KEYNOTE-119, KATE2, and future directions
Both the randomized, open-label, phase 3 KEYNOTE-119 study of the checkpoint inhibitor pembrolizumab vs. single-agent chemotherapy for mTNBC, and the phase 2 KATE2 trial of the antibody-drug conjugate trastuzumab emtansine (T-DM1) + either atezolizumab or placebo in previously treated HER2-positive breast cancer patients, failed to meet their respective primary study endpoints.
But the news isn’t all bad, Dr. Bianchini said.
For example, in KEYNOTE-119, second- or third-line pembrolizumab monotherapy did not significantly improve OS vs. chemotherapy for mTNBC, but the pembrolizumab treatment effect increased as PD-L1 enrichment increased, he explained.
Pembrolizumab showed promising antitumor activity and manageable safety in mTNBC in prior trials, and was therefore further assessed in the KEYNOTE-119 study of 601 patients with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, progression on the latest therapy, and a prior anthracycline or taxane, Javier Cortés, MD, PhD, of Instituto Oncológico, Madrid, reported at the congress.
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Dr. Javier Cortés
Pembrolizumab was given at a dose of 200 mg every 3 weeks, and chemotherapy was physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine.
At a median follow-up of 9.9 months in the pembrolizumab group and 10.9 months in the chemotherapy group, OS did not differ significantly between the groups; this was true overall, in patients with a CPS of 10 or greater, and in those with a CPS of 1 or greater.
In all-comers, the HR for OS was 0.97, compared with 0.78 in patients with CPS of 10 or greater, and 0.86 in those with CPS of 1 or greater, Dr. Cortés said.
“One of the most interesting exploratory analyses was OS in those patients with CPS of 20 or higher,” he said, noting that median OS in that group was 14.9 vs.12.5 months with pembrolizumab vs. with chemotherapy (HR, 0.58).
Pembrolizumab did not improve overall PFS, but again, the rates improved with higher CPS. Duration of response, however, was longer with pembrolizumab vs. chemotherapy (12.2 vs. 8.3 months overall; 12.2 vs. 6.5 months for CPS of 1 or greater; and not reached vs. 7.1 months for CPS of 10 or greater).
Grade 3-5 AEs occurred in 35% vs. 49% of patients in the pembrolizumab vs. chemotherapy groups, with nine deaths occurring in each, Dr. Cortés said, adding that treatment-related AEs occurred in 14% (with one death) and 36% (with two deaths), respectively, and grade 3-4 immune-mediated AEs and infusion reactions occurred in 3.2% vs. 1.0% (no deaths), respectively.
In the double-blind, signal-seeking KATE2 trial, as reported in 2018 at the San Antonio Breast Cancer Symposium, no overall PFS improvement was seen with atezolizumab + T-DM1 (median of 8.2 vs. 6.8 months; HR, 0.82; 12-month PFS 38% vs. 34%), but again, a possible benefit was seen in PD-L1-positive patients (8.5 vs. 4.1 months; HR, 0.60).
KATE2 included 202 patients with advanced HER2-positive breast cancer that progressed after treatment with T-DM1 and a taxane. They were randomized 2:1 to receive intravenous T-DM1 at a dose of 3.6 mg/kg plus atezolizumab (1,200 mg) or placebo every 3 weeks until loss of clinical benefit or intolerable toxicity.
The “overall survival and final safety results” show that at a median follow-up of 19.0 months in the atezolizumab arm and 18.2 months in the placebo arm, with 52 OS events reported, median OS was not reached in either arm and 1-year survival was similar in the two groups (89.1% and 89.0%), Leisha A. Emens, MD, PhD, professor of medicine in hematology/oncology and co-leader of the Hillman Cancer Immunology and Immunotherapy Program at Hillman Cancer Center, University of Pittsburgh Medical Center (UPMC) reported at the congress.
Dr. Leisha A. Emens
The 1-year OS rate in the PD-L1-positive subgroup, however, was numerically higher with vs. without atezolizumab (94.2% vs. 87.9%), said Dr. Emens, director of translational immunotherapy for the Women’s Cancer Research Center at UPMC.
Of note, all additional biomarkers of T-cell activation and quantity analyzed, including PD-L1 gene expression, CD8 gene expression, T effector signature gene expression, and stromal tumor infiltrating lymphocytes (TILs), were enriched in the PD-L1-positive subgroup vs. the PD-L1-negative patients.
Further, OS rates in other immune biomarker subgroups (those with PD-L1 RNA expression, CD8 RNA expression, and T effector signature at or below vs. above the median, and those with TILs less than 5% vs. 5% or greater) were consistent with those in the PD-L1 IC-positive subgroup, and the biggest difference between the atezolizumab and placebo arms related to stromal TILs, she said.
The safety profile in this final analysis was consistent with the known safety profile of each drug, she added, noting that grade 3 or greater AEs occurred in 52.6% vs. 44.8% of patients in the atezolizumab vs. placebo arms, and serious AEs – primarily pyrexia – occurred in 36.1% vs 20.9%, respectively.
The rate of grade 5 AEs was similar in the groups.
T-DM1 is indicated for the treatment of HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, either separately or in combination, Dr. Emens said.
