Expert commentary on recent T-DM1 Trials

[Hopeful]

A Phase II Study of Trastuzumab Emtansine in Patients With Human Epidermal Growth Factor Receptor 2 –Positive Metastatic Breast Cancer Who Were Previously Treated With Trastuzumab, Lapatinib, an Anthracycline, a Taxane, and Capecitabine

J Clin Oncol. 2012 May 29;[Epub Ahead of Print], IE Krop, P LoRusso, KD Miller

TAKE-HOME MESSAGE

Activity seen in heavily pretreated patients with HER2-positive breast cancer was remarkable in this phase II study (EMILIA) of the antibody–drug conjugate trastuzumab–emtansine (T-DM1). The safety profile of this agent was also encouraging.

Lee S Schwartzberg, MD FACP

EXPERT COMMENTARY

Recognition that overexpression of HER2 in a subset of patients with breast cancer is associated with a more aggressive and deadly form of this disease led to the successful development of HER2-targeted agents, such as the monoclonal antibody trastuzumab and the small molecule intracellular inhibitor lapatinib. Despite the marked success achieved in slowing down the course of the disease in the metastatic setting, HER2+ cancers eventually develop resistance and progress. A new approach to targeting HER2 is the use of antibody–drug conjugates (ADC), which couple the specificity of a monoclonal antibody with the cytotoxic power of a covalently bound chemotherapeutic moiety, which ideally delivers its cytotoxic effect only to the cancer cell, sparing normal tissues of toxicity. With emerging technology, fashioning such drugs has become feasible. The power of this approach was demonstrated in a plenary presentation of the EMILIA trial at ASCO 2012 by Blackwell. The investigators compared the novel T-DM1, an ADC coupling the potent cytotoxic maytansine to trastuzumab, to standard capecitabine and lapatinib in trastuzumab-resistant HER2+ breast cancer. T-DM1 was both more effective, improving progression-free survival by 35% and a median of 3.2 months, and less toxic, with fewer adverse events or discontinuation due to toxicity. As such, T-DM1 will be a clear practice changer when it becomes commercially available. Rationally designed drugs can achieve the holy grail of cancer treatment: better results and fewer side effects.

SUMMARY

OncologySTAT Editorial Team

Addition of lapatinib, an HER1/2 tyrosine kinase inhibitor, to capecitabine has been shown to delay time to disease progression in patients with HER2-positive advanced breast cancer after prior therapy with trastuzumab, an anthracycline, and a taxane. Unfortunately, progression subsequently occurs, with HER2 overexpression continuing beyond progression and no standard HER2-directed regimen available.The antibody–drug conjugate (ADC) trastuzumab–emtansine (T-DM1) uses a novel thioether linker molecule to combine the selective delivery of DM1, a derivative of maytansine, with trastuzumab. Thus, this linker is thought to target HER2-expressing cancer cells while limiting exposure of DM1 to normal tissue. Based on preliminary evidence, the open-label EMILIA study was designed to evaluate the antitumor activity of T-DM1 in patients with advanced HER2-positive breast cancers that were refractory to multiple lines of therapy.

Patients in the study had received trastuzumab, lapatinib, a taxane, an anthracycline, and capecitabine. In addition, patients were treated with and then progressed on >2 anti–HER2-directed therapies in the advanced disease setting. Exploratory analysis of efficacy based on biomarker status was included. The study enrolled 110 patients. Efficacy and safety analysis included all who received >1 dose of T-DM1 (given intravenously at 3.6 mg/kg every 3 weeks). Primary endpoints were overall response rate (ORR) as reviewed by an independent radiologic facility (IRF). Secondary endpoints were clinical benefit rate (CBR), duration of objective response (DOR), progression-free survival (PFS), and pharmacokinetic (PK) profile.

Excluding hormonal therapy, patients had received a median of 8.5 prior therapies; a median of 7.0 for metastatic disease. By IRF review, 38 patients achieved objective tumor responses (ORR, 34.5%; 95% CI, 26.1%–43.9%). Median PFS was 6.9 months (95% CI, 4.2–8.4 months). ORR was similar for the entire cohort and for patients with progressive disease after trastuzumab, lapatinib, and chemotherapy. Median DOR was 7.2 months (95% CI, 4.6 months–not estimable [N/E]).

By investigator review, ORR was 32.7% (95% CI, 24.1%–42.1%), median DOR was 9.7 months (95% CI, 7.1 month–N/E), and median PFS was 5.5 months (95% CI, 4.2–7.9 months).

