AstraZeneca's monovalent bispecific antibody, MEDI5752, targeting PD-1 and CTLA-4, induces clinical benefit, but is limited by safety concerns
Sep 12, 2022 | DelveInsight
Lung cancer is the leading cause of cancer death in the United States. In several studies it was also found that only about 26% of all patients with NSCLC are alive ≥5 years after the diagnosis. The 5-year relative survival rate for metastatic disease is approximately 6% when patients receive historic cytotoxic chemotherapy regimens. However, certain patients with metastatic NSCLC who are eligible for newer targeted therapies or immunotherapies are now surviving longer, with 5-year survival rates ranging from 15% to 50%, depending on the biomarker. Also, medical treatment of advanced NSCLC has improved over the last two decades, with the main increase in the number of active drugs, the development of effective regimens, and the introduction of salvage therapy after failure of the first-line treatment.
MEDI5752, which is a bispecific antibody blocking PD-1/CTLA-4 demonstrated beneficial results in the phase Ib/II study (NCT03530397). The randomized cohort of the trial included MEDI5752 (1500mg) in combination with chemotherapy (CTx) compared with pembrolizumab in combination with CTx, while the single-arm cohort evaluated MEDI5752 (750mg). After a median follow-up of 22.8 months and 14.5 months for the MEDI5752 and pembrolizumab arms, the objective response rate (ORR) was found to be 50% vs. 47.6% in MEDI5752 vs pembrolizumab arm. The Disease control rate was observed at 85% vs. 95% in MEDI5752 and pembrolizumab arm. The median duration of response (DoR) was more than double in the MEDI5752 arm compared with the pembrolizumab arm with 20.5 months in the MEDI5752 arm and 9.9 months in the pembrolizumab arm. Median progression-free survival (PFS) was also almost double with 15.1 months in the MEDI5752 arm vs only 8.9 months in the pembrolizumab arm, while the median overall survival (OS) was yet not reached in the MEDI5752 arm while it was 16.5 months in the pembrolizumab arm.
At a 750 mg dose, with a median follow-up of ∼3.9 months, MEDI5752 plus chemotherapy showed an ORR of 44% in ITT and 48% in PD-L1<1%.
|
Efficacy (Data cut-off 12 July 2022) |
MEDI5752 plus chemotherapy (1500 mg); ITT, n=20 (PD-L1<1%, n=9) |
Pembrolizumab plus Chemo ITT, n=21 (PD-L1<1%, n=10) |
|
Median follow-up, months |
22.8 |
14.5 |
|
Objective response rate (ORR), % (95% CI) |
50.0 (27.2–72.8) |
47.6 (25.7–70.2) |
|
ORR in PD-L1<1% |
55.6 (21.2–86.3) |
30.0 (6.7–65.2) |
|
Median duration of response (mDOR), in months (95% CI) |
20.5 (4.1–NE) |
9.9 (2.8–NE) |
|
mDOR in PD-L1<1% |
13.8 (4.4–NE) |
NR (4.3–NE) |
|
Median progression-free survival (mPFS), in months (95% CI) |
15.1 (5.5–NE) |
8.9 (4.2–15.0) |
|
mPFS in PD-L1<1% |
13.4 (4.0–NE) |
9.0 (1.4–15.0) |
|
Median overall survival (OS), in months (95% CI) |
NR (16.4–NE) |
16.5 (12.8–NE) |
Sixteen patients (80.0%) in the experimental arm were current or former smokers compared with 90.5% in the control arm. All patients in the MEDI5752 arm and 90.5% in the pembrolizumab arm had stage IV disease. In terms of safety, around 70% of patients in the 1500 mg group discontinued the treatment compared with only 28.6% of patients in the pembrolizumab arm and 20% in the 750 mg arm group. Around 80% of the patients in the high-dose group experienced grade¾ treatment-related adverse events compared with 61.9% in the pembrolizumab arm and 50% in the 750mg arm group.
Conclusion- CTLA-4 has been a not so easy to catch target for AstraZeneca and many others. BMS’s Yervoy (ipilimumab) is the first and the only approved CTLA-4 checkpoint inhibitor. AstraZeneca’s tremelimumab is pending an FDA decision before the end of this year in liver cancer. The results which were presented at ESMO 2022 were shown to have a very good efficacy profile mainly concerning the duration of response and progression-free survival. Although MEDI5752 plus chemotherapy showed a better response rate at the 1500-mg dose, it was just comparable with pembrolizumab plus chemotherapy (50.0% vs. 47.6%). On the safety front, it was observed that a large number of patients (around 70%) led to discontinuation of the drug while only 20% of patients led to discontinuation of the drug in the 750mg arm group. Although the 1500mg arm group showed improved efficacy with very high toxicity and discontinuation rate, the drug does not improve much on the existing safety terms of the previously approved regimen. So, for evaluating the safety of the drug longer follow-up is needed.
Expert Opinion: “We know that the more you dose a CTLA-4 inhibitor, the higher the efficacy gets, of course, the limiting factor has been the safety profile, and that means that you’ve been limited in the efficacy that you can achieve in that inhibition to doses that can be tolerable.”
For more insights: Small cell lung cancer (SCLC) Market, Prostate cancer Market, Ovarian cancer Market, Mesothelioma Market, Extensive-stage SCLC Market
