Analyzing the Nuances of Trastuzumab Therapy for HER2-Positive Breast Cancer

Debu Tripathy,MD

Trastuzumab is the clear standard of care for firstline therapy for nearly all HER2-positive breast cancers, and the oncology community has come a long way toward understanding how best to use the drug.

But there are still questions clouding the use of the humanized monoclonal antibody that was initially approved in 1998. These include whether the benefit of treatment with anthracyclines exceeds its risks, and in the adjuvant setting, whether it can be given for less than a year without a loss of efficacy; how to predict which patients will benefit or encounter cardiac toxicities; and establishing its value in the smallest and lowest-risk HER2-positive tumors, said Debu Tripathy, MD, during a presentation at the 12th International Congress on the Future of Breast Cancer.

Tripathy, professor of Medicine and co-leader of the Women’s Cancers Program at Norris Comprehensive Cancer Center at the University of Southern California, addressed best practices in adjuvant and neoadjuvant HER2-targeted therapy during the conference, held July 17-19 in Huntington Beach, California.

Before choosing trastuzumab, he cautioned, practitioners must navigate the sometimes tricky task of establishing a patient’s HER2 status in the first place.

A guideline issued by the American Society of Clinical Oncology and the College of American Pathologists in 2006 recommended diagnosing HER2-positive breast cancer when a tumor scores ≥3+ on an immunohistochemistry (IHC) assay, or is fluorescence in situ hybridization (FISH)-positive with an amplification rate ≥2.2. However, the guideline included a gray area, defining an IHC between 2+ and 3+ as equivocal, with diagnosis to then be determined by a FISH test. A FISH amplification rate between 1.8 and 2.2, meanwhile, was also considered “equivocal,” or not a definitive means of diagnosing the disease.

“This 1.8 to 2.2 equivocal range has confused some people, but a 2011 clarification said that, for all adjuvant clinical trials, the criteria was FISH of 2 or greater, and that’s what we’re using in our practice, rather than letting people remain in limbo with an equivocal number,” Tripathy said.¹

Questioning Anthracyclines

While pairing trastuzumab with chemotherapy is preferred in adjuvant treatment, it’s not clear whether that chemotherapy needs to contain an anthracycline, Tripathy said. Investigators want to understand the relative value of anthracyclines for patients in this population, he said, because the drugs raise the risk of cardiac complications, compounding the already higher risk that comes with trastuzumab use.

Tripathy pointed to half a dozen adjuvant trials— including the HERA, NSABP B-31/NCCTG 9891, and BCIRG 006 studies—that were launched when trastuzumab was experimental to determine whether adding the agent to anthracycline-based chemotherapy would improve outcomes for patients with early-stage HER2-positive breast cancer. Consistently, Tripathy said, the trials demonstrated that adding trastuzumab reduced disease recurrence by 30% to 50% and mortality by 20% to 30%.

However, he said, they left open the question of whether anthracyclines are a critical component of adjuvant chemotherapy regimens for this population, since the nonanthracycline arms included in some of the trials demonstrated similar benefits to the anthracycline arms.

“Study BCIRG 006² looked at docetaxel and carboplatin with trastuzumab [TCH regimen] and compared that to anthracycline therapy followed by docetaxel as the control arm, and to the same therapy with trastuzumab overlapping docetaxel,” Tripathy said. “Both trastuzumab regimens showed an improvement in outcome, so there’s still a controversy as to how important anthracyclines are.

Can we get away with a TCH regimen? The jury is still out, because the study was not designed to compare the two trastuzumab arms, but to compare the control to each of the trastuzumab arms.” Tripathy noted that numerically more deaths and recurrences were recorded in the anthracycline arm; however, he said, that difference was not statistically significant.

The value of overlapping anthracycline with trastuzumab was explored in the neoadjuvant setting in study ACOSOG Z1041 (NCT00513292), which showed no difference in complete pathological response rate with sequential versus overlapping anthracycline and trastuzumab, Tripathy said.