Centrally assessed HER2 expression analysis showed HER2-positive disease in 95 patients and HER2-normal disease in 15 patients. ORR by IRF review was 41.3% (95% CI, 30.4%–52.8%) vs 20.0% (95% CI, 5.7%–44.9%), respectively. Median PFS was 7.3 months vs 2.8 months, respectively. No association between response to T-DM1 and marker status for HER2 mRNA level, FISH copy number, or phosphatidyl inositol-3-kinase (PI3K) mutation status emerged.

Safety with T-DM1 appeared promising. Therapy was discontinued because of toxicity in 7 patients. Dose reductions occurred in 18 patients, most often associated with serum transaminase abnormalities and thrombocytopenia. The most common adverse events (AEs) were fatigue (61.8%), nausea (37.3%), and thrombocytopenia (38.2%). Thrombocytopenia (9.1%), fatigue (4.5%), and cellulitis (3.6%) were the most commonly reported >grade 3 events. Grades 4 and 5 AEs were reported in 6 and 3 patients, respectively. Half-life of T-DM1 was 3.96 days, with no significant accumulation during treatment. In this study, T-DM1 was active and had acceptable toxicity in a group of patients with advanced HER2-positive breast cancer who had progressive disease despite receiving both trastuzumab and lapatinib-based therapy and multiple chemotherapy regimens. Thus, T-DM1 may offer a new standard in this population that has limited treatment options.

In addition, activity was seen in a subgroup of patients designated as HER2-normal by central testing, indicating that tumors with HER2 expression below currently used levels may respond to T-DM1. Very low plasma levels of free DM1 associated with the novel linker used in T-DM1 is likely responsible for the favorable efficacy and safety profile of this agent. Combined with recent positive data of ADC targeting CD30 in lymphoma, these data suggest that ADC may represent a novel therapeutic paradigm with broad applicability.

A phase III trial of T-DM1 will be conducted in patients randomly assigned to either single-agent T-DM1 or physician’s choice.

Hopeful

[gdpawel]

Harold J. DeMonaco, MS
Director of the Innovation Support Center
Massachusetts General Hospital

Journalists’ reporting on the information presented at the annual meeting of the American Society for Clinical Oncology (ASCO) is always interesting and this year is no exception. Cancer, after all, is a disease that can strike fear in the heart of just about everyone. So, it is understandable that many with the disease along with their friends and family members will be interested in realistic stories about new and promising treatments. But realism is not always present in the stories written about the ASCO meeting. Phrases that should never be used in a news report (breakthrough, miracle, stunning, etc.) seem to appear with some frequency. This year, stories about the results of a phase 3 trial of the experimental drug T-DM1 unfortunately follow the troubling trend of hyperbole and incomplete reporting.

This year’s media star of the ASCO meeting is a drug-antibody combination known as T-DM1 or trastuzumab emtansine. The phrase “smart bomb” appears in many of the stories we have seen, as does “magic bullet.” The phrase “magic bullet” was made popular in the 1940’s biopic film on the life of Dr. Paul Ehrlich and his development of a drug treatment for syphilis. Ehrlich envisioned his drug, salvarsan would selectively target the bacteria that caused syphilis and not produce any side effects. Although effective, salvarsan proved to be far less magical than it originally appeared, producing significant side effects. It was replaced with the discovery of penicillin, a far less toxic and more effective treatment.

T-DM1 is an antibody-drug conjugate and is designed to bind specifically to HER-2 receptors in breast cancer cells. Once bound to the HER-2 receptor, the toxic component (DM1) is released into the cancer cell. In theory the drug-antibody combination would only strike at HER-2 receptor positive cells while leaving normal cells unscathed. The results of the Phase 3 EMILIA study of T-DM1 in patents with advanced HER-2 receptor positive beast cancer were presented yesterday. And once again, many in the media appear to have only half read the report.

Here are a few of the story headlines I found online:

New ‘smart bomb’ drug attacks breast cancer, doctors say
Roche Smart-Bomb Cancer Drug Delays Breast-Tumor Growth
Breast cancer’s magic bullet?

The Phase 3 EMILIA study compared T-DM1 with a standard regimen for HER-2 positive patients who have failed previous treatment with Herceptin and a taxane chemotherapy drug. About 500 patients were treated in each arm. Here are the interim results from the company’s press release:

T-DM1 patients had a median time to disease progression of 9.6 months as compared to 6.4 months for the control patients

T-DM1 response rate was 43.6% as compared to 30.8% for the control group

T-DM1 one year survival was 84.7% as compared to 77% for controls

T-DM1 time to symptom progression was 7.1 months compared to 4.6 months in the control group

As for toxicity, T-DM1 patients had fewer grade 3 or higher side effects (40.8%) compared to those who received standard treatment (57%). It is important to remember that these results are interim and the final story won’t be known until 2014.

