Anita T. Shaffer

Anitbody-drug conjugates (ADCs), a two-in-one drug treatment strategy, might help meet the pressing need for new therapies for metastatic triple-negative breast cancer (TNBC), according to Dr. Aditya Bardia, an assistant professor of medicine at Harvard Medical School and attending physician in medical oncology at Massachusetts General Hospital in Boston.

ADCs consist of an antibody, which homes in on proteins that sit on the surfaces of cancer cells, and a potent chemo- therapy equipped to kill those cells. A linker joins the two drugs and releases the chemotherapy once it has entered the cell and the target has been reached. The ADC furthest along in development for TNBC is sacituzumab govitecan. The Food and Drug Administration (FDA) has already approved another, Kadcyla (T-DM1), to treat HER2-positive breast cancer, a different subtype.

The promise of this class of drugs in TNBC represents a change in the way scientists characterize the disease. Until now, TNBC was defined by the fact that it would not respond to targeted drugs because it is not driven by hormones or an overexpression of the protein HER2.

“Triple-negative breast cancer, as we know, is a mixed bag,” Bardia said during a presentation at the 36th Annual Miami Breast Cancer Conference® (MBCC). “It’s a diagnosis of exclusion. It’s defined by something it does not have, rather than something that it has ... but there are actionable targets in triple-negative breast cancers.”

Bardia explained the need for new treatments in TNBC: For cases that have recurred or become resistant to treatment, there is no standard chemotherapy regimen; responses to treatment are usually short and followed by rapid relapse; and the disease commonly spreads to the gut and brain. With chemotherapy, the median time without disease progression is from 1.7 months to 3.7 months; the median overall survival from the onset of metastasis is 10 months to 13 months, Bardia said.

Against this backdrop, investigators are exploring strategies that take aim at targets in TNBC. Bardia said these targets fall into three main categories: cancer-driving genes such as BRCA and PIK3CA; intercellular signaling pathways such as the PI3K/AKT/mTOR and androgen receptor networks; and proteins on the surfaces of cancer cells, which allow drug delivery with ADCs.

The components of ADCs are “important considerations that could impact the efficacy/toxicity ratio” of an individual drug, Bardia said. One concern about side effects relates to ADCs’ apparent “bystander” effect, he said: “Some of the (chemotherapy) payload leaks from the cancer cell and affects cells that do not express that antigen” — in other words, healthy cells.

The precedent for ADC activity in breast cancer was set in 2013 with the FDA’s approval of Kadcyla, which linked a HER2-targeted antibody and a microtubule inhibitor and was approved for patients with HER2-positive, metastatic breast cancer who had previously received Herceptin (trastuzumab) and a taxane chemotherapy.

During his presentation, Bardia reviewed data for three emerging ADCs: sacituzumab govitecan (IMMU-132), which targets the protein TROP-2; ladiratuzumab vedotin, which targets LIV1; and trastuzumab deruxtecan (DS-8201), which targets HER2.

In the ADC pipeline, sacituzumab govitecan has reached the most advanced stage of development. It combines SN-38, an active metabolite of the chemotherapy irinotecan, with a drug targeted against TROP-2, which is expressed on the cells of metastatic TNBC and many solid cancers. In preclinical studies, findings showed that the drug conjugate delivered up to 136-fold more SN-38 compared with standard irinotecan, Bardia said.

In a phase 2 trial, sacituzumab govitecan elicited a confirmed objective response rate (the percentage of patients whose treated cancer shrinks or disappears) of 33.3% in the 108 participants, which included one man. The median progression-free survival (the time from when treatment started until disease progressed) with sacituzumab govitecan was 5.5 months and overall survival was 13.0 months — all higher numbers than would be expected with standard chemotherapy drugs.

Responses occurred at a median of two months and lasted an estimated median of 7.7 months. Notably, patients were able to remain on sacituzumab govitecan longer than they had on prior therapies, suggesting that previous treatments had not made their cancer resistant to it, said Bardia, who is the lead investigator on the study.