While “there’s a lingering sense that maybe anthracyclines are a better partner” for trastuzumab in terms of outcome, he said, “I feel comfortable that a nonanthracycline therapy with less cardiac risk is still a reasonable way to go, even in highrisk disease.”

Exploring Other Adjuvant Issues

Also being considered in the adjuvant setting is whether giving trastuzumab for less than the standard one year might bring the same benefits, Tripathy said.

He pointed out that the PHARE trial³ is one of several studies exploring shorter durations of trastuzumab, in this case comparing six-month and one-year regimens, with no statistically significant difference so far.

“There weren’t quite enough events in the study’s population to make a definitive conclusion, so we’ll need a longer follow-up of this study and then another study before we can say that six months might be as good,” Tripathy said. “This is important for patients with subclinical drops in ejection fraction but high-risk disease, when you’re struggling as a clinician to say, ‘Should I stop at six months, or press ahead?’” Another concern in the adjuvant treatment of these patients is whether those with T1a/b node-negative tumors should be given trastuzumab, Tripathy said.

A large, retrospective European study published last year compared the outcomes of such patients who either received adjuvant trastuzumab-based chemotherapy or did not, and demonstrated a statistically significant 2% to 3% improvement in recurrence-free survival on the trastuzumab arm after a multivariate analysis, Tripathy said. Hormone receptor (HR) status also proved to be noteworthy.⁴

“Bigger differences were seen in patients with high-risk features such as HR-negative or lymphatic vascular invasion,” he said, “so it stands to reason that I will treat these tumors, especially if they are T1b or have other poor risk features.”

Examining Neoadjuvant Options

Tripathy began his discussion of neoadjuvant treatment with a caveat: that only tried-and-true adjuvant regimens should be used until clear evidence emerges to support newer regimens.

“The outcome most critical for patients getting neoadjuvant therapy is not response in the breast, but long-term disease-free and overall survival benefit, which is why I believe that the best neoadjuvant regimen is a proven adjuvant regimen, with the power of numbers to reassure us of benefit and safety,” he said. “You’ll see innovative HER2 regimens, but they should not be incorporated into standard practice until we have long-term disease- free and overall survival outcome.”

As in adjuvant treatment, studies have shown that trastuzumab is the standard of care for these patients, Tripathy said.

Of course, he said, investigators are also studying novel treatments for HER2-positive breast cancer in the neoadjuvant population, including two agents recently approved for later lines of therapy for HER2-positive metastatic disease, pertuzumab and ado-trastuzumab emtansine (T-DM1).

Currently, pertuzumab is indicated in combination with trastuzumab and docetaxel for patients who have not received anti-HER2 therapy or chemotherapy for metastatic disease, or have recurred after one year of adjuvant trastuzumab. Notably, the FDA is scheduled to decide by October 31 whether pertuzumab can be used in neoadjuvant settings for HER2-positive, early-stage disease. In many cases, researchers are modernizing trial design by using pathologic complete response (pCR) as an endpoint. That’s a reasonable idea, Tripathy said, since pCR correlates to long-term outcome and is quicker than waiting, possibly for years, for data about recurrences or deaths. ⁵

pCR has been used as an endpoint in studies of dual blockade in neoadjuvant HER2-positive breast cancer, which generated promising results, Tripathy said. In four trials looking at combinations of trastuzumab with lapatinib or pertuzumab— including NeoALTTO (NCT00553358) and Neo- Sphere (NCT00545688)—dual blockade garnered a higher pCR rate, he said. However, he pointed out that more validation is needed in linking response to longer-term outcome, and that these studies are powered to ultimately assess these endpoints.

Evaluating New Regimens

Looking ahead in the treatment of neoadjuvant HER2-positive breast cancers, the I-SPY 2 trial is investigating a variety of agents, both in combination with trastuzumab and alone, including T-DM1 and pertuzumab, as well as AKT inhibitors. Meanwhile, the KATHERINE study will look at residual disease after neoadjuvant therapy, weighing T-DM1 versus trastuzumab in the posttreatment period. Finally, Tripathy said, a HER2 peptide vaccine study is under way for sub-positivity level HER2 expression.

