's, even when IBI363 is compared against the Standard of Care (SOC) ORR of $6.1\%$. The key caveat, as you note, is the very small sample size ($N=5$ vs $N=22$) for Leronlimab's $60\%$ ORR, which came from a compassionate use/basket study.Confirmation of Leronlimab ORR: Recent data from CytoDyn's compassionate use study of leronlimab in mCRC indeed reported that 3$3$ out of 4$5$ patients experienced at least a partial response, including one complete response (CR), supporting your 5$60\%$ ORR figure in that specific small cohort.6 This early data is the basis for CytoDyn's ongoing Phase II trial.2. Overall Survival (OS) and Metastasis ControlIBI363 (Monotherapy): Median Overall Survival (OS) was 7$14$ months for patients with liver metastases and 8$17$ months for those without.9 The overall median OS for IBI363 monotherapy in late-line mCRC was reported as 10$16.1$ months (11$N=68$).12Leronlimab: You stated you didn't have the OS numbers, but a recent presentation on the 5 mCRC patients from the basket/compassionate use study reported a median OS of $15.5$ months with a follow-up of $20.1$ months. Critically, one patient with liver metastasis who received leronlimab with chemotherapy remained alive with no evidence of disease for almost 5 years.13The Relation:Leronlimab's preliminary OS of $15.5$ months in a very small, heavily pre-treated cohort is comparable to the $16.1$ months reported for the larger IBI363 monotherapy cohort.The idea that Leronlimab's strength is controlling metastasis aligns with its mechanism as a CCR5 antagonist, as CCR5 signaling is implicated in metastasis. The long-term survival and CR observed in the single patient with liver metastasis further supports the potential for controlling metastatic disease, though more data is needed.143. Combination Therapy NumbersIBI363 + Bevacizumab: ORR is $15\%$ in all metastatic patients ($N=73$), rising to $31\%$ in metastatic patients without liver metastases.Leronlimab: Your current Phase II trial for mCRC is evaluating Leronlimab in combination with Trifluridine/Tipiracil (TAS-102) and Bevacizumab.15 It is an open-label, randomized study (16$N \approx 60$) looking at two doses of leronlimab (17$350$ mg vs 18$700$ mg).19The Relation:The IBI363 combination data sets a bar: 20$15.1\%$ ORR in metastatic patients.21The ongoing Leronlimab trial is also using a combination (with 22$TAS-102$ and Bevacizumab), making it a more relevant comparison to the IBI363 + Bevacizumab data than the monotherapy-like compassionate use data.23 The expectation is that the $60\%$ ORR from the small monotherapy/basket trial will likely not hold in a larger, more rigorous Phase II combination study, but a result superior to the IBI363 combination ORR of $15\%$ would be highly positive.4. Immuno-Oncology Combination (ICI)Leronlimab and ICIs: The rationale for pairing Leronlimab with an Immune Checkpoint Inhibitor (ICI) like a PD-1 blocker is strong. Data in Triple-Negative Breast Cancer (TNBC) suggested that leronlimab may act as a "priming" agent by increasing PD-L1 expression, potentially turning "cold" tumors "hot."24 This is a key part of the "backbone immuno-oncology treatment" hypothesis. In one small TNBC cohort, 25$5/5$ patients who showed increased PD-L1 and received an ICI remain alive.26IBI363: IBI363 is itself a first-in-class PD-1/IL-2 27$\alpha$-bias bispecific antibody fusion protein.28 It already has an immuno-oncology component (PD-1 blockade and IL-2 signaling) built into the monotherapy.The Relation:Leronlimab's potential lies in its ability to enhance the effect of existing ICIs in CCR5-positive solid tumors by addressing the tumor microenvironment (e.g., controlling metastasis, modulating the immune landscape).IBI363 is an ICI-type drug. Your hypothesis is that the combination of Leronlimab with an established ICI could yield a "quite substantial" benefit, a prediction rooted in the proposed mechanism of action and the TNBC data.In summary, the preliminary, small-sample Leronlimab mCRC data ($60\%$ ORR, $15.5$ months OS) is highly encouraging when compared to the initial IBI363 data ($13.6\%$ ORR, $16.1$ months OS). The true test will be the results of Leronlimab's ongoing Phase II combination trial in a larger, randomized setting.
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