NEW YORK – The combination of two Roche drugs, the investigational TIGIT-targeting monoclonal antibody tiragolumab and the anti-PD-L1 drug atezolizumab (Tecentriq), demonstrated preliminary activity in PD-L1-positive solid tumors, particularly non-small cell lung cancer.
The data presented from a Phase Ia/Ib trial by Sarah Cannon Research Institute's Johanna Bendell at the second virtual session of the American Association for Cancer Research's annual meeting laid the groundwork for the recently presented Phase II CITYSCAPE study in first-line, PD-L1-positive, metastatic NSCLC. That data released earlier this month at the American Society of Clinical Oncology's virtual annual meeting found in an exploratory analysis that 66 percent of metastatic NSCLC patients with a PD-L1 score of at least 50 percent saw their tumors shrink on tiragolumab-atezolizumab compared to 24 percent on just atezolizumab.
TIGIT is a receptor expressed on T cells and natural killer cells. When TIGIT binds to the PVR protein on tumor cells and antigen-expressing cells, it allows cancers to evade an immune system attack. Tiragolumab is designed to block this interaction between TIGIT on immune cells and PVR on tumor cells, enabling an immune response.
Another mechanism by which cancer cells evade an immune system attack is by linking PD-L1 receptors on the tumor cell surface with PD-1 receptors on T cells. Atezolizumab targets PD-L1 on cancer cells and blocks them from joining up with PD-1 receptors on T cells. Since TIGIT is co-expressed with PD-1 on T cells and NK cells, researchers have hypothesized that the combination of an anti-TIGIT antibody and an anti-PD-L1 drug may be particularly effective in firing up the immune system against cancer cells.
Bendell noted in a presentation during the AACR virtual meeting that ahead of launching the Phase Ia/Ib trial, preclinical mouse models had also shown antitumor activity with the combination of tiragolumab-atezolizumab but not with the anti-TIGIT antibody alone.
This preclinical finding was further tested clinically in order to identify the maximum tolerated dose for tiragolumab for Phase II trials. Phase Ia included patients with advanced solid tumors who were given escalating doses of tiragolumab, and Phase Ib involved patients who got the tiragolumab-atezolizumab combination. Researchers were also tracking the preliminary safety, tolerability, and efficacy of tiragolumab and the combination regimen.
The study participants received increasing doses of tiragolumab in both Phase Ia and Phase Ib, as well as a fixed dose of atezolizumab in Phase Ib. Patients continued on the study until their cancers progressed, they could no longer tolerate the treatment toxicities, or they or their physicians decided to discontinue on the study. Based on the clinical activity in the Phase Ib portion, researchers opened dose expansion cohorts using the 400 mg and 600 mg dose for tiragolumab.
One of these cohorts involved NSCLC patients, and another cohort included patients with other solid tumors. All patients in the expansion cohorts were expected to have PD-L1 expression of at least 1 percent and not have had prior immunotherapy. "We do know that TIGIT expression correlates with PD-L1 expression and is often co-expressed on the same immune cells," Bendell said, explaining that PD-L1 expression served as a surrogate for TIGIT expression. Patients had their PD-L1 expression status established using Roche's Ventana SP142 PD-L1 assay.
As of the data cutoff on Dec. 2, 2019, 73 patients were enrolled in the Phase Ia/Ib trial with colon, rectum, breast, head and neck, ovarian, lung, melanoma, endometrial, sarcoma, and a range of other cancers. There were 24 patients in Phase Ia and 49 patients in Phase Ib.
In Phase Ia, several patients saw tumor reductions on single-agent tiragolumab but not enough to qualify as an objective response. Ultimately, all patients receiving just the anti-TIGIT antibody discontinued due to progression of disease, and half crossed over to the tiragolumab-atezolizumab portion of the study. "None of the patients who crossed over to the Phase Ib had a response," Bendell said, noting that PD-L1 expression was low in this group and many had tumor types that are traditionally resistant to immunotherapy.
