Tag Archives: KEYNOTE-012

ASCO 2017: Metastatic Breast Cancer Highlights

 

 

The American Society of Clinical Oncology (ASCO) Annual Meeting took place two weeks ago in  Chicago. I was among the estimated 38,800 people in attendance.

If all of the attendees were present at the same day at the same time, they would fill Fenway Park.  And if we could convince all of them to stop everything and  sing “Sweet Caroline” on the penultimate day of this five-day meeting–well, that would be a dream achieved.

ASCO got started in 1964 with the goal of putting the patient front and center. At a time when most cancer-focused organizations concentrated resources on pathology and research, the seven founding members stressed the clinical considerations and the care of patients with cancer.

As someone living with metastatic breast cancer, I am grateful ASCO is patient-centric. I attended plenary sessions featuring some brilliant and compassionate speakers as well as some sessions specifically  for patient advocates. I also visited some exhibitors, talked to some pharmaceutical companies about their latest efforts and tried to take in some of the many posters on display.

 

HORMONE RECEPTOR POSITIVE NEWS

Some say that CDK 4/6 inhibitors are revolutionizing treatment options for estrogen-receptor-positive metastatic disease. Palbociclib (Ibrance) can claim bragging rights for being first on the market. It has since been joined by Ribociclib (Kisqali) and a third option, Abemaciclib, is expected to gain FDA approval in the Fall of 2017.

As the Breast Cancer Research Foundation (BCRF) reported in this blog post: 

Dr. George Sledge presented new data from Monarch 2 that showed the addition of abemaciclib improved progression free survival from 9.3 months to 16.4 months, further demonstrating a clinical benefit of CDK4/6 inhibitors for this group of patients. In addition, early results from another trial suggest that abemaciclib may have some antitumor activity in brain metastases as well. These positive results suggest that abemaciclib will be approved later this year or in 2018.

Discussing the promising results seen with CDK 4/6 inhibitors, Dr. Ingrid Mayer of Vanderbilt University Medical Center summarized the current status of CDK4/6 in the treatment of HR+ metastatic breast cancer:

1) CDK4/6 inhibitors are likely to be most effective in combination with other treatments, as has been shown with endocrine (anti-estrogen) therapies.

2) CDK4/6 inhibitor are good options as second line therapies.

3) CDK4/6 should definitely be considered for treatment of HR+ metastatic breast cancer.

Some thoughts from a patient perspective: All three drugs are pills and don’t cause hair loss. Although most patients with Stage IV breast cancer will ultimately have IV chemotherapy at some point, CDK inhibitors are another option in the “least-toxic-option-first” tool box. Some patients may enjoy a long stretch of time before having to move on to another treatment.

Duly noted: Palbociclib and Ribociclib can cause blood counts to tank–neutropenia can be an issue. Unlike chemotherapy, however, counts generally rebound–it doesn’t appear to be a long-term consequence. Abemaciclib can cause loose stools. Lilly is actively evaluating Abemaciclib in lung cancer, pancreatic cancer, and patients with brain metastases.

Take the CDK Inhibitor Challenge: One practitioner said the decision to use one of these drugs vs. the other is  “like Coke vs. Pepsi.” Because these drugs are fairly new (and in one case not yet on the market) it remains to be seen why one would be given over the other. At the moment, Ribociblib is slightly cheaper than Palbociclib which carries a monthly (before insurance) price tag of $9,850.

Additional observations: When given in combination with antihormoneal therapy, the time to disease progression is significantly longer. But so far, there isn’t a survival benefit. “What we want to find out is if this will translate into patients living longer,”  said Dr. William Gradishar of Northwestern University’s Lurie Cancer Center at post-ASCO patient meeting hosted by Chicago’s Silver Lining Foundation.

“That’s not to minimize the delay in how long it take [before a patient] has to change therapy–that is very important–but ultimately we want to see patients living longer. So far that has been a little frustrating and may require a longer follow up.”

HER2 POSITIVE NEWS

Targeted therapies  like Herceptin (Trastuzumab ) and Perjeta (Pertuzamab) are the mainstays of HER2 positive treatment. When these two antibodies were added to chemotherapy, the survival of patients–not just progression-free survival, but patients’ actual survival–improved by over a year. “Is that good enough?” asked Gradishar. “No. but it’s actually a fairly dramatic improvement in outcomes that we don’t often see in the therapies we use. It’s dramatically changed how we take care of patients with this type of breast cancer.”

