Novel Bispecific therapies in oncology

Written By Paul Rennert

Lemmings

We wrote recently about the lemming phenomena with respect to the bispecific modality combining VEGF pathway inhibition plus PD-1 pathway inhibition¹. Our hope is not all the lemmings dive off the cliff, however we are not optimistic. 

This does not mean that VEGF pathway inhibition should not be exploited – this is obvious based on the synergy seen when approved VEGF pathway inhibitors are administered alongside approved PD-1 pathway inhibitors¹. Also, we see the BioNTech and Summit programs as advanced enough to avoid the cliff.

Similarly, we worry about the futility of combining TGF-β inhibition with PD-1 pathway inhibition in a bispecific or fusion protein format. The lead program here was bintrafusp alfa, now terminated. Our skepticism was based on our understanding of the biology of those pathways and informed by observations made by the Antonia lab, several Roche groups and others that TGF-β expression is sufficient to prevent T cell activation. Where TGF-β is present there is no or limited IFN-γ secretion by T cells and that means no PD-L1 expression within the tumor microenvironment, aka the TME. So, you cannot link antagonist targeting these two pathways together, at least in the TME². 

Less clear is whether we can productively and safely inhibit TGF-β activity at all given the toxicity issues associated with TGF-β inhibition. We recently viewed quite positive updates from Scholar Rock who have a TGF-β-1 antagonist in the clinic³. Conversely, Novartis recently terminated their (Xoma-derived) anti-TGF-β program⁴. The recent integrin inhibition program that was being developed by Pliant has not yet demonstrated a positive/risk benefit profile at least in pulmonary fibrosis⁵. 

It is certainly not encouraging that there are no presentations on Pliant’s bexotegrast program in either IPF or oncology left on the Pliant website (note here that specific integrins enable TGF-β release – that is the well-founded basis for their program). 

An emerging concept is to localize the inhibition of VEGF or the inhibition of TGF-β within the disease microenvironment, e.g. in the context of cancer and the TME. Such a strategy should limit any systemic toxicities associated with blocking those pathways. Here we look at several examples of these bispecific therapeutics.

Ficerafusp alfa

Bicara Therapeutics (BCAX) is developing ficerafusp alfa, a bispecific antibody that targets EGFR and TGF-β. Thus, rather than linking TGF-β inhibition to PD-L1 inhibition, this programs links TGF-β inhibition to tumor antigen expression. The critical question then becomes one of clinical translation – finding tumor types that are EGFR-positive and are believed to be immunosuppressed by TGF-β.

Bicara has focused ficerafusp alfa clinical development on head and neck squamous cell carcinoma (HNSCC), adding pembrolizumab to separately block the PD-1 pathway. Both EGFR inhibitors like cetuximab and PD-1 pathway inhibitors (pembrolizumab, nivolumab) induce responses in HNSSC. 

Interim data Phase 1/1b clinical trial data showed that combining ficerafusp alfa with pembrolizumab resulted in anti-tumor activity in patients with recurrent/metastatic HPV-negative HNSCC:

Based on these results, Bicara initiated a pivotal Phase 2/3 clinical trial named FORTIFI-HN01 that has just begun enrollment. This is a global, randomized, double-blind, placebo-controlled study to evaluate the efficacy of ficerafusp alfa plus pembrolizumab versus pembrolizumab alone as a first-line treatment for patients with HPV-negative population recurrent/metastatic HNSCC⁶. No chemotherapy regimen is used in the trial.

This design will set up an interest comparison to pembrolizumab plus chemotherapy as used in combination. Results from the Keynote-048 study in first-line HNSCC showed the following:

Therefore one comparative regimen to ficerafusp alfa plus pembrolizumab that is not being explored in the Bicara trial is the use of pembro plus chemo; however, the numbers may tell the tale regardless of active comparison⁷. Note one important difference in the trials is the inclusion of HPV-positive patients, which the Bicara trial will exclude. Another clinical program that has making headlines in HNSCC is petosemtamab, an anti-EGFR x LGR5 bispecific antibody.

In first-line NHSCC the ORR = 67% regardless of HPV status and regardless of PD-L1 expression⁸.

Back to Bicara: we see in ficerafusp alfa a clear example of the use of a TGFβ antagonist with no accumulation of unexpected toxicities and preliminary efficacy. Should this continue to be the case this may become a very exciting program.

Tovecimig 

The second interesting up-and-coming bispecific is from Compass Therapeutics (CMPX), the subject of recent upgrades by biotech analysts. 

Tovecimig is a bispecific antibody targeting DLL4 and VEGF-A. Here the activity of the anti-VEGF arm is biased to the tumor site where the antigen DLL4 is highly expressed. VEGF is a secreted protein present in solution, but is also bound to VEGF receptor R2-positive endothelial cells within the TME. Tovecimig demonstrated promising early clinical data in combination with the chemotherapy paclitaxel in biliary tract cancer (BTC). In a Phase 2 study of tovecimig + paclitaxel in second and third line BTC, the ORR was 37.5%, the median PFS = 9.4 months and the median OS = 12.5 months. The interest from analysts is driven by near-term readouts from the COMPANION-002 Phase 2/3 Study including ORR in March and median PFS later in 2025. Notably, data from diverse chemotherapy, regimens show median PFS values in the 5 to 8 month range median OS values anywhere from 6 to 17 months. Median PFS for  various immunotherapy approaches range from 4 - 9 months with median OS from 1 - 2 years.

Importantly, these upcoming results may support a class of assets in which VEGF inhibition is localized to the site of tumor antigen expression.

We feel obliged to point out that Compass has joined the PD-1xVEGF bispecific lemmings, per their latest pipeline – they may be well-positioned here vis-à-vis their VEGF expertise, but awfully late to the cliff.

Stay tuned.





Paul Rennert
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PD1 x VEGF bispecific landscape: examining Hope versus Hype.