 Updated findings from the phase III RESONATE-2 trial presented at the 2016 ASH Annual Meeting showed that at 29 months’ follow-up, frontline ibrutinib (Imbruvica) reduced the risk of of progression or death by 88% versus chlorambucil in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

RESONATE-2 included 269 treatment-naïve patients aged ≥65 years with CLL or SLL. The study was the pivotal trial that led to the March 2016 approval of ibrutinib for the frontline treatment of patients with CLL/SLL.

The benefit with ibrutinib shown in the data presented at ASH extended across high-risk subgroups, such as patients with deletion 11q.

“This suggests that ibrutinib may be even more effective in these high-risk groups than what you would expect to see with any traditional chemotherapeutic regimen,” Danelle James, MD, said in an interview with 

, James, an assistant adjunct professor in the Division of Hematology-Oncology at the Chronic Lymphocytic Leukemia Research Consortium and head of Oncology at Pharmacyclics (an AbbVie company), the manufacturer of ibrutinib, discussed the updated RESONATE-2 data and the next steps with ibrutinib in CLL.

The phase III RESONATE-2 trial explored ibrutinib versus chlorambucil for the frontline treatment of patients 65 or older with active CLL. The trial was originally reported at the 2015 ASH Annual Meeting and showed an impressive progression-free survival (PFS) benefit, overall survival benefit, and benefit for response and hematologic improvement over chlorambucil.

At ASH, we shared 29 months of follow up with these patients and it shows impressive continued tolerability of ibrutinib. Seventy-seven percent of these 70-year-old patients continue to take daily ibrutinib. What is even more impressive is the PFS. About 90% of the patients are now progression-free with over 2 years of follow up.

It is interesting because what we traditionally consider to be bad prognostic features in CLL—such as deletion 11q or immunoglobulin heavy-chain gene-mutational status&shy;&mdash;did not confer any adverse outcomes with ibrutinib. It suggests that ibrutinib may be even more effective in these high-risk groups than what you would expect to see with any traditional chemotherapeutic regimen.

How could the findings with this agent impact the CLL community?

Ibrutinib is approved in all lines for CLL and SLL in the United States. It also has a broad approval outside the United States in the EU, so it is available as a single agent for patients to be treated in the frontline setting. The NCCN has given it several category 1 recommendations, including fairly large patient subsets in the frontline setting.

This updated data set will help bring physicians and patients more security and understanding of what the drug does over a long period of time. Interestingly, in addition to preventing disease progression, we see the quality of the responses get better over time. Therefore, we see patients who originally had a partial response now achieving complete responses to therapy.

For this study, we are going to continue to follow the patients. We haven’t even come close to establishing a median PFS in the frontline setting, so we really want to see what the true benefit is of ibrutinib by following those patients long term.

Right now, the program is also looking at ibrutinib in combination in the frontline setting and is looking at ibrutinib versus many other comparators. Basically, we want to review all of the standard comparators that you use to treat patients with CLL in the community, such as bendamustine and rituximab (Rituxan; BR), fludarabine, cyclophosphamide, and rituximab (FCR) and the obinutuzumab (Gazyva) and chlorambucil combination.

We have an ongoing study exploring ibrutinib in combination with obinutuzumab in terms of further developing the frontline program as well as 2 big studies looking at ibrutinib or ibrutinib/rituximab against FCR or bendamustine and rituximab.

 What are the toxicity concerns with ibrutinib?

In addition to diarrhea, we usually see grade 1/2 fatigue. It is a small proportion of patients who will get arthralgias. We also usually see low-grade bleeding events, in about up to 50% of the patients and that’s consistent with our label. Atrial fibrillation is seen in patients treated with ibrutinib, and that tends to also be an AE that resolves. However, that is probably one of the adverse events that physicians pay the most attention to with ibrutinib.

What other details from ASH regarding ibrutinib are important mention?