Here are a few of the snippets from the media’s reporting:

“Doctors have successfully dropped the first “smart bomb” on breast cancer, using a drug to deliver a toxic payload to tumor cells while leaving healthy ones alone.” Balderdash. T-DM1 is clearly not without side effects and does not leave healthy cells alone.

“An experimental breast cancer drug from Roche Holding AG (ROG) that carries chemotherapy directly into malignant cells while bypassing healthy ones delayed tumors longer and with fewer side effects than an established therapy.” True, but let’s put the results into perspective. The drug does not bypass healthy cells and 40% of patients had severe side effects from T-DM1.

“An experimental drug has shown stunning results in delaying the progression of a specific type of breast cancer and prolonging the lives of patients.” Stunning? How stunning is a 3 month difference in disease progression and an absolute difference of 6.3% in one year survival?

“For patients facing metastatic breast cancer, this is a breakthrough.” Promising, yes. But it is not a breakthrough. At least not based on the interim report.

The ability to specifically target cancer cells is certainly a worthy goal and the development of T-DM1 is a clear step in the right direction. The drug worked in less than half the patients treated in prolonging the disease-free interval and was not without significant side effects. That’s better than anything available at the moment. But it is remains to be seen if it is a “magic bullet, smart bomb or miracle drug.”

http://cancerfocus.org/forum/showthread.php?t=3768

[gdpawel]

Vancouver, B.C. June 11th, 2012 – biOasis Technologies Inc. announced that research underway at Texas Tech University Health Sciences Center has yielded some compelling data on preclinical studies designed to evaluate the pharmacokinetics of BT2111 (a proprietary conjugate of Transcend and Herceptin) in animal models of breast cancer metastasis to the brain.

The studies were conducted for biOasis under the direction of Drs. Quentin Smith and Paul Lockman, both recognized experts on the Blood-Brain Barrier and in evaluating drug delivery to the central nervous system for the treatment of brain tumors. The data showed that 6.6% of the injected dose of BT2111 penetrated the Blood-Brain Barrier and entered brain tissue.

This is consistent with previous studies showing that Transcend can effectively deliver several types of different compounds to the brain. The rate of BT2111 uptake into the brain was 1000-fold greater than Herceptin on its own. BT2111 was clearly present in the metastatic breast cancer tumors as determined by measurement of radioactive molecules using phosphorescence imaging of normal brain and brain metastases.

The uptake of BT2111 into the brain was similar to that observed for the Transcend vector alone, supporting previous observations that Transcend can effectively carry large biologics across the Blood-Brain Barrier. The next steps at Texas Tech University are to complete the study plan to show that the delivery of BT2111 into the brain has a therapeutic effect on metastatic breast cancer.

BT2111 is a conjugate between biOasis’ Transcend brain delivery vector and trastuzumab (trade name Herceptin), a humanized monoclonal antibody used clinically in the treatment of HER2+ breast cancer. It is reported that up to 30% of HER2+ breast cancer patients develop brain metastasis for which therapeutic options are limited. Because of its ability to cross the blood- brain barrier, biOasis is researching the potential of BT2111 for treatment of HER2+ metastatic breast cancer in the brain.

biOasis Technologies Inc. is a biopharmaceutical company in Vancouver, Canada. Based on Transcend, a proprietary brain delivery platform of biOasis, the Company is focused on creating new drugs that can cross the blood-brain barrier to address unmet medical needs in the treatment of brain diseases such as neurodegeneration, metastatic cancer and metabolic diseases.

[gdpawel]

The FDA just approved the new treatment for about 20% of breast cancer patients who have a particular form of the disease that overproduces the protein HER-2.

The drug now called Kadcyla, combines the Herceptin with a powerful chemotherapy toxin and a third chemical linking the medicines together. The chemical keeps the drugs intact until they bind to a cancer cell, where the medication is released.

The cost of the drug is about $9,800 a month or $94,000 for a typical course of treatment. It is about twice the price of Herceptin itself and similar to the price of some other new cancer drugs.

The label of Kadcyla has a warning saying the drug can cause liver toxicity, heart toxicity and death. It can also cause serious birth defects or fetal death for women of childbearing age.

http://www.fda.gov/NewsEvents/Newsro.../ucm340704.htm

The US Food and Drug Administration (FDA) today approved ado-trastuzumab emtansine (Kadcyla, Genentech), also known as T-DM1, for the treatment of patients with HER2-positive metastatic breast cancer.