The most frequently reported side effects, of any severity, were nausea (67%); neutropenia, a lack of sufficient neutrophils in the blood (64%); anemia (50%); diarrhea (62%); and fatigue and weakness (55% each), Bardia said. Events that were severe or medically significant but not life-threatening included neutropenia (26%), anemia (11%), fatigue/weakness (11%), diarrhea (8%) and nausea (6%). Life-threatening neutropenia was reported in 16% of participants. These side effects can occur with irinotecan because of the small amount of drug that leaks into the bloodstream but generally are less frequent and severe than those seen with regular chemotherapy.

Importantly, Bardia said, there were no reports of peripheral neuropathy (tingling and weakness in the extremities). That may be a noteworthy attribute if the tested drug is combined with other therapies that cause neuropathy.

The ADC is being explored in the multicenter phase 3 ASCENT trial (identified as NCT02574455 on clinicaltrials. gov) in patients with TNBC previously treated with at least two systemic chemotherapy regimens.

Although the FDA was evaluating sacituzumab govitecan under its priority review program, the agency decided in January to delay approval, raising questions regarding chemistry, manufacturing and control matters, according to Immunomedics, the company developing the drug. The company said it is working with the FDA to resolve the issues.

In response to a question, Bardia said no issues have been raised concerning the clinical data, and pending trials have not been interrupted.

LADIRATUZUMAB VEDOTIN AND TRASTUZUMAB DERUXTECAN

The target for ladiratuzumab vedotin is LIV1, a trans-membrane cell adhesion molecule highly expressed in metastatic breast cancer. The drug employs monomethyl auristatin E, a microtubule disrupting agent, as its chemo- therapy payload.

The ADC is being evaluated in an ongoing phase 1 study in patients with metastatic TNBC who have received at least two chemotherapies for inoperable, locally advanced or metastatic disease (NCT01969643).

In findings presented at the 2017 San Antonio Breast Cancer Symposium, the objective response rate to the treatment was 25% (15 of 60 patients). The median progression-free survival was 11 weeks and the median duration of response was 13.3 weeks. All-severity side effects included hair loss (40.7%), neutropenia (24.7%), vomiting (23.5%) and peripheral neuropathy (19.8%).

Bardia highlighted a third ADC under study: trastuzumab deruxtecan (DS-8201), which targets HER2 but has shown efficacy among patients with low HER2 expression. In a phase 1 study, the objective response rate to the drug was 50% (17 or 34) in patients with HER2-low breast cancer. It is also being tested in other malignancies that express HER2, such as stomach cancer.

Trastuzumab deruxtecan is being developed under a breakthrough therapy designation, which means the FDA will expedite its development for patients with HER2- positive, locally advanced or metastatic breast cancer who have been treated with Herceptin and Perjeta (pertuzumab) and have disease progression after taking Kadcyla.

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Linking a targeted drug to a chemotherapy shows promise for treating metastatic triple-negative breast cancer.

Pairing Up Against Triple-Negative Breast Cancer

Recurrence rates were slightly improved overall when Perjeta (pertuzumab) was added to standard postoperative Herceptin (trastuzumab) therapy for patients with HER2-positive early breast cancer, but the addition of the drug had a larger benefit for patients with high-risk disease as time went on, according to early results from the phase 3 APHINITY trial.

The findings suggest that the dual HER2 targeting strategy in early-stage adjuvant settings should be stratified by risk level, experts said while discussing the results at the 2017 ASCO Annual Meeting.

The APHINITY findings demonstrated that patients who received adjuvant Perjeta along with Herceptin plus chemotherapy had an invasive disease-free survival (IDFS) rate of 94.1 percent after three years’ follow-up versus 93.2 percent for those who received Herceptin plus chemotherapy and placebo. In all, 4805 patients participated in the study.

The benefit was more pronounced among higher-risk subgroups, with the curve widening over time. After a follow-up of four years, the IDFS rate for patients with node-positive disease was 89.9 percent with Perjeta versus 86.7 percent with standard therapy. For participants with hormone receptor (HR)—negative disease, the IDFS rate with Perjeta was 91.0 percent after four years compared with 88.7 percent in the control group.