“We’re using the neoadjuvant model to discover what drugs might partner with trastuzumab to make it more effective,” he said. “The model gives us a window into long-term effect, because those that achieve a complete pathologic response have a much better survival.”

Being studied, or recently studied, in the adjuvant setting are the addition of bevacizumab to a trastuzumab regimen in the BETH trial; trastuzumab and lapatinib in the ALTTO trial; trastuzumab and pertuzumab in the APHINITY trial; and many other compounds, including mTOR inhibitors, Tripathy said.

Finally, there is a need to find predictors of which patients will most benefit from trastuzumab- containing therapies, he noted.

Currently, Tripathy said, there are few known markers, and confusion about some that have emerged.

For instance, he said, p95, a truncated HER2 protein that had been associated with resistance to trastuzumab, was unexpectedly linked with a stronger response to the drug when tested in the GeparQuattro study.⁶

Selected Clinical Trials in HER2-Positive Breast Cancer

Trial

Description

Estimated Number of Patients

Estimated Primary Completion Date^a

Neoadjuvant

I-SPY 2^b (NCT01042379)

9 arms:

• Neratinib
• ABT-888 + carboplatin
• Standard therapy—paclitaxel + trastuzumab followed by doxorubicin and cyclophosphamide treatment depending on HR/HER2 status
• Trebananib (AMG 386)
• Ganitumab (AMG 479) + metformin
• MK-2206 with or without trastuzumab
• Trebananib + trastuzumab
• T-DM1 + pertuzumab
• Pertuzumab + trastuzumab

800

February 2014

Adjuvant

ALTTO (NCT00490139)

4 arms:

• Trastuzumab
• Lapatinib
• Trastuzumab followed by lapatinib
• Lapatinib + trastuzumab

8400

July 2013

APHINITY (NCT01358877)

2 arms:

• Pertuzumab + trastuzumab + standard chemotherapyc
• Placebo + trastuzumab + standard chemotherapy^c

4800

November 2023

BETH (NCT00625898)

2 arms:

• Trastuzumab + carboplatin + docetaxel, followed by trastuzumab
• Bevacizumab + trastuzumab + docetaxel + carboplatin followed by trastuzumab + bevacizumab

3509

March 2013

KATHERINE^d (NCT01772472)

2 arms:

• T-DM1
• Trastuzumab

1484

March 2023

^aDate is defined as final data collection date for primary outcome measure.

^bHER2-negative patients also are eligible for I-SPY 2.

^cChemotherapy can be either nonanthracycline-based or anthracycline-based.

^dPatients must be HER2-positive with residual tumor in the breast or axillary lymph nodes following preoperative therapy.

HER2 indicates human epidermal growth factor receptor 2; HR, hormone receptor; T-DM1, ado-trastuzumab emtansine.

Source: NIH Clinical Trials Registry, http://clinicaltrials.gov

References

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2. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273- 1283.
3. Pivot X, Romieu G, Debled M, et al. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): a randomised phase 3 trial. Lancet Oncol. 2013;14:741-748.
4. Rodrigues MJ, Peron J, Frénel JS, et al. Benefit of adjuvant trastuzumab- based chemotherapy in T1ab node-negative HER2-overexpressing breast carcinomas: a multicenter retrospective series [published online ahead of print October 26, 2012]. Ann Oncol. 2013;24(4):916-924.
5. Buzdar AU, Ibrahim NK, Francis D, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer [published online ahead of print, February 28, 2005]. J Clin Oncol. 2005;23(16):3676-3685.
6. Loibl S, Bruey J, Von Minckwitz G, et al. Validation of p95 as a predictive marker for trastuzumab-based therapy in primary HER2-positive breast cancer: a translational investigation from the neoadjuvant GeparQuattro study. J Clin Oncol. 2011;29(suppl; abstr 530).