WASHINGTON—The greater the overexpression of HER2 in a breast tumor, the more sensitive the tumor is to anti-HER2 therapy; this opens the possibility that women who undergo highly effective anti-HER2 treatment may not need chemotherapy for locally advanced or metastatic disease.
The second part of that statement is speculation, but the first is based on progression-free and overall survival outcomes from the Phase III EMILIA study (NEJM 2012;367:1783-1791) of the antibody conjugate trastuzumab emtansine (T-DM1). That trial led to the approval of T-DM1 by the U.S. Food and Drug Administration on Feb. 22 of this year as second-line treatment for breast cancer.
Now, an analysis of biomarkers in EMILIA patients shows that those who have tumors containing HER2 mRNA levels above the median benefitted most from T-DM1 treatment.
José Baselga, MD, PhD, Physician-in-Chief at Memorial Sloan-Kettering Cancer Center, an author of the first EMILIA report, and the first author of the new study, speculated on the possibilities of highly effective anti-HER2 treatment during a news conference here at the American Association for Cancer Research Annual Meeting.
“What we're going to have is a group of tumors that are hypersensitive to [trastuzumab] Herceptin and will not need chemotherapy,” he said. “In some of the neoadjuvant studies we have conducted with Herceptin there is a proportion of patients who had complete, durable remissions without chemotherapy, and we speculate that these are the patients…who are super HER2 expressors.”
EMILIA included 991 patients with HER2-positive locally advanced or metastatic breast cancer who had received prior therapy with taxanes and trastuzumab and who had disease progression on metastatic treatment or within six months of adjuvant therapy.
In the original report, the 495 patients treated with T-DM1 had significantly longer median progression-free and overall survival compared with the 496 patients treated with capecitabine-lapatinib (9.6 months progression-free survival vs. 6.4 months; and 30.9 months for overall survival vs. 25.1 months).
The new data (Abstract LB63) on response by HER2 levels show that patients receiving T-DM1 whose tumors had above-median levels of HER2 had a median overall survival of 34.1 months, vs. 26.5 months for patients with lower levels. Progression-free survival with T-DM1 was 10.6 months for patients with higher HER2 levels vs. 8.2 months for lower levels.
In the capecitabine-lapatinib arm, HER2 levels made a small difference: overall survival was 24.8 and 23.7 months for higher and lower levels, respectively; progression-free survival was 6.9 vs 6.4 months, respectively.
“The higher-level expression T-DM1 group had a 47 percent decreased risk of death compared with those receiving lapatinib and capecitabine, and this was in patients who were in second-line therapy,” Baselga said.
The mechanism of action of T-DM1 is different from the classical HER2 therapies, he noted. When trastuzumab is bound to the cytotoxic agent emtansine (DM1), the antibody-drug conjugate retains the mechanisms of action of trastuzumab, including HER2 targeting and interruption of HER2 signaling, while delivering emtansine directly to the HER2-positive tumor.
Emtansine is not a standard chemotherapy agent because of its potency and accompanying toxicity—“It's 10,000 times more potent than vinorelbine,” Baselga said.
During the study the researchers collected tumor blocks for many patients for analysis of biomarkers including EGFR, HER2, HER3, mRNA by RT-PCR, and PIK3CA kinase mutations. PIK3CA in particular is associated with resistance to anti-HER2 therapies, but this apparently did not occur with T-DM1 treatment as outcomes for the T-DM1 study arm were approximately the same whether PIK3CA was mutated or not.
T-DM1 patients with mutated PIK3CA had 10.9 months progression-free survival, and 9.8 months for those with wild-type PIK3CA.
PIK3CA status did make a difference for the capecitabine-lapatinib treated patients: progression-free survival was 4.3 months for patients with mutated PIK3CA and 6.4 months for those with the wild type.
Overall survival for T-DM1 patients with mutated or wild-type PIK3CA was not reached; for the capecitabine-lapatinib group, overall survival was 17.3 and 27.8 months, respectively.
Baselga said the biomarker analysis from EMILIA is not practice-changing at this point but is still a matter of practical importance, in terms of including PIK3CA analysis in HER2-positive breast cancer in clinical trials.
“We should start sequencing and checking for the presence of PIK3CA kinase mutations—first, because we're going to have a number of compounds in clinical trials that have shown activity against tumors that have PIK3CA kinase mutations; and second, because it could well be that we further fragment the world of HER2-positive breast cancer into those that are PIK3CA positive and negative because there might be an antibody conjugate that could deal with that problem.”
He noted that MSKCC has an ongoing trial evaluating T-DM1 earlier in the treatment of patients with metastatic breast cancer, and another testing whether T-DM1 will reduce breast cancer recurrence after surgery in women with earlier-stage disease.
Gordon Mills: Focusing on Tumor Cell's Differences, Not Vulnerabilities
After Baselga's oral presentation at the meeting, Gordon Mills, MD, PhD, Professor of Medicine and Immunology and Chair of the Department of Systems Biology at the University of Texas MD Anderson Cancer Center, gave a scheduled commentary.
He said the new EMILIA conclusions were so convincing he would not challenge them, but instead would look at what might be the next step. He said targeted therapy over the past 10 years has focused on understanding the vulnerabilities engendered on cancer cells by genetic aberrations, and, in most cases, attacking the tumor's Achilles' heel as defined by addiction to those aberrations.
“T-DM1 is now offering us a new approach—simply capitalizing on the difference between tumor cells and normal cells,” he said. To date there has been “an unexpected failure for most therapeutic agents,” and only a subpopulation of patients benefit even for agents with biomarkers. The key challenges are intrinsic and selective resistance mechanisms, inter- and intra-tumoral heterogeneity, and adaptive tumor responses to therapies.
One of the key opportunities with T-DM1, because it may be blocking signaling from the receptor, is whether it will prevent or reverse resistance to HER2-targeted therapy and whether this effect can be translated to other malignancies, Mills said.
Drug Therapy and Immunology Collaborate
At the news conference, Louis Weiner, MD, Director of the Lombardi Comprehensive Cancer Center, Georgetown University, said the take-home point for him was that “when you have drugs that work really well, the predictive biomarkers that you might have been identified earlier no longer matter, because you basically overwhelm the tumor's defense mechanisms directed against the therapy.
“I think that this is a really lovely collaboration between drug therapy and immunology in order to create an effective therapeutic platform,” he continued. “You can deliver a cytotoxic poison into the interior of that cell and you can kill it—that's a very powerful tool, because these very powerful drugs are working where you could not give them otherwise because of the side-effect profile.
“I think this is where the field is going as we develop novel cytotoxics in the future.”