Lung Cancer | Pancreatic Cancer | Prostate Cancer

Poster 620P: MGC018, an Anti-B7-H3 Antibody-Drug Conjugate (ADC), in Patients with advanced solid tumors: preliminary results of phase I cohort expansion

With the ESMO 2021 congress running around, the oncologists, pharmaceutical companies and the patients are so excited to embrace the new advancements in oncology. Day 1 of ESMO 2021 marked a good kick start to the conference where companies such Macrogenics, Zymeworks, Leap therapeutics and others presented the updated results from their clinical trials. Macrogenics, being one of them presented the early results from the study evaluating MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in multiple solid tumors, including prostate cancer, non–small cell lung cancer (NSCLC).

The company has still not lost its hopes for the asset even after the implementation of the clinical hold on one of its previous assets, orlotamab (MGD009), a B7-H3 × CD3 bispecific DART molecule, by the US FDA in December 2018. The partial clinical hold was initiated following MacroGenics’ reporting of hepatic adverse events on the MGD009 monotherapy trial to the FDA.

Macrogenics’ another asset, enoblituzumab, a B7-H3–targeting antibody, was withdrawn before the starting of its phase II/III trial in combination with anti-PD-1 MAb, retifanlimab. However, it is still being investigated in a new phase II study in the head and neck indication that pairs enoblituzumab either with retifanlimab or with tebotelimab, an anti-PD-1/Lag-3 bispecific. With all these efforts for B7-H3 molecules, it is clear that enoblituzumab is not dead, but it seems that Macrogenics is increasingly pinning its B7-H3 hopes on MGC018. The phase I MGC018 trial (NCT03729596) also tests a retifanlimab combo, but for now the focus is on monotherapy.

The previous results presented at the ASCO 2020 conference showed that patients with >50% prostate-specific antigen (PSA) reduction in metastatic castration-resistant prostate cancer (mCRPC) cohort. At ESMO 2021, the company decided to present the updated results from the mCRPC and the NSCLC cohorts. As of August 16, 2021, a total of 32 treated patients had first 9-week imaging and were evaluable for tumor response (mCRPC, n=16; NSCLC, n=16). Best overall response rates were 25% in both the mCRPC and the NSCLC cohorts. In the CRPC cohort, 53.8% had reductions in PSA from baseline of more than 50%. Out of all enrolled patients (86) in the expansion cohorts, grade ≥3 treatment emergent adverse events were observed in 55.8% of the patients. The results concluded that the study demonstrated a manageable safety profile with a low rate of treatment discontinuation due to AEs (6 of 86 patients in the expansion cohort to date).

INSIGHTS: As B7-homolog 3 (B7-H3) is highly expressed in multiple solid tumors, including prostate cancer, non–small cell lung cancer (NSCLC), the company is quite optimistic with the early study results even after the implementation of partial hold on its previous asset orlotamab targeting the same biomarker. As per the Delveinsight’s analysis, it would be quite early to comment anything about the future of asset as we believe that more upcoming data is still required from the study. Another candidate from the same platform is Daiichi’s DS-7300 which is also going to present the early data of the asset in patients with advanced solid tumors. Let us now wait to see which clinical asset would have more clinical benefit over the other, where we have no approved assets for this targetable biomarker.

Poster 538P: Nadunolimab (CAN04), a first-in-class monoclonal antibody against IL1RAP, in combination with chemotherapy in subjects with pancreatic cancer (PDAC) and non-small cell lung cancer (NSCLC)

The emergence of novel targets in cancer have always a hot topic in oncology. Since last two decades, cancer has seen much growth related to discovery of new targets every now and then and all the credits for these advancements should be owed to researchers and oncologists who had always pushed themselves beyond limits to improvise the lives of the patients. At the medical oncology conferences, the oncologists and the researchers present data from their clinical trials which decides the fate of clinical assets in the global market. At the ongoing ESMO 2021 medical conference, many companies presented the phase I data from their clinical trials which showed early significant clinical efficacies of the assets.

One such data readout was presented by Cantargia for its clinical asset, CAN04 (nadunolimab), an IgG1 antibody that targets IL1RAP and blocks IL-1α and IL-1β signaling. The company presented the interim efficacy and safety results of CAN04 in combination with gemcitabine/nab-paclitaxel in first-line pancreatic ductal adenocarcinoma (PDAC) and with gemcitabine/cisplatin in first-line non-small cell lung cancer (NSCLC) from the CANFOUR, a phase I/IIa study (NCT03267316).