T-DM1 is indicated for patients who were previously treated with the anti-HER2 therapy trastuzumab (Herceptin, Genentech) and a taxane chemotherapy.

This product offers a new twist on an older product; it is an antibody–drug conjugate in which the HER2-targeted antibody trastuzumab is chemically linked to the cytotoxin mertansine (DM1). The antibody homes in on HER2 breast cancer cells, delivering the chemotherapy directly to the tumor, which reduces the risk for toxicity.

T-DM1 "delivers the drug to the cancer site to shrink the tumor, slow disease progression, and prolong survival," said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products at the FDA Center for Drug Evaluation and Research, in a press statement. "It is the fourth approved drug that targets the HER2 protein."

In the pivotal phase 3 EMILIA study, patients receiving T-DM1 survived nearly 6 months longer than patients receiving the standard therapy of lapatinib (Tykerb) plus capecitabine (Xeloda) (median overall survival, 30.9 vs 25.1 months). Also, there were fewer grade 3 or higher (severe) adverse events with TDM-1 than with standard therapy (43.1% vs. 59.2%), according to the company.

The approval represents a "momentous" day in breast cancer, said Kathy Miller, MD, from Indiana University in Indianapolis, in her Miller on Oncology Medscape blog.

"Our HER2-positive patients with metastatic disease have another very powerful therapy that offers the real hope for prolonged disease control with less toxicity," she said.

"This is the classic light-beer scenario; it's less filling and tastes great," she summarized, adding that T-DM1 was more effective in EMILIA than standard therapy on every outcome: overall response rate, disease-free survival, progression-free survival, and overall survival.

However, another expert sees T-DM1 in a less dramatic light.

Steve Vogl, MD, a private practitioner and former academic who practices in the Bronx, New York, called T-DM1 a "nice" drug when he discussed the product in an online essay last year.

T-DM1 causes "no alopecia, little neutropenia, and only moderate thrombocytopenia. It requires only a short infusion every 3 weeks, lacks cumulative toxicity, and has a response rate as first-line chemotherapy that is about the same as that of docetaxel and trastuzumab, with apparently longer remissions," he wrote.

However, Dr. Vogl called the EMILIA control regimen (lapatinib and capecitabine) "distinctly suboptimal" and not a standard of care, even though it is an FDA-approved treatment option in this setting.

"TDM-1 does not meet [the] goals of a major advance," wrote Dr. Vogl, who explained that such an advance must cure some patients, increase the rate of clinical complete remission, or produce a high rate of very long partial response.

TDM-1 does not provide a "major change in prognosis" for women with metastatic disease who have progressed on trastuzumab treatment, he wrote, adding that it is likely to be "very expensive."

Study Data and Boxed Warning

The international open-label EMILIA study involved 991 patients with HER2-positive locally advanced breast cancer or metastatic breast cancer who had previously been treated with trastuzumab and a taxane chemotherapy. The study met the coprimary efficacy end points of overall survival and progression-free survival (assessed by an independent review committee).

Median progression-free survival was longer with TDM-1 than with lapatinib plus capecitabine (9.6 vs 6.4 months). In addition, patients treated with TDM-1 lived significantly longer without their disease getting worse (hazard ratio [HR], 0.65; reduction in risk of disease worsening or death, 35%; P < .0001).

The risk of dying was 32% lower with TDM-1 than with lapatinib and capecitabine (HR, 0.68; P = .0006).

For patients receiving TDM-1, the most common adverse events (occurring in more than 2% of participants) of grade 3 or higher were low platelet count (14.5%), increased levels of enzymes released by the liver and other organs (8%), low red blood cell count (4.1%), low levels of potassium in the blood (2.7%), nerve problems (2.2%), and tiredness (2.5%).

T-DM1 was reviewed under the FDA's priority review program, which provides for an expedited 6-month review of drugs that might provide safe and effective therapy when no satisfactory alternative exists, or that offer significant improvement over comparable products on the market.

T-DM1 is being approved with a boxed warning that alerts patients and healthcare professionals that the drug can cause liver toxicity, heart toxicity, and death. The drug can also cause severe life-threatening birth defects, so pregnancy status should be verified prior to starting T-DM1 treatment.

Dr. Vogl has disclosed no relevant financial relationships. Dr. Miller reports financial ties with Genentech, Bristol-Myers Squibb, AstraZeneca, Roche, and Clovis Oncology.

Citation: FDA Approves New Treatment for Metastatic HER2 Breast Cancer. Medscape. Feb 22, 2013.

http://cancerfocus.org/forum/showthread.php?t=3768

[ElaineM]

Thanks for sharing these articles.