“These are very early results, but given that the absolute benefit from adding pertuzumab was modest, we should consider using it primarily in women with the highest risk — those with node-positive and hormone receptor-negative breast cancer,” said lead study author Gunter von Minckwitz, M.D., Ph.D., said in a statement.

Von Minckwitz, who is president of the German Breast Group in Neu-Isenburg, Germany, said the study met its primary endpoint by exceeding a preset threshold for reducing the risk of an IDFS event. He said the Perjeta -containing regimen reduced the risk of developing invasive breast cancer by 19 percent. After a median follow-up of 45.4 months, 7.1 percent (171 patients) in the Perjeta group had developed invasive breast cancer, compared with 8.7 percent (210 patients) in the standard therapy group.

The number of patients needed to treat to achieve benefit was 112 for the study overall, 63 in the HR-negative subgroup, and 56 in the node-positive subgroup.

The APHINITY trial results represent “a step forward in the treatment of HER2-positive breast cancer,” said ASCO expert Harold J. Burstein, M.D., Ph.D., FASCO, during a presscast on June 5, where the findings were discussed. “The relatively narrow benefits in numerical terms that you are seeing reflect the overall good prognosis.”

Burstein, an associate professor at the Dana-Farber Cancer Institute, said the prognosis for HER2-positive breast cancer had evolved “from worst to first” in the 12 years since adjuvant Herceptin was first shown to improve disease-free survival for patients with HER2-positive breast cancer. “Because of that success, when you look at data from studies like the APHINITY trial, the boats have been raised very high.”

In translating the potential for the dual HER2 regimen into clinical practice in early breast cancer, Burstein said the strategy seems most beneficial in the subgroups where it showed more activity but not for patients with stage 1 disease where the risk of recurrence is less than 5 percent.

 “In the management of HER2-positive breast cancer, we really are seeing two diverging strands,” Burstein said. “For low-risk, particularly stage 1 tumors, there’s a lot of talk about de-escalating regimens, finding biologically driven regimens, and sparing patients longer durations of treatment or extra medicines and, on the other extreme for higher-risk cases, demonstrating that additional anti-HER2 therapy will help lower the risk of recurrence.”

Perjeta and Herceptin are monoclonal antibodies that target HER2 activity by different mechanisms of action. Perjeta targets the HER2 dimerization domain, blocking its interaction with other HER family members including EGFR, HER3 and HER4, while Herceptin inhibits proliferation of HER2-overexpressing tumor cells.

The FDA has approved Perjeta in combination with Herceptin and docetaxel as neoadjuvant therapy for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (>2 cm or node positive). The combination also is approved for HER2-positive metastatic disease.

The APHINITY trial sought to determine whether the addition of Perjeta would improve outcomes in the adjuvant setting. The study recruited patients with T1-3 HER2-positive early breast cancer who had undergone mastectomy or lumpectomy. Overall, 63 percent of the participants had node-positive disease, and 36 percent had HR-negative disease.

Participants were randomized to receive adjuvant chemotherapy for 18 weeks and one year of either Perjeta plus Herceptin (2,400 patients) or Herceptin plus placebo (2,405 patients). A choice between several standard anthracycline-taxane sequences or a nonanthracylcine (TCH) regimen was permitted. Additionally, patients could receive radiotherapy and/or endocrine therapy after the end of adjuvant chemotherapy.

Von Minckwitz said the addition of Perjeta did not significantly increase cardiotoxicity, which can be a worrisome adverse event with anti-HER2 therapy. The primary cardiac endpoint was heart failure, defined as New York Heart Association class 3/4 failure plus a drop in left ventricular ejection fraction (at least 10 percent from baseline and to up to 50 percent). Heart failure was reported in 17 patients (0.7 percent) in the Perjeta -containing arm versus eight participants in the standard therapy group (0.3 percent). Approximately half of the patients in each group recovered, and there were two cardiac deaths in each arm.

