Roche’s First Anti-TIGIT Data Support Dual Checkpoint Inhibition Strategy
Executive Summary
Tiragolumab plus Tecentriq increased response rates versus Tecentriq alone in a Phase II study, with the greatest benefit in PD-L1-high NSCLC. The combination regimen already is being test in Phase III.
The first public data disclosure for Roche’s anti-TIGIT antibody tiragolumab in combination with the company’s PD-L1 inhibitor Tecentriq (atezolizumab) in first-line metastatic non-small cell lung cancer (NSCLC) showed improved response rates versus Tecentriq alone – including a notable improvement in high PD-L1-expressing tumors – and without adding significant toxicity.
The dual checkpoint inhibitor strategy could give Roche’s Tecentriq a critical boost in PD-1/L1 market share before competing combinations reach the market, since analysts estimate that other anti-TIGIT antibodies are at least a year behind. Data from the Phase II CITYSCAPE clinical trial, which will be presented during the American Society of Clinical Oncology (ASCO) virtual meeting at the end of May, supported Roche’s decision to move the tiragolumab/Tecentriq combination into two ongoing Phase III trials in NSCLC and small cell lung cancer (SCLC).
TIGIT (T-cell immunoglobulin and ITIM domain protein) is a protein receptor on immune cells that acts as an immune checkpoint. Scientists at Roche subsidiary Genentech Inc. discovered the immuno-oncology drug target and developed tiragolumab to bind with TIGIT, blocking its interaction with the poliovirus receptor, a protein that can suppress the body’s immune response. Blocking TIGIT and PD-L1 together may reactivate T-cells and enhance natural killer (NK) cells’ antitumor activity.
Alan Sandler, Genentech senior vice president of oncology product development for solid tumor therapies, told Scrip the goal was to create a “double-teaming” effect that could boost responses to checkpoint inhibitor therapy. And with the CITYSCAPE data, he said, “we have clear-cut evidence that the hypothesis of combining this checkpoint blockade provides a clinical benefit to patients.”
Doubling And Tripling ORR Versus Tecentriq Alone
An ASCO abstract released on 13 May for the Phase II CITYSCAPE study showed an overall response rate (ORR) of 31.3% for tiragolumab and Tecentriq versus 16.2% for Tecentriq alone in the intent-to-treat (ITT) group of previously untreated NSCLC patients with PD-L1 expression of 1% or more, as of 30 June 2019 with a median follow-up of 5.9 months.
There was a 43% reduction in the risk of disease worsening or death in the ITT group (HR=0.57) and a 1.8-month improvement in progression-free survival, with median PFS of 5.4 months in the combination arm of the study and 3.6 months in the Tecentriq-only arm. ORR and PFS are the co-primary endpoints in CITYSCAPE, with safety and overall survival as secondary endpoints.
The ORR in patients with PD-L1 expression of 50% or more was 55.2% for tiragolumab plus Tecentriq versus 17.2% for Tecentriq alone with a 67% reduction in the risk of disease worsening or death (HR=0.33). PFS was not reached in the combination arm of the study compared with a median of 3.9 months in the monotherapy arm.
Biomedtracker analysts, in a pre-ASCO report published on 13 May, described the CITYSCAPE results as “encouraging,” noting the “meaningfully higher” response rates for high PD-L1 expressers treated with the dual checkpoint inhibitor approach. Tiragolumab plus Tecentriq are “likely be positioned to compete with both Tecentriq and [Merck & Co. Inc.’s PD-1 inhibitor] Keytruda monotherapy, which are typically used in patients who cannot tolerate the combination of chemotherapy and a checkpoint inhibitor.”
Roche and Genentech also shared results on 13 May based on six months of additional follow-up that showed responses were maintained over the longer period. The ORR in the ITT group was 37.3% with tiragolumab and Tecentriq versus 20.6% for Tecentriq alone with median PFS of 5.6 months versus 3.9 months with the longer-term follow-up. Results in the PD-L1 high group were described as consistent with the primary analysis, with Roche and Genentech noting that median PFS still was not reached in the tiragolumab/Tecentriq group.
Wolfe Research analyst Tim Anderson noted that the combination’s benefit “is exclusive to PD-L1 high expressers (roughly a third of 1L NSCLC patients) where results are quite impressive, suggesting tiragolumab plus Tecentriq (or other anti-PDx therapies, off label) will likely become standard of care in this segment of the market, assuming the Phase III study replicates Phase II.”
Merck, whose Keytruda (pembrolizumab) is the top-selling PD-1/L1 inhibitor globally, also has an anti-TIGIT candidate, but Anderson noted that it is about a year behind the tiragolumab.
Safety Adds To Anti-TIGIT’s Efficacy Profile
“Roche released strong tiragolumab Phase II data in first-line NSCLC in combination with Tecentriq that reduced the risk of progression or death by 67% in patients with high levels of PDL1 expression versus Tecentriq alone. Also, tiragolumab didn’t appear to add safety concerns,” Morningstar analyst Damien Conover commented in a 14 May note.