The study enrolled 36 and 31 patients in the PDAC and NSCLC cohorts respectively. In the PDAC cohort, 27% of the patients achieved objective response rate (ORR) with a disease control rate of (DCR) 72%. The median duration of response (DoR) was 6.8 months with the median overall survival (mOS) of 12.6 months and 6-month survival rate of 71% and 1-year survival rate 55%. Median progression-free survival (mPFS) iPFS was 7.8 months with 6 months iPFS rate of 62% and 19% at 1 year. For non-squamous NSCLC, 75% of patients post-pembrolizumab achieved response, versus 25% of squamous NSCLC patients. In the overall NSCLC cohort, 48% of the patients achieved the ORR with 85% DCR. The median progression-free survival (mPFS) PFS was 7.2 months with 6-month PFS of 75% and 1-year PFS of 14%. Grade ≥3 adverse events occurred in 92% and 74% in the PDAC and NSCLC cohorts respectively.

Expert Oipinion: “We are happy to present these updated positive clinical results at one of the major clinical oncology conferences. The results strongly support our development strategies for nadunolimab to increase efficacy with chemotherapy in both NSCLC and PDAC and provide valuable information on patients most likely to benefit. We are grateful to the patients and clinical centers participating in the trial, and their extra-ordinary contributions during the COVID-19 pandemic”.

INSIGHTS: The study demonstrated that in the NSCLC cohort, trends showed more pronounced effects in non-squamous histology. Moreover, non-squamous NSCLC patients pretreated with pembrolizumab showed the greatest response benefit. These data support the continued development of nadunolimab in NSCLC; combination therapy with the cytotoxic drugs in patients with non-squamous NSCLC showing progression after immunotherapy. As per DelveInsight’s analysis, the company might move forward with the non-squamous NSCLC to investigate further safety and efficacy of the drug candidate which might help the company to move forward with further clinical developmental phase.

Poster #983P - Phase I dose escalation study in patients with advanced solid tumors receiving first-in-class BI 765063, a SIRPα inhibitor, in combination with ezabenlimab (BI 754091), a PD-1 inhibitor.

On the first day of ESMO 2021, OSE Immunotherapeutics presented data from its ongoing phase I clinical trial of BI 765063, a first-in-class selective signal-regulatory protein α (SIRPα) inhibitor, alone and in combination with ezabenlimab (BI 754091), a programmed cell death protein 1 (PD-1) inhibitor. The trial is being conducted by OSE Immunotherapeutics as part of a collaboration and license agreement with Boehringer Ingelheim, which has exclusive rights to BI 765063. The phase I trial is being conducted in two steps: Step 1 is the dose escalation phase and Step 2 is the expansion phase.

The poster presentation included data readout with a cutoff month of June 2021. The presented results demonstrated that the combination of BI 765063 with BI745091 was well tolerated with no dose-limiting toxicities. However, the maximum tolerated dose was not reached. The early efficacy was promising and three partial responses in patients with microsatellite stable (MSS) advanced endometrium or colorectal cancer was observed. Moreover, the recommended dose for Phase II trial and dosing schedule of BI 765063 was determined as 24 mg/kg with full receptor occupancy using a once every three weeks dosing schedule.

Expert opinion: “The data presented at ASCO in June and now at ESMO are very interesting as they show early evidence of clinical efficacy of BI 765063 combined with anti-PD-1, BI 754091 in patients with MSS tumors for which anti-PD-1 in monotherapy have shown limited activity and whose medical need is very strong. Based on these Phase I escalation dose promising results, we look forward advancing the trial’s expansion phase to confirm the potential of a combination approach as a relevant therapeutic strategy in solid tumors.”

Insights: Recently, SIRPα has come up as an important innate immune checkpoint that can be targeted for treating various oncology indications and has therefore, caught the eye of major companies focusing on developing therapies for oncology, OSE Immunotherapeutics being one of them. The company had previously presented data at the ASCO 2021 meeting, which demonstrated that BI 765063 was well tolerated with a durable partial response observed in an advanced hepatocellular carcinoma patients in particular. The updated results presented in ESMO 2021 have also been promising, which shows the potential of the therapy for advanced solid tumors. The company is also planning to move forward with the development of the drug and is currently recruiting MSS advanced colorectal and advanced endometrium cancer patients for the expansion of Phase I trial. Therefore, it might emerge as a key player in the pipeline for advanced solid tumors in the future, which also includes other key players like Novartis (NIR178), Celgene (CC-95251), and others.