Part 1 of 2
Pathways and targets covered: TGF-beta, PD-L1, PD-1, TIGIT
Companies mentioned: Merck KgaA, GSK, Roche, Merck, Mereo, iTeos, BMS, Arcus/Gilead, Compugen, Seagen, Beigene, Innovent, Agenus
Last week we had the bad news that Merck KGaA and GSK had thrown in the towel on bintrafusp alfa therapy for first-line advanced NSCLC. Bintrafusp alfa is an anti-PD-L1/TGFbR2 TRAP therapeutic designed to selectively antagonize TGF-beta isoforms 1 and 3 while also blocking PD-L1, thereby delivering two-for-one anti-immunosuppression. Bintrafusp alfa was being tested in a head-to-head trial vs. pembrolizumab and showed no added benefit in a patient population selected for PD-L1-high tumor expression (50%+ of cells in the tumor biopsy sample positive for expression).
This stirred up a fair amount of discussion, as TGF-beta blocking therapies are in vogue for immuno-oncology (IO), with small molecules, biologics, RNA-antagonists and genetic knockouts (in CAR T cells) all in the pipeline. I have high hopes for this space, despite the news out of Darmstadt. And to be fair, the press release stressed the ongoing bintrafusp alfa trials in bladder cancer, cervical cancer, and NSCLC using various drug combinations, and noted new trials in urothelial cancer and TNBC (https://www.emdgroup.com/en/news/bintrafusp-alfa-037-update-20-01-2021.html). Still, the failure stung, due mainly to the promise of the early (open label) Phase 1 expansion cohort data that had suggested significant benefit from the therapy.
This got me thinking about TIGIT, another hot IO target. The last time I wrote about TIGIT I ended with this question: “How to select patients who should respond to anti-TIGIT co-therapy (or anti-TIM-3 or anti-LAG-3)…?” (http://www.sugarconebiotech.com/?p=841). This is a question we should ask about any pathway – including TGF-beta of course – particularly as we are now in the post-immune-checkpoint era, that is, in a setting where many patients in the most IO-responsive indications like melanoma and NSCLC will have already been treated with an anti-PD-1 or anti-PD-L1. So, is there anything known about TIGIT expression that can guide us in patient (or indication) selection?
Roche leads the field with tiragolumab an anti-TIGIT Fc-competent IgG1 that has shown activity in combination with the anti-PD-L1 antibody atezolizumab in first-line NSCLC, and only in patients with PD-L1- expressing tumors (> 1% of cells in the tumor biopsy sample positive for expression). We can pause here to recall that this is about where we started the discussion above regarding the TGF-beta TRAP/anti-PD-L1 asset from Merck KGaA, being trialed in the PD-L1-high (>50%) setting in NSCLC.
In front-line NSCLC (EGFR and ALK wildtype), Roche reported responses higher than with atezolizumab alone. Data were shown at AACR and then updated at ASCO. Here are some of the ASCO data:
The response rate with dual therapy looks rather better than atezo alone, especially in the PD-L1 high cohort (middle panel). Atezo alone appears to have underperformed, with an ORR = 21% (left panel, all patient data (ITT)). In the comparable phase 3 trial of atezo vs chemotherapy in front-line NSCLC (also EGFR and ALK wildtype) the ORR = 38.3% in the atezo arm (n=285) and 28.6% in the chemotherapy arm (n=287), see nejm.org/doi/full/10.1056/NEJMoa1917346. Regardless the 66% response rate in the PD-L1-high cohort (middle panel) attracted attention.
The PFS data were also striking when compared to the prior trial. This is tiragolumab plus atezolizumab / PD-L1 high cohort:
We can go back and compare this to the atezo alone Phase 3 interim data shown at ESMO in 2019 (I was stuck in the overflow “room” which was a curtained space on the floor of the Barcelona convention center). This is the PD-L1-high cohort:
Here the median PFS is 8 months, certainly shorter than what is shown for tiragolumab plus atezolizumab, but again, note the disparity with the atezo alone arm of the study (medPFS for = 4 months).
Just to be clear, here are the PD-L1-high patient data compared:
We’re left with the always troubling question of variability between trials and the possibility that the tiragolumab plus atezolizumab results are a fluke. Unfortunately, we will have to wait and see.
There are two features here worth noting. One is that TIGIT, the target, is expressed on T cells, along with PD-1. So far this makes sense – they might very well synergize, particularly given the function of DNAM-1 in the context of T cell signaling (see part 2). But the anti-TIGIT antibody is an IgG1 isotype, thought to trigger ADCC and CDC-mediated target cell (ie. the T cell) death. But we want the T cells, that’s the whole point of blocking PD-L1 with atezo. So what the heck is going on here?
Merck seems to have an answer, but first, some more data. Merck’s anti-TIGIT antibody, vibostolimab, like Roche’s tiragolumab, is a wildtype IgG1. Early data on the combination of vibostolimab and pembrolizumab (anti-PD-1), presented at ESMO2020, looked promising in immune checkpoint naïve patients (75% had prior chemotherapy, the rest were treatment naïve):
We can benchmark these results to monotherapy, just as we did with the Roche data, focusing on the PD-L1-positive subset (here we can see data using a cutoff of >1% or >50% of cells positive in the tumor biopsy):
The results compare favorably with pembro-alone using the >1% PD-L1 cutoff and are similar to pembro-alone using the >50% PD-L1 cutoff. As usual it is difficult to compare between trials, but the signal is encouraging.