In Phase Ib, five of the 49 patients had objective responses to tiragolumab-atezolizumab. Two had NSCLC, one had head and neck cancer, one had triple-negative breast cancer, and one had esophageal cancer. Still, approximately 90 percent of patients in this portion of the study discontinued, most of them due to disease progression.
There were no dose-limiting toxicities in the Phase Ia/Ib study. In the Phase Ia portion, 67 percent had adverse events, the most common being fatigue. In Phase Ib, 59 percent had adverse events, most commonly anemia. Approximately 4 percent of patients in each portion of the study experienced grade 3 or higher toxicities. The immune-related adverse events associated with atezolizumab were previously known and expected.
Based on the Phase Ib safety and efficacy data, researchers launched expansion cohorts in immunotherapy-naive NSCLC and other solid tumors at the 400 and 600 mg tiragolumab doses in combination with atezolizumab. In NSCLC patients with PD-L1 positive tumors, six out of 13 patients, or 46 percent, had an objective response, with two patients having a complete response. Eleven out of 13, or 85 percent, had their disease controlled with the tiragolumab-atezolizumab combination.
"We saw no real pseudo-response or delayed responses," noted Bendell.
Based on the efficacy seen in the NSCLC expansion cohort, a randomized Phase II study was launched in this patient population, called CITYSCAPE, comparing tiragolumab-atezolizumab versus atezolizumab. Researchers presented data from this study at ASCO's virtual annual meeting earlier this month, which showed that the tiragolumab-atezolizumab combination worked better than just atezolizumab, particularly in NSCLC patients who had high PD-L1 expression.
In the Phase II study, 135 PD-L1-positive, metastatic NSCLC patients were randomized to receive tiragolumab-atezolizumab or atezolizumab as first-line treatment. All patients had to have a PD-L1 tumor proportion score of at least 1 percent as determined by the Roche PD-L1 22C3 IHC assay in a local or central lab. In the overall cohort, the response rate was 37 percent on tiragolumab-atezolizumab and 21 percent on atezolizumab; the median progression-free survival was 5.55 months and 3.88 months, respectively.
However, when researchers looked at the subset of patients with high PD-L1 scores (at least 50 percent), the overall response rate was 66 percent on tiragolumab-atezolizumab and 24 percent with atezolizumab. Median progression-free survival was not reached in the combination arm but was 4.11 months for those receiving atezolizumab.
Based on the CITYSCAPE data, researchers have now launched the Phase III SKYSCRAPER trial in NSCLC patients with PD-L1 scores of 50 percent or higher.
In reviewing the data from the Phase Ia/Ib trial, Michele Teng from the QIMR Berghofer Medical Research Institute discussed additional predictive markers that researchers might consider to further refine their understanding of responders and non-responders. For example, past studies have shown that high levels of CD155 expression correlates with poor prognosis in cancer patients. Teng's group demonstrated in preclinical studies that CD155 loss on tumor cells enhances tumor suppression and response to immunotherapy, as well as to a regimen containing immunotherapy and an anti-TIGIT antibody. In metastatic melanoma patients, Teng's group has further shown that tumor CD155 expression is associated with resistance to anti-PD-1 immunotherapy.
Trials targeting TIGIT may also benefit from factoring in DNAM-1 expression. Teng said her colleagues are close to publishing "compelling" data from two studies showing that tumor CD155 expression downregulates DNAM-1 expression on CD8-positive T cells and confers resistance to immunotherapy. In particular, patients with a high DNAM-1-positive T cell ratio appear to have improved progression-free survival on immunotherapy compared to patients with a low DNAM-1-positive T cell ratio.
"These studies suggest that it may be useful to not only stain for PD-L1 [expression], but also CD155 and DNAM-1, as potential biomarkers to select for patients that will best respond to PD-L1 and TIGIT co-blockade," Teng said, adding that researchers should consider the role other receptors, such as CD96 and CD112R, play in suppressing T cell function after TIGIT blockade.