Leisha A. Emens, MD, PhD, discusses the rationale behind the KATE2 study and the results that may signal clinical significance.
Leisha A. Emens, MD, PhD
Updated results of the randomized, phase II KATE2 trial suggest an overall survival (OS) benefit with atezolizumab plus ado-trastuzumab emtansine (T-DM1; Kadcyla) compared with T-DM1 alone for patients with HER2-positive breast cancer who have PD-L1 expression on immune cells, reported Leisha A. Emens, MD, PhD.
The 1-year OS rate of this patient subgroup was numerically higher than in patients who received T-DM1 without atezolizumab at 94% versus 88%, respectively. Also, the median OS was not estimable in either arm (stratified HR, 0.55 favoring atezolizumab/T-DM1; 95% CI, 0.22-1.38).
However, in the intent-to-treat population, neither OS nor progression-free survival (PFS) was statistically improved. In an exploratory analysis of a patient subgroup who had PD-L1 expression in immune cells, the median PFS was 8.5 months with atezolizumab/T-DM1 and 4.1 months with T-DM1 alone (stratified HR, 0.60; 95% CI 0.32-1.11).
Overall, the combination of atezolizumab plus T-DM1 suggests greater efficacy together than as single agents, Emens said.
“It is intriguing that the expression of PD-L1 in immune cells is relevant in both triple-negative breast cancer and in HER2-positive breast cancer,” Emens said. “It seems to be emerging, at least for atezolizumab, as a way of selecting patients most likely to benefit. We will need further studies, but these results are encouraging.”
In an interview with OncLive during the 2019 ESMO Congress, Emens, a professor of medicine in hematology/oncology, co-leader of the Hillman Cancer Immunology Program, director of translational immunotherapy for the Women's Cancer Research Center at UPMC Hillman Cancer Center, discussed the rationale behind the KATE2 study and the results that may signal clinical significance.
OncLive: Could you discuss the rationale for the KATE2 study?
Emens: Currently, there is a large effort to develop effective immunotherapy combinations that can enhance the activity of single-agent PD-1/PD-L1 blockade. HER2-positive breast cancer is unique in that there are a number of HER2-targeted agents that could potentially be combined with immune checkpoint blockade. The main ones include trastuzumab (Herceptin) and T-DM1, an antibody-drug conjugate (ADC).
Both have the trastuzumab antibody as a backbone, which has immune-modulating activity itself. The ADC also has a chemotherapeutic agent conjugated directly to the antibody, which could potentially have immune-modulating activity.
Therefore, the rationale underlying KATE2 is that combining atezolizumab and T-DM1 may be additive or even synergistic relative to the clinical activity of the single agents alone.
Could you elaborate on the study design and the eligibility criteria?
KATE2 was a global, randomized, placebo-controlled, double-blind study that enrolled HER2-positive patients with locally advanced or metastatic breast cancer. Patients had to have received prior therapy with a taxane and trastuzumab. They had to have progressed on HER2-directed therapy for metastatic disease or were within 6 months of completing adjuvant HER2-based therapy. Also, they had to have measurable disease by RECIST criteria.
Patients were randomized 2:1 to receive T-DM1 either with atezolizumab or placebo. Patients continued to be treated with their assigned combination until loss of clinical benefit or the development of intolerable toxicity.
Stratification factors included PD-L1 expression on the immune cells, the region of the world in which the patients were from, and the presence or absence of liver metastases.
The primary endpoint for the study was PFS in the intent-to-treat patient population. Secondary endpoints included overall response rate and duration of response, as well as safety.
An exploratory prespecified endpoint was PFS specifically in the PD-L1 immune cell—positive patient population. OS was an additional secondary endpoint.
At the 2019 ESMO Congress, we reported an additional post-hoc analysis of OS specifically in the PD-L1 immune cell—expressing patient population.
What were the KATE2 findings?
This trial showed that the addition of atezolizumab to T-DM1 did not improve PFS in the patient population overall. However, there was an improvement in PFS in patients who expressed PD-L1 on their immune cells. This was a clinically significant improvement in PFS, as indicated by the hazard ratio (HR), which was 0.6. It is interesting that this HR is the same one associated with the clinical benefit of atezolizumab in the IMpassion130 trial, in which we evaluated the clinical benefit of adding immunotherapy to nab-paclitaxel (Abraxane), a chemotherapy commonly used for triple-negative breast cancer (TNBC).
Although this is a small number of patients, this may be clinically meaningful.
What data were reported with regard to the secondary or exploratory endpoints?
We did focus on OS, which was the main endpoint presented here at the 2019 ESMO Congress.
There was a numerical improvement in OS in the patient population overall, with an HR of 0.74. There was no significant difference in the 1-year OS rate between arms, which was about 89%. However, specifically in the PD-L1—positive patient population, there was an improvement in the OS rate from about 87% to about 93%.
Altogether, the data suggest that PD-L1 expression on immune cells, as determined by the VENTANA (SP142) assay, is a reliable way of predicting, at least for patients with TNBC and HER2-positive breast cancer, response to atezolizumab.
What about the toxicity of the combination?
The combination of atezolizumab with T-DM1 was pretty well tolerated. In the immunotherapy arm, in which patients received T-DM1 plus atezolizumab, there was a higher rate of infusion reactions, which is a common adverse event (AE) of monoclonal antibody¬—infusions. There were also higher rates of thrombocytopenia and transaminitis, which are known AEs of T-DM1.
Immune-related AEs could potentially be attributed primarily to atezolizumab. The three most common immune-related AEs were rash, hypothyroidism, and pancreatitis. Only 2 cases of rash turned out to be grade ≥3. Hypothyroidism is fairly common, but is low-grade and typically treated with just thyroid replacement.
If this combination is taken to a larger trial, would it be worthwhile to explore HER2-low patients?
The data are clear with these particular agents that patients with HER2 overexpression are the ones that benefit from them. For this particular HER2-directed therapy, I am not sure the HER2-low patient population is going to be where we would want to go. I would probably focus on the high HER2-expressers for these particular therapies. There are certainly other HER2-directed therapies that are antibody-based and could potentially have activity in patients who express low-levels of HER2, unlike trastuzumab, pertuzumab (Perjeta), and T-DM1.
Given that there are different ways to test for PD-L1, is there a rationale for doing it in immune cells?
The VENTANA (SP142) assay has been co-developed along with atezolizumab. The priority at the beginning of this clinical development program was to focus on immune cells because that is the target of the drug—it is unleashing immune cells, in particular T cells and their ability to attack the tumor.
It turns out that in breast cancer, there is not a significant level of tumor cell expression above and beyond what you find in immune cells. At least for breast cancer, it appears that immune cell expression is the most important.
Is there anything else from this trial that is important to highlight?
The trial did not meet its primary endpoint; however, the exploratory analysis of clinical benefit for PFS in the PD-L1¬—positive patient population is encouraging. The fact that we found that also reflected in OS somewhat confirms that. If you look at the other secondary endpoints in the trial, they also were consistently better in the PD-L1¬–positive patient population.
Emens LA, Esteva F, Beresford M, et al. Overall survival (OS) in KATE2, a phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+T-DM1 in previously treated HER2+ advanced breast cancer (BC). Presented at 2019 ESMO Congress; September 27 to October 1, 2019; Barcelona, Spain. Abstract 305O.