Gradishar then went on to discuss T-DM1 (Kadcyla) which he characterized as Herceptin attached to a chemotherapy drug. “We found through a series of trials if you give T-DM1 after the disease has gotten worse on Perjeta and Trastuzumab, you also incrementally improve patients’ outcomes.”

Although T-DM1 does incorporate chemotherapy, there are far fewer side effects than one would experience on chemo alone, thanks to its Herceptin-provided targeting capabilities.

What if a patient got T-DM1 first, rather than Herceptin and Trastuzumab–would it make a difference in outcome? Not really.  Here is how BCRF put it:

As more HER2-targeted treatments become available, there is a growing interest in combining these targeted therapies and reducing exposure to chemotherapies. T-DM1 (Kadcyla®) was originally approved as second line treatment based on results from the EMELIA trial. Those results led researchers to ask if T-DM1 could be a better first line treatment than current treatments.

The MARIANNE trial was a Phase III study comparing dual HER2- targeting (adding pertuzumab to T-DM1) to standard of care (trastuzumab plus chemotherapy. New data from the MARIANNE trial were presented this week that showed that addition of T-DM1 was as good as, but not better than the standard of care. There were fewer adverse effects however, which suggests T-DM1 may be an option for first line HER2+ metastatic breast cancer patients. Results from other trials, like ALTERNATIVE, suggest that in patients with HER2+/ HR+ metastatic breast cancer, combining dual HER2-targeted therapies with hormone therapy may be as effective as regimens that include chemotherapy.

Hey MARIANNE: Although some might say the MARIANNE results were disappointing, Gradishar offered a more pragmatic perspective: “It tells us we have equally effective drugs that can be used and that’s a good thing.”

Not forgetting SOPHIA. . . This wasn’t the focus of an ASCO 2017 presentation, but for HER2 positive patients tracking new developments, the ongoing phase III SOPHIA trial (NCT02492711), researchers are comparing margetuximab plus chemotherapy with trastuzumab (Herceptin) plus chemotherapy. In a previous phase I study, margetuximab demonstrated single-agent activity in HER2-positive tumors, leading researchers to explore the regimen in the phase III trial.

In an interview with OncLive during the 2016 San Antonio Breast Cancer Symposium, Mark D. Pegram, MD, director of the Breast Cancer Oncology Program at Stanford Medicine, called margetuximab “an exciting molecule.” He explained patients in both arms of the study will receive chemotherapy of physician’s choice; there is a menu of options— capecitabine, gemcitabine, vinorelbine, and eribulin (Halaven)—and they’ll get that in combination either with trastuzumab in the control arm or in combination with margetuximab in the experimental arm.

“In this pivotal trial, it will go toe-to-toe against trastuzumab in the salvage setting after prior treatment with trastuzumab, pertuzumab (Perjeta), and trastuzumab emtansine (T-DM1),” Pegram told OncLive earlier this year.  “The primary endpoints are progression-free survival and overall survival. Patients with brain metastases—if they are previously treated and stable—are allowed to enroll, so that is not an absolute exclusion criteria. It is a fairly liberal eligibility and exclusion criteria. It is an important study that will test the hypothesis of whether you can go 1 above and beat trastuzumab.”

TRIPLE NEGATIVE NEWS 

“Triple negative breast cancer is notoriously difficult to treat with targeted therapies,” notes BCRF. “Since it doesn’t express hormone receptors or the HER2 receptor, there are fewer biological molecules to target. Data presented at ASCO does suggest there may be ways to determine which patients will respond best to different treatments.”

According to BCRF, Jelmar Quist from King’s College, London, presented data on a 4-gene signature of TNBC. Depending on if each of these 4 genes has high expression or low expression, six different subtypes can be determined. From these subtypes, it can be determined which patients would be most responsive platinum-based chemotherapy.

Poly (ADP-ribose) polymerase (PARP) inhibitors, have elicited both great excitement and significant disappointment in equal measure in recent years. At ASCO 2017, we saw that there might be some application for those with BRCA1 and/or BRCA2 mutations.

PARPs are a family of enzymes implicated in a host of key cellular processes, including chromosome stability, regulation of apoptosis, cell division, and transcriptional regulation and differentiation. A particularly important role of PARPs is in repairing DNA damage that results from everyday environmental stresses and DNA replication errors.