Susan O’Brien, MD, presented the 5-year follow-up from our first pivotal study of single-agent ibrutinib, the PCYC-1102 trial. These are 130 patients who have been followed now for over 5 years. Again, we see good tolerability; about 65% of the patients who are aged 65 and up are still taking daily ibrutinib. It speaks to the tolerability of the agent when a patient can remain on treatment for so long. Additionally, we see enduring remissions throughout the high-risk subgroups within that phase II clinical study.

Barr PM, Robak T, Owen CJ, et al. Updated efficacy and safety from the phase 3 RESONATE-2 study: ibrutinib as first-line treatment option in patients 65 years and older with chronic lymphocytic leukemia/small lymphocytic leukemia. Presented at: 58th ASH Annual Meeting and Exposition; December 3-6, 2016; San Diego, CA. Abstract 234.

The most frequent adverse events AEs with ibrutinib are traditionally grades 1/2. Diarrhea is one of our most common AEs. We have a safety poster that looks at a number of patients across the frontline setting, relapse setting, and long-term follow-up—establishing that ibrutinib has a nice tolerability profile. Most of the AEs are short-lived and resolved.

Articles

Danelle James, MD, discusses the updated RESONATE-2 data presented at the ASH Annual Meeting and the next steps with ibrutinib in CLL.
 

Frontline Ibrutinib Benefit Sustained in Pivotal CLL Trial Update

The Fc-modified monoclonal antibody margetuximab in combination with chemotherapy may offer a new treatment option for patients with HER2-positive metastatic breast cancer.

In 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.

SOPHIA is randomizing patients with HER2-positive metastatic breast cancer who had prior anti-HER2 targeted treatment to receive margetuximab or trastuzumab with the chemotherapy of physician’s choice.

 during the 2016 San Antonio Breast Cancer Symposium, Mark D. Pegram, MD, director of the Breast Cancer Oncology Program at Stanford Medicine, provided an overview of the SOPHIA trial and the continued need to advance treatment in HER2-positive breast cancer.

: SOPHIA is a randomized phase III pivotal registration trial exploring a new Fc domain-engineered antibody called margetuximab. It binds to the same epitope as does trastuzumab. However, it has enhanced immune-effector function. In other words, the Fc domain of margetuximab is engineered so that it has higher binding affinity for activating Fc gamma receptors on human immune-effector cells and lower binding affinity to some of the decoy negative regulatory receptors on those same cells.

Therefore, it is more potent in eliciting antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab can do this, too, but margetuximab is like a super-humanized antibody that can do it even more efficiently. The antibody is actually chimeric, so it has a murine-antigen specificity domain, but the Fc domain is all human amino acid sequence.

It is a very exciting molecule; it can augment the immune access of HER2 antibodies. 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). 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)&mdash;and they’ll get that in combination either with trastuzumab in the control arm or in combination with margetuximab in the experimental arm.

Are there earlier findings with this drug that demonstrate the rationale for the phase III trial?

What is the unmet need for a trial such as this one?

The primary endpoints are progression-free survival and overall survival. Patients with brain metastases—if they are previously treated and stable&mdash;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. Starting in the salvage setting&mdash;if that’s a positive trial&mdash;there will no doubt be a great interest to move up further in earlier lines.

Absolutely. There was a phase I dose-escalation study of margetuximab presented at ASCO a couple of years ago. It was quite exciting because heavily pretreated HER2-positive solid tumors had responses even during dose escalation with a single agent. One of the patients had HER2-positive breast cancer with prior progression—even after T-DM1&mdash;and still had an objective clinical response to single-agent margetuximab. It is anecdotal evidence so far, but it’s pretty promising. That really bodes well for the outcome of the phase III trial.

There is still a high unmet need in metastatic HER2-positive disease. Sadly, despite our best efforts and a plethora of very active agents—which have indeed improved overall survival significantly&mdash;they have not absolutely resulted in cures, except for the rare exceptional responders that we occasionally see.

However, it is too occasional so, in that regard, HER2-positive breast cancer is still a large lethal condition. We need better treatment. If we demonstrate success in the metastatic disease setting, there is nothing to stop up us from