“While the data needs to be confirmed in Phase III studies (data likely in 2022) and the monotherapy benefit of Tecentriq was unusually low (setting up a potentially stronger relative performance for tiragolumab), we still believe the data is strong enough to support an increase in our assumed market share for Roche in non-squamous NSCLC to 32% (from 22%) by 2025 largely at the expense of Merck (share falling to 54% from 64%),” Conover continued.
In terms of safety at the primary analysis, the rate of treatment-related adverse events (TRAEs) of any kind was 80.6% for tiragolumab plus Tecentriq and 72% for Tecentriq alone, while rates of grade 3 and higher TRAEs were 14.9% for dual checkpoint inhibition and 19.1% for PD-L1 inhibition alone.
The rates of all grade 3 or higher adverse events were 41.8% for tiragolumab and Tecentriq versus 44.1% for Tecentriq alone while 7.5% of patients treated with the combination regimen discontinued treatment due to grade 3 or higher adverse events versus 10.3% treated only with Tecentriq.
No new safety findings were identified with six months of additional follow-up.
The Phase II data presentation at the ASCO virtual meeting will precede the first glimpse of data from Roche’s Phase I study of the dual checkpoint inhibitor regimen across a range of solid tumors. Those results would have been presented at the American Association for Cancer Research (AACR) annual meeting in April, but when AACR cancelled its in-person conference due to the COVID-19 pandemic it split the presentations into two online sessions, the first of which occurred at the end of April, while the second is scheduled for 22-24 June.
The Phase I study of tiragolumab alone and in combinations with Tecentriq, with or without monotherapy, supported the initiation of the Phase II CITYSCAPE study in NSCLC and the ongoing Phase II SKYSCRAPER-4 study of tiragolumab plus Tecentriq in PD-L1-positive metastatic and/or recurrent cervical cancer.
The Phase III SKYSCRAPER-1 study is testing Tecentriq plus tiragolumab in previously untreated locally advanced unresectable or metastatic NSCLC, while the Phase III SKYSCRAPER-2 study is evaluating Tecentriq plus chemotherapy with or without tiragolumab in previously untreated extensive-stage SCLC.
Combined Efficacy, Safety Show Differentiated IO-IO Combo
“The [CITYSCAPE] results encourage a push into tumor types where PD-L1 expression plays a role,” Wolfe’s Anderson concluded. “Already underway is a mid-sized trial (possibly registrational, given its size) in cervical cancer, and more trials will likely follow in settings such as head and neck cancer, bladder cancer and more. In this sense, tiragolumab brings to Roche a new, novel IO platform that can be expandable in multiple ways.”
For Roche, he noted, tiragolumab is a second-generation immuno-oncology (IO) agent “that will finally likely make it to the finish line after a lot of false starts across the industry and it has the potential to begin re-shaping the IO landscape as we know it. Second, it makes anti-PDx therapies better (at least in high expressers), which by themselves are already a paradigm shift in how many different cancers are managed. And third, Roche is ahead of competitors, and similar to the anti-PDx space, order of entry will matter.”
Sandler explained that the first wave of Roche’s IO strategy was to look at single-agent Tecentriq’s activity then combine it with chemotherapy and targeted agents in the second wave, which then led to the current third wave of combining Tecentriq with another immunotherapy agent without chemotherapy. The final element is finding the precise treatments that match patients with the best combination therapy for their cancers without having to go through chemotherapy, he said, which makes the lack of added toxicity when combining tiragolumab with Tecentriq all the more important.
Anderson noted that the good safety profile of tiragolumab is a valuable attribute for Roche’s dual checkpoint inhibitor regimen, because it contrasts with the first-generation dual checkpoint combination of Bristol Myers Squibb’s PD-inhibitor Opdivo (nivolumab) with the company’s CTLA-4 inhibitor Yervoy (ipilimumab), which adds efficacy with much greater side effects. (Also see "Checkpoint Inhibitor Deals: Searching For IO Combinations To Unlock Cancer’s Black Box" - In Vivo, 4 Mar, 2020.)
However, the push for new IO-IO combinations has not been as fruitful as hoped. The combination of indoleamine 2,3-dioxygenase (IDO) inhibitors with anti-PD-1/PD-L1 antibodies had initial promise, but ultimately flamed out in 2018. (Also see "A Wake For IDO: Bristol Ends Registrational Trials Of High-Priced Flexus Drug" - Scrip, 30 Apr, 2018.) While companies continue to chase PD-1/PD-L1 combinations with therapies targeting interleukin-2 (IL-2), early results have not always lived up to high hopes. (Also see "A Plea For Patience: Bristol/Nektar's Opdivo/NKTR-214 Combo Responses Deepen Over Time" - Scrip, 3 Jun, 2018.)