SAN ANTONIO – Data on two Genentech drugs presented at the San Antonio Breast Cancer Symposium this week suggest new precision medicine strategies for breast cancer patients with poor prognosis and limited treatment options.
The data on Genentech's Kadcyla (ado-trastuzumab emtansine or T-DM1) came from the Phase III KATHERINE trial, which involves around 1,500 HER2-positive early breast cancer patients who still have evidence of cancer despite neoadjuvant treatment with chemotherapy and a HER2-targeted drug before surgery. This group of patients is at increased risk of recurrence and death compared to early-stage patients who have no evidence of invasive cancer in the breast and lymph nodes after the same treatments.
A second study, IMpassion130, demonstrated the potential for Genentech's PD-L1 inhibitor Tecentriq (atezolizumab) to be a treatment option for metastatic triple-negative breast cancer patients with PD-L1-positive tumors. TNBC patients have the worst outcomes of all the breast cancer subtypes because they lack expression of receptors that can be treated with targeted drugs, so they typically receive chemotherapy. The study is "the first Phase III study to demonstrate a benefit for immunotherapy in metastatic triple-negative breast cancer," said Leisha Emens from the University of Pittsburgh, who presented the data at the meeting. She also noted that the study established PD-L1 immune cell expression status as a predictive marker in this setting.
In KATHERINE, researchers led by Charles Geyer from Virginia Commonwealth University reported that after three years, more than 88 percent of patients in the trial receiving Kadcyla didn't see their cancer return versus 77 percent of those treated with just Herceptin (trastuzumab). The 11 percent improvement in the invasive disease-free survival rate — an endpoint that describes the time a patient lives without return of invasive disease after adjuvant treatment — makes it likely that the KATHERINE study will "form the foundation of a new standard of care in this population and increase the use of neoadjuvant therapy in HER2-positive early breast cancer," said Geyer, who presented the data at the meeting.
The researchers also analyzed subgroups based on whether patients had inoperable or operable cancer, their hormone receptor status, whether they received Herceptin or dual HER2-targeted treatment in the neoadjuvant setting, and whether they had residual disease in their lymph nodes. The impact of Kadcyla on invasive disease-free survival was consistent across all these groups, Geyer said.
The researchers expected to see more adverse events in patients receiving Kadcyla compared to those on Herceptin. However, most of the adverse events were milder symptoms, such as fatigue and nausea. The more serious toxicities with the drug, although infrequent, were lower platelet counts and increases in liver enzymes. "Overall, this does appear to be a tolerable, manageable regimen," Geyer said.
Simultaneously with the meeting presentation, the data from this study were published in the New England Journal of Medicine. The researchers plan to do further follow-up to confirm the effect of Kadcyla on overall survival.
Kadcyla is currently approved in the US for patients with HER2-positive metastatic breast cancer after they've received HER2-targeted treatment and a taxane. Genentech said in a statement that it will submit data from KATHERINE to health regulators, including the US Food and Drug Administration and the European Medicines Agency.
"I think this was a big boost for [the use] of T-DM1," said Eric Winer from the Dana Farber Cancer Institute after reviewing the data from KATHERINE. "I think we will be using T-DM1 broadly in this setting and we'll think about how to use this in other settings with patients with early-stage breast cancer on trial."
A small number of patients in the study also received Genentech's other HER2-targeted drug Perjeta (pertuzumab) in addition to Herceptin before surgery, but this didn't seem to matter much in terms of an outcome benefit after they received Kadcyla post surgery. As such, Winer said, the trial data will likely lead to oncologists not using Perjeta as much, or even another drug for HER2-postive breast cancer called Nerlynx (neratinib), because the data for Kadcyla are so strong. "The standard of care has changed," he said.
He wondered whether researchers are hitting "a ceiling of effectiveness" in HER2-positive breast cancer and added that researchers need to also investigate why Kadcyla failed to help the 20 percent of patients in KATHERINE who experienced recurrence. "Maybe we need to be taking a slightly different focus," he said. "Maybe we should be spending a lot of our time designing the best-tolerated regimen and at the same time conducting in-depth translational studies on the tumor … and the small minority who have systemic recurrences."
At the meeting, researchers also presented data on the IMpassion130 study, which showed that metastatic TNBC patients, particularly those with PD-L1-positive tumors, lived longer without progression on Genentech's PD-L1 inhibitor Tecentriq (atezolizumab) with the chemotherapy nab-paclitaxel versus those on placebo plus the same chemo regimen. Tecentriq is currently FDA approved for ceratain PDL1-positive, advanced bladder cancer patients and advanced non-small cell lung cancer patients unresponsive to platinum chemotherapy.
Median progression-free survival in the 900-patient study was 7.2 months for those on Tecentriq, compared to 5.5 months for those on the placebo. It was 7.5 months and 5 months, respectively, in patients with PD-L1 expression in at least 1 percent of tumor-infiltrating cells. Median overall survival was 21.3 months for those on Tecentriq and 17.6 months for those on the placebo in the overall study population, which was not statistically significant.
However, in the PD-L1-positive subset, patients receiving Tecentriq experienced clinically meaningful increases in overall survival compared to those on the placebo, 25 months versus 15.5 months. "A treatment effect was not seen for adding atezolizumab to chemotherapy in the PD-L1-negative subgroup," Emens said.
In this study, 41 percent of patients in the study were PD-L1 positive based on the expression seen in tumor-infiltrating immune cells using Ventana's immunohistochemistry test. Most patients had PD-L1 expression on immune and tumor cells, and around 2 percent had PD-L1 expression only in tumor cells, which didn't provide additional predictive information.
The researchers also looked at CD8-positive T cells, the presence of stromal tumor-infiltrating lymphocytes, which have been associated with response to checkpoint inhibitors, and BRCA1 and BRCA2 mutations using Foundation Medicine's FoundationOne NGS test, since the presence of such mutations has been associated with response to Tecentriq plus nab-paclitaxel.
IMPassion130 revealed PDL1 expression status on immune cells to be the only predictive biomarker in this setting in terms of progression-free survival and overall survival. Among the 15 percent of patients with BRCA1/2 mutations, for example, tumors that were PD-L1 immune cell negative showed no association with progression-free survival or overall survival benefit with Tecentriq treatment.
In contrast, patients who had BRCA1/2 mutations and were PD-L1 immune cell positive did have better progression-free survival and tended to have a greater overall survival benefit with Tecentriq, Emens said, noting that the sample size for this subpopulation analysis was small.
Overall, IMpassion130 demonstrated that PD-L1 immune cell expression status is a predictive marker for determining which patients are likely to benefit from treatment with Tecentriq plus nab-paclitaxel. "Patients with newly diagnosed metastatic and unresectable locally advanced triple-negative breast cancer should be routinely tested for their PD-L1 immune cell status to determine whether they might benefit from the combination of atezolizumab and nab-paclitaxel," Emens said.