Colorectal Cancer Highlights: ASCO 2021

DelveInsight has hand-picked major abstracts from the plethora presented at ASCO21 Day2 focusing on Colorectal Cancer. Read on and stay up to date with the latest happenings at ASCO21. 

Abstract #3564: Encouraging results from LEAP-005 study evaluating Keytruda–Lenvima combination in previously treated Non-MSI-High/pMMR CRC patients

This Friday marked the beginning of ASCO 2021, with major key players such as Merck, Amgen, AstraZeneca and Eisai. The companies are all set to present the updated findings from their lead candidates targeting oncologic indications, including CRC. On 4th June 2021, Merck, in collaboration with Eisai presented recent findings from LEAP-005 (NCT03797326) study evaluating the efficacy and safety of Lenvima- Keytruda Combination in patients with previously treated advanced solid tumor– CRC cohort.

Results showed that the ORR—the primary endpoint of the study—was 22%, all of which were partial responses. 25 percent of the patients experienced SD, while 38% experienced PD. The median duration of response was not reached. 6 month PFS was 31%, and estimated 6 month OS was 62%. There were only one or more TRAEs with only 47% with Grade 3 and 4 TRAE. There was one fatal TRAE. Additionally, based on the findings, the trial size has been expanded from 32 patients to 100 for CRC cohort.

Expert ViewsPatients with previously treated advanced non-MSI-high or (proficient mismatch repair) colorectal cancer, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile.”

Apart from CRC, the companies have jointly initiated new clinical studies through the LEAP (LEnvatinib And Pembrolizumab) clinical program and are evaluating the combination in 13 different tumor types (melanoma, endometrial carcinoma, HCC, NSCLC, RCC, and others) across more than 20 clinical trials. Recently, the combination has been granted priority review by FDA in May 2021 in both advanced RCC and advanced endometrial carcinoma. Thus, it can be concluded that the pembrolizumab combined with lenvatinib may offer some hope for patients in this setting.

*SD= Stable disease, PD= Progressive disease, OS= Overall survival, PFS= Progression free survival, CR= Complete response, PD= Partial response, TRAE= treatment-related adverse event, AE= Adverse events

Abstract #3584: Evaluation of Merck’s anti-LAG-3 antibody, MK4280 (favezelimab) in combination with its blockbuster PD-1, Pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer

Big pharmaceutical companies have recently noticed LAG-3 as a novel target in oncology which is expressed in some of the tumour types. Merck, one of them, has brought its anti-LAG-3 antibody MK4280 (favezelimab) to investigate it both as monotherapy and in combination with its own lead candidate Keytruda in previously treated, advanced microsatellite stable colorectal cancer. Recently, the company presented data from this first-in-human phase Ib trial at ASCO 2021 annual meeting, which demonstrated potent activity in the same target pool.

The study enrolled 20 patients in the favezelimab arm (mono) and 80 patients in the favezelimab + pembrolizumab arm (combo). More than 85 percent of the patients have received ≥3 prior lines of therapy in the mono arm and 72.5% in the combo arm. 60 percent of the patients had PDL1 CPS ≥ 1 in the mono arm vs 45% in the combo arm. The cut-off data date of the study was October 2020.

The early efficacy results from the study were evaluated in the combo arm and were categorised on the basis of combined positive score of (CPS) of PDL1 expression, which showed that the overall response rate was 11% in the patients who had tumours with PD-L1 CPS ≥1 and 2.9% in patients with PD-L1 CPS <1 tumours. For patients with PD-L1 CPS ≥1, complete response (CR) and partial response (PR) rates were 2.8% and 8.3%, respectively; however, there was no CR observed in patients with PD-L1 CPS <1 and had PR of 2.9%. The former had a disease control rate (DCR) of 36.1%, and the latter showed a DCR of 14.3%. The median duration of response observed for both cohorts was 10.6 months. Median Progression-free survival (mPFS) and median overall survival (mOS) were also seen in total patients and in patients categorised on PDL1 scores. mPFS for the entire population was 2.1 months and consistent with the PDL1 population. PFs rate observed at 12 months was 7% for the entire population and 12% for the patients with PDL1 CPS ≥1. The overall survival was evaluated in terms of mOS and was highest in patients with PDL1 CPS ≥ 1 (12.7 months) and was lowest in patients with PD-L1 CPS <1 (6.7 months). The 12-month OS rate was 41% for the entire cohort and 51% for the patients with PDL1 CPS ≥1. The safety results showed that the treatment-related adverse events (TRAEs) were observed in 65% with the mono arm and 65.2% with the combo arm. 

Expert Views: “The data is limited, but it does look like PD-L1 staining is predictive for efficacy in this combination. Like any biomarker, it’s not perfect, but I think it identifies a patient population that is more likely to benefit from this treatment. It will come in handy down the line when Merck starts designing registrational studies for the combination”

INSIGHTS: The early study results demonstrated a manageable safety profile in the mono and combo arm with promising anti-tumour activity in the combo arm, notably in patients with PDL1 CPS ≥1. Since there is a high unmet need for the previously treated patients who had progressed on more than two prior lines of therapy, this combination strategy could provide some clinical benefits with a reasonable safety profile. However, the results are too early to predict anything; the later clinical study would be helpful to provide the actual benefits in patients.

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