Preclinically, Merck has addressed the MOA, stressing the requirement for the intact Fc functionality imparted by the IgG1 antibody isotype. As mentioned earlier, the mechanistic puzzle is that canonical IgG1 activity includes the triggering of target cell killing via ADCC and CDC mediated cytotoxicity. Of course, TIGIT is expressed on the very T cells we want to preserve and activate, not kill. Given this reality we need alternate hypotheses for the action of the IgG1 antibodies. The predominant hypothesis is that anti-TIGIT antibodies are selectively depleting T-regulatory cells that are TIGIT-bright and immunosuppressive. This is reminiscent of the now-T-regulatory cells that are TIGIT-bright and immunosuppressive. It’s an easy hypothesis to advance, similar to the now-debunked arguments made on behalf of anti-CTLA4 and anti-GITR antibodies, and very likely incorrect.
Merck has demonstrated in preclinical models that antagonistic anti-TIGIT antibodies having a FcgR-engaging isotype induce strong anti-tumor efficacy whereas anti-tumor activity is drastically reduced when using the same anti-TIGIT antibodies that are null for FcgR-engagement (doi: 10.3389/fimmu.2020.573405). These results are consistent with data presented by multiple groups, eg. Mereo and iTeos. The Merck team further showed shown that FcgR engagement persistently activated myeloid lineage antigen-representing cells APCs, including the induction of proinflammatory cytokines and chemokines while TIGIT blockade simultaneously enhanced T cell activation including elevated secretion of granzyme B and perforin, which synergizes with anti-PD-1 antagonism. I favor this hypothesis. Nb. This suggests we’ve a lot to learn still about the best way to engage Fcg receptors, a theme I introduced in the last post (link).
Where does this hypothesis leave everyone else in the TIGIT space? Let’s line them up:
A few quick notes: EMD Serono/Merck KGaA and Innovent have anti-TIGIT programs without disclosed isotype information; Arcus has disclosed a second, Fc-competent, anti-TIGIT program (AB308); Agenus is developing both IgG1 and IgG4 anti-TIGIT antibodies.
A question: is Seagen’s hyper-killing IgG1 a step too far?
In summary, we have preliminary data in NSCLC that suggest that anti-TIGIT may synergize with anti-PD-1 or anti-PD-L1 therapies, consistent with the expression of TIGIT on PD-1 positive (ie. activated) T cells. We have several hypotheses addressing the Fc-end of the therapeutics, and some information on why blocking TIGIT may enhance T cell responses.
Other than selecting patients with PD-L1-positive tumors, can we gate on TIGIT expression? Apparently not, at least not in NSCLC, as just reported at the World Conference on Lung Cancer (abstract P77.02 – Efficacy of Tiragolumab + Atezolizumab in PD-L1 IHC and TIGIT Subgroups in the Phase II CITYSCAPE Study in First-Line NSCLC).
Here’s their text:
“Among the 135 enrolled patients with PD-L1-positive NSCLC (intent-to-treat [ITT] population), 113 had results from the SP263 assay and 105 had results from the TIGIT assay. The biomarker-evaluable populations (BEP) for both of these assays were similar to the ITT population. Comparable PFS improvement with tira + atezo relative to atezo monotherapy was seen in PD-L1–high (≥50% TC) subgroups defined by SP263 (PFS HR 0.23, 95% CI: 0.10–0.53) when compared with PD-L1-high subgroups defined by 22C3. However, for patients whose tumors were defined as TIGIT-high (≥5% IC), no strong association with PFS improvement was observed.
|Biomarker subgroup||Subgroup, n (BEP, N)||PFS HR (CI) relative to atezo monotherapy arm|
|ITT (PD-L1 IHC 22C3 >1% TPS)||135 (135)||0.58 (0.39–0.88)|
|PD-L1 IHC 22C3 (≥50% TPS)||58 (135)||0.30* (0.15–0.61)|
|PD-L1 IHC SP263 (≥50% TC)||45 (113)||0.23* (0.10–0.53)|
|TIGIT IHC (≥5% IC)||49 (105)||0.62* (0.30–1.32)|
Prevalence of PD-L1 subgroups in the BEP was comparable with previous reports for both IHC assays. The PFS benefit observed with tira + atezo in patients with tumors defined as PD-L1-high by 22C3 was also observed using the SP263 IHC assay, but not in tumors classified as TIGIT-high using an exploratory TIGIT IHC assay. Our results suggest that PD-L1 expression, assessed by 22C3 or SP263, may be a biomarker for tira + atezo combination therapy in metastatic PD-L1-positive untreated NSCLC.”
So that the answer to the question we started with, can we pick patients, is ‘no’ for TIGIT expression, at least in this indication.
Regardless, to actually understand what blocking TIGIT does, we need to better understand the pathway.
That will be discussed in Part 2, coming soon.