“In addition to its cytotoxic activity, T-DM1 may potentiate tumor immunity,” she explained, adding that KATE2 was designed to assess whether combining T-DM1 with atezolizumab, an anti-PD-L1 antibody that restores anti-tumor immunity, would result in greater clinical activity than either drug alone.
Although the number of OS events was small, the data suggest an OS benefit with the addition of atezolizumab to T-DM1, specifically in the PD-L1 IC-positive patients, but follow-up was short and the study lacked statistical power, therefore additional study of HER2-targeted agents with atezolizumab in previously treated HER2-positive, PD-L1 IC-positive advanced breast cancer is warranted, Dr. Emens concluded.
Indeed, the finding of improved OS in the PD-L1-positive subgroups of both KEYNOTE-119 and KATE2, is of interest, Dr. Bianchini said.
Both trials failed to meet their primary endpoints, but a closer look into KEYNOTE-119 shows that PD-L1 as a continuous biomarker (using CPS, 22C3) was associated with a “continuous and strong trend” toward improved ORR with the addition of pembrolizumab.
The ORR was 9.6% vs. 10.6% in unselected patients, compared with 26.3% vs. 11.5% in those with CPS of 20 or greater.
“And when you look at duration of response, you see an increase not just in the number ... but the quality of the response,” he said, noting that for PFS, as well, a trend toward superiority is seen “that is consistent with all the other endpoints.”
“So overall, the application of incrementally restrictive cut-off of CPS lends weight to the exploratory analysis showing better survival from pembrolizumab in tumors with CPS more than 20,” Dr. Bianchini said, noting that the “real question,” however, is whether the finding “is worth clinical implementation.
“We know a lot about the primary tumor and immune infiltration. We’ve learned ... that if you wait and look ahead at immune infiltration in the advanced stage, you find that the tumor becomes smart,” he said, explaining that tumor/immune co-evolution leads to increased immuno-editing and immune subversion and it becomes “much harder to just hit the tumor with PD-L1, because this is not the only mechanism of immune escape.”
A review of several studies shows that in similar populations defined by biomarkers, response rates in patients treated with checkpoint inhibitors decrease in the second- and third-line setting vs. the first-line setting, he said.
For example, pembrolizumab response rates in the first-line and second-line or greater setting in cohort B of the KEYNOTE-086 study were 21.4% and 5.7%, respectively, compared with 12.3% in the second- to third-line setting in KEYNOTE-119, he said.
Another consideration is whether monotherapy or combination therapy is preferable, and the data suggest that regardless of how PD-L1-positivity is defined (by CPS cutoff of 1 vs. 20, for example), most patients treated with monotherapy progress within the first 3 months, he said.
“I don’t see that this is a safe approach for the majority of these patients. So without better biomarkers, combinations should always be preferred, at least to avoid early progression,” Dr. Bianchini said, adding that the open question, then, is: “If we set the new standard in the first-line as the combination of nab-paclitaxel and atezolizumab for PD-L1-positive patients defined by the VENTANA [SP142 assay], should we continue with immune checkpoint [inhibition] using different combinations?”
“Of course, at the time the trial was designed, the results of IMpassion were not available, but it’s very important, because [the findings] add to the evidence that immunotherapy is extremely relevant for some patients,” he said.
KATE2 further demonstrated the importance of PD-L1 status, he said, adding that due to its limitations, including small sample size and short follow-up, longer follow-up is needed to better evaluate duration of response and PFS.
“Despite the trial limitations, the qualitative effect seen in all clinical endpoints – overall response rate, progression-free survival, overall survival – in PD-L1-positive tumors defined by SP142 ... provided strong and robust signals supporting the investigation of immune checkpoint inhibitors in HER-positive breast cancer,” he said, noting that “many trials are ongoing in the early setting and the advanced setting.”
In addition to the lessons of these trials with respect to the interchangeability of PD-L1 IHC assays and the value of PD-L1 assessment for identifying the likelihood of benefit from immune checkpoint inhibitors, the findings highlight the possibility that PD-L1-negative tumors require different immunotherapy approaches or alternative therapeutic strategies, and underscore that the benefit of immunotherapy in PD-L1-positive patients is still restricted to a minority.
“So new studies and approaches with immuno-oncology are needed, and we need more effective biomarkers, because we need to have precision oncology applied – we need to go in that direction,” he concluded.
Dr. Bianchini reported consultancy/honorarium and or advisory board activity associated with Roche, MSD, AstraZeneca, Pfizer, Chugai, EISAI, Lilly, Novartis, Amgen, Sanofi, Neopharm, and Genomic Health. The IMPassion30 trial was funded by F. Hoffmann-La Roche Ltd.; Dr. Rugo reported research grants, other funding, and or travel/accommodation/expenses from Pfizer, Novartis, Eli Lilly, Merck, OBI, EISAI, Plexxikon, Genentech/Roche, MacroGenics, PUMA, Mylan, Immunomedics, Daiichi Sankyo, and Celltrion. KEYNOTE-119 was funded by Merck Sharp & Dohme Corp.; Dr. Cortés and Dr. Emens reported numerous funding relationships but none with F. Hoffman-La Roche. KATE2 was funded by F. Hoffmann-La Roche.
Sources: IMPassion130; ESMO Abstract LBA20; KEYNOTE-119: ESMO Abstract LBA21; KATE2: ESMO Abstract 305O.