Diarrhea of grade 3 or higher severity was more common with the Perjeta -containing therapy, affecting 9.8 percent of patients in the safety analysis versus 3.7 percent of those who received standard therapy. Von Minckwitz said the incidence of diarrhea occurred predominantly during chemotherapy and more frequently among patients who were administered TCH.

The APHINITY study was funded by Hoffmann-La Roche Ltd, which is developing Perjeta and Herceptin along with Genentech, a member of the Roche Group.

Adding Perjeta (pertuzumab) to postoperative Herceptin (trastuzumab) improved survival in certain patients with breast cancer.

Adjuvant Perjeta Benefits Some Patients With Breast Cancer

With earlier intervention with Zytiga (abiraterone acetate) the risk of death was decreased by nearly 40 percent for men with high-risk advanced or metastatic prostate cancer who were newly diagnosed and now not yet received hormone therapy, according to findings of two clinical trials presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

Experts said results from the LATITUDE and STAMPEDE trials would immediately change clinical practice.

Results from the phase 3 LATITUDE trial demonstrated that the addition of Zytiga plus prednisone to androgen deprivation therapy (ADT) lowered the risk of death by 38 percent. The combination more than doubled median progression-free survival (PFS) to 33 months compared with 14.8 months for ADT plus placebo in men with newly diagnosed, high-risk metastatic disease.

In the STAMPEDE trial, which consisted of a broader population of high-risk hormone-naïve patients including some participants with nonmetastatic disease, results showed that the addition of Zytiga to standard initial therapy lowered the relative risk of death by 37 percent and improved the PFS by 71 percent. The three-year survival rate was 83 percent with Zytiga plus standard therapy compared with 76 percent for standard therapy alone.

“It is remarkable to see the similarity in survival benefit across the two studies in the metastatic population,” said Sumanta Kumar Pal, M.D., a medical oncologist at City of Hope in Duarte, California, who served as ASCO’s expert commentator during the presscast Saturday where both studies were discussed.

He said the LATITUDE data “should immediately reshape our treatment algorithms for prostate cancer, and Zytiga with conventional hormone therapy should become a new standard of care for men with high-risk metastatic prostate cancer.” He said the STAMPEDE data confirm that approach for metastatic patients but that more study is needed to move Zytiga forward for individuals with nonmetastatic disease.

However, Nicholas James, BSc, MBBS, Ph.D., lead investigator on the STAMPEDE trial, said Zytiga plus prednisone improves the standard of care for men with hormone-naïve prostate cancer regardless of metastatic disease status.

“Based on the magnitude of clinical benefit, we believe that the upfront care for patients newly diagnosed with advanced prostate cancer should change,” James said in a statement.

The evidence in favor of earlier treatment for patients with advanced or metastatic prostate cancer has been an emerging development in recent years, experts noted at the press conference. In 2014, results from the randomized phase 3 CHAARTED study involving 790 men demonstrated that the addition of docetaxel to ADT prolonged median overall survival (OS) for men with newly diagnosed metastatic, hormone-sensitive prostate cancer by nearly 14 months compared with ADT alone.

 In 2015, a noteworthy benefit was observed in another part of the STAMPEDE study, which is an ongoing multiarm, multistage randomized clinical trial being conducted in the United Kingdom and Switzerland. The much larger trial, which involved 2962 patients, demonstrated a median OS of approximately 77 months for patients receiving docetaxel plus standard therapy versus 67 months for standard therapy alone in men with newly diagnosed, hormone-naïve advanced prostate cancer.

Although docetaxel improves outcomes, toxicities associated with the chemotherapy agent are a concern, particularly for older patients who are more likely to develop metastatic prostate cancer, noted Pal. He said Zytiga “provides an important alternative to the use of chemotherapy.”

Zytiga has been approved by the FDA since 2011 in combination with prednisone for patients with metastatic castration-resistant prostate cancer. The drug, which is orally administered, blocks androgen production by inhibiting CYP17, an enzyme expressed in testicular, adrenal, and prostate tumor tissue.

“The benefit from early use of Zytiga we saw in this study is at least comparable to the benefit from docetaxel chemotherapy which was observed in prior clinical trials, but Zytiga is much easier to tolerate, with many patients reporting no side effects at all,” said Karim Fizazi M.D., Ph.D., lead author of the LATITUDE study, in a statement.