Gradishar explained that patients with the BRCA1 and BRCA2 mutations have a genetic predisposition to developing breast cancer–because of the mutations, the cell is sort of limping along–PARPs can potentially deliver another blow.

“So you have a tumor cell that’s already mutated–things aren’t working properly,” Gradishar said. “In a sense, you already have one hit–the cell isn’t working on all eight cylinders–it’s working on a few. If you come at the cell with another way of injuring it…if you were able to hit the cancer cell again, you might drive it into cell death and that would be a good thing. What PARP inhibitors do is prevent another pathway from repairing DNA. With the BRCA mutation there’s one hit, and now you knock the other leg out from the cell’s ability to repair itself.”

 

BCRF reports that results from the ABRAZO study suggest the PARP inhibitor, talazoparib, was well tolerated and may have antitumor activity in patients with TNBC and BRCA1 or BRCA2 mutations.

Overall for TNBC treatments, as BCRF Investigator, Dr. Leisha Emens, stated in her discussion of these trials, integrating the biology of TNBC tumors will be key to improving therapy selection for patients.

In a late breaking abstract presentation, Dr. Mark Robson, presented new data on OlympiAD study, a Phase III clinical trial comparing the single agent PARP inhibitor olaparib (Lynparza) to standard-of-care chemotherapy in patients harboring inherited mutations in BRCA1 or BRCA2 with HER2-negative metastatic breast cancer. Earlier this year, the study met its primary endpoint in showing an improvement in progression free survival of 7 months versus 4.2 months in patients receiving standard of care. At this week’s ASCO meeting, Dr. Robson presented additional analysis from the study. Sixty percent of patients in the olaparib group experienced tumor shrinkage compared to 29 percent in the chemotherapy group and subgroup analysis suggests that olaparib may be more effective in triple negative breast cancer, the most common BRCA- associated breast cancer subtype. You can read more about the study here.

Gradishar noted that most people with breast cancer don’t have BRCA mutations, but for that specific  patient population, OlympiAD showed promise. “This isn’t a home run, but it does demonstrate proof of principle–that these drugs are active in [this subset of patients].”

IMMUNOTHERAPY NOTES

Immunotherapy can take many forms–infusions, checkpoint inhibitors, vaccines and more. Although immunotherapy drugs have achieved some success in melanoma and lung cancer, it’s early days for breast cancer. “Although there are some signals, there’s not a lot we can hang our hat on and say [to date] these drugs have made a big difference, but we are hopeful that they will,” said Gradishar.

Results from KEYNOTE-012 showed that the immunotherapy drug, pembrolizumab (Keytruda) generally had few side effects and may be effective for TNBC patients. Gradishar described the drug as an antibody that interferes with tumor cells’ ability to fool the immune system. “It’s not targeted therapy, it’s not chemotherapy, it’s not antihormonal therapy. It’s a way of fooling the immune system so it can really activate itself against tumor cells.”

There were 170 patients on this trial. The results were not overly impressive (only about 5% of patients had evidence of tumor shrinkage), some who did respond continued on the therapy for upwards of a year.

“If they are going to get a response, it takes about three months,” said Gradishar. “Although the number of patients who did respond was modest, when they do have a response it can last a long time.”

SIDEBAR: Keytruda has come to the general public’s attention because former President Jimmy Carter has used it with good results for his melanoma.

A PARTING THOUGHT

At past ASCOs, sometimes there have been slim pickings for people with metastatic breast cancer–a few footnotes glossed over on the final day. That certainly wasn’t the case at the 2017 meeting.

We heard updates on numerous therapies for those with hormone-receptor positive disease as well as HER2 positive metastatic breast cancer. There wasn’t quite as much buzz in the triple-negative sector, but some potentially promising studies for a small TNBC subset–those who have BRCA1/2 mutations.

More ASCO News…

Eric Fitzsimmons, LBBC’s copy editor and content coordinator, offered these updates.

SHARE Webinar: Report Back from ASCO on Metastatic Breast Cancer

Tuesday, June 20, 2017

1:00 pm – 2:00 pm

Anne Moore, MD, Medical Director of the Weill Cornell Breast Center, will share her experiences from the American Society of Clinical Oncology’s June 2017 Conference. She will update us on the latest research from the conference as it relates to metastatic breast cancer. More information and registration is here. 

 

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