The next step for the research would be to determine whether adding Zytiga to docetaxel and ADT further improves outcomes, said Fizazi, who is head of the department of cancer medicine at Gustave Roussy, University Paris-Sud in Villejuif, France.

The multinational LATITUDE trial enrolled men who had not previously received ADT therapy and had at least two of three risk factors: Gleason score greater than or equal to 8, measurable visceral metastases or three or more bone lesions. Results presented at the conference were from the first interim analysis involving 1,199 patients: 597 in the Zytiga arm and 602 in the control group.

Patients with newly diagnosed metastatic disease live less than five years on average, Fizazi said. He said this category includes 3 percent to 5 percent of patients in the United States and other Western countries, and rises as high as approximately 60 percent of newly diagnosed patients in some Asian countries.

The co-primary endpoints for the study were OS and radiographic PFS. Based on results thus far, the International Data Monitoring Committee has unanimously recommended unblinding the study and allowing patients to cross over to the Zytiga arm.

 After a median follow-up of 30.4 months, the median overall survival (OS) had not yet been reached (NR) in the Zytiga arm; the median OS in the control group was 34.7 months. The OS rate at three years was 66 percent in the Zytiga group versus 49 percent with placebo.

The Zytiga -containing regimen also has been shown to significantly improve secondary endpoints compared with the control group in the time to pain progression (NR vs 16.6 months), prostate-specific antigen (PSA) progression (33.2 vs 7.4 months), chemotherapy (NR vs 38.9 months) and subsequent prostate cancer therapy (NR vs 21.6 months).

In terms of toxicities, the Zytiga -containing regimen resulted in higher rates of grade 3/4 adverse events compared with the control arm including hypertension (20.3 percent vs 10.0 percent); hypokalemia (10.4 percent vs 1.3 percent); elevated alanine aminotransferase (5.5 percent vs 1.3 percent), and elevated aspartate aminotransferase (4.4 percent vs 1.5 percent).

“We need to be cautious when using abiraterone in men who have an increased risk for heart problems, such as those with diabetes,” said Fizazi.

The STAMPEDE trial is the largest study of first-line Zytiga ever conducted in patients with locally advanced or metastatic prostate therapy. In all, 1,917 patients were randomized in a 1-1 ratio to receive either Zytiga at 1000 mg daily plus prednisone at 5 mg daily plus standard of care (SOC) versus SOC alone. SOC consisted of ADT for at least two years with radiotherapy required for participants with N0M0 disease and encouraged for those with stage N+M0.

Treatment duration depended on stage and intent to administer radiotherapy: patients not receiving radiotherapy or with M1 disease were eligible to continue treatment until radiological, clinical, or prostate-specific antigen (PSA) progression. Other patients continued therapy at least two years or until progression.

The median age of participants was 67 years (range, 39-85 years); 52 percent had prostate cancer that had spread, of whom 88 percent had disease that spread to the bone; and 95 percent were newly diagnosed.

At a median follow up of 40 months, 184 deaths had occurred in the Zytiga group and 262 deaths in the standard therapy arm. The median adjusted HR for the median OS was 0.63.  Zytiga -containing therapy also markedly improved skeletal-related outcomes with a 55 percent reduction in the time for such problems to develop.

Although most adverse events (AEs) were similar between the two groups, researchers reported that serious AEs occurred more frequently among participants who received Zytiga, with 41 percent of patients reporting grade 3/4 AEs compared with 29 percent in the standard therapy group.

As with the LATITUDE trial, the main AEs occurring more frequently with Zytiga were cardiovascular problems such as high blood pressure; there were also more liver problems. There were two treatment-related deaths in the Zytiga group and in the standard therapy group, researchers reported.

Some newly diagnosed patients with prostate cancer reduced their risk of death with earlier use of Zytiga, according to two trials presented at the ASCO Annual Meeting. 

Zytiga Can Be Paradigm-Shifting for Prostate Cancer Treatment

A web-based stress management program improved quality of life and lowered distress levels for patients who were newly diagnosed with cancer, according to a study that was presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

The randomized study demonstrated that most of the participants reported feeling distressed at baseline and that a structured online program guided by psychologists was an effective method of offering them assistance, researchers said when discussing the findings during a presscast in advance of the presentation.

“Our online stress management program was feasible with newly diagnosed cancer patients during active treatment,” said lead study author Viviane Hess, M.D., a medical oncologist at the University Hospital of Basel in Switzerland. “We were able to reach cancer patients via the Internet. At baseline, three of four patients were highly distressed, so we reached a target population in need of support.”

Hess said most patients who receive a cancer diagnosis experience a “high level of distress,” but do not have access to psychological support. She said studies in patients without cancer have shown that web-based, therapist-guided interventions can be as effective in helping individuals cope with mental disorders such as anxiety and depression.

In order to meet such needs, oncologists and psychologists designed the STREAM program as an intervention that covers eight weekly topics such as bodily reaction to stress, cognitive stress reduction, feelings and social interactions. For each topic, participants receive written and audio information and complete exercises and questionnaires. Psychologists review patients’ feedback on a weekly basis and offer written guidance and support through a secure online portal; patients can then respond in writing.

To test the STREAM program, 129 patients newly diagnosed with cancer were randomized within 12 weeks of starting anticancer treatment to an immediate intervention (64 patients) or to a control group who would have access to the program after a two-month period (65 patients). The psychologists were based in Basel, but the patients were living in Germany, Switzerland, and Austria.

Overall, the median age of the participants was 52 years (range, 46-58) and 84.5 percent were female. The cancer diagnoses covered approximately 10 tumor types; more than 70 percent had breast cancer while 8.5 percent had lymphoma, 5.4 percent each had gynecological or gastrointestinal tract cancers, 3.9 percent had lung cancer, 3.1 percent had central nervous system or head and neck cancer, 2 percent had urogenital tract cancer and 0.8 percent had skin or soft tissue cancer. Eighty-six percent had localized disease while 14 percent had metastatic disease.

To evaluate the program, investigators measured quality of life including fatigue using the Functional Assessment in Cancer Therapy-Fatigue (FACIT-F) scale, psychological distress with Psychological distress on the Distress Thermometer (DT), and anxiety and depression with the Hospital Anxiety and Depression Scale (HADS).

 Investigators found that patients who participated in the intervention program experienced significantly improved quality of life with FACIT-F scores that were an average of 8.59 points higher. Similarly, those who received the intervention had a greater improvement in their distress levels, with an average 0.85 decline on the DT scale. Anxiety and depression as measured by the HADS score also declined for the intervention group by 1.28 points but this difference was not statistically significant.

Hess said the findings support the use of remote technologies. “I think online psychological support will be much more important in the years to come, as the digital generation reaches the age when they are at higher risk of cancer. For them, it will be natural to use such online tools and communicate without face-to-face interaction, and so now is the time to standardize and validate the tools,” Hess said in a press release.

Researchers plan to translate the STREAM program, which is currently available only in German, into other languages.

Commenting on the research, ASCO expert Don S. Dizon, M.D., FACP, said the study demonstrated the value of psychological support after therapy starts. He said most oncologists assume patients will experience distress when initially diagnosed but that such feelings would abate as they undergo curative therapy.

“Trying to get these patients support can be an issue because they’re at cancer centers quite frequently for medical therapy,” he said. “Trying to squeeze psychological expertise into their treatment plans can become difficult. Utilizing an online system not only has been shown to be feasible, but the promise of being effective as well is quite grounded now in an evidence-based randomized trial.”

A recent study proved an online program to be helpful in reducing anxiety in many newly diagnosed patients. 

Anita T. Shaffer

Pairing Up Against Triple-Negative Breast Cancer

Adjuvant Perjeta Benefits Some Patients With Breast Cancer

Zytiga Can Be Paradigm-Shifting for Prostate Cancer Treatment

Online Program Decreases Anxiety in Patients Newly Diagnosed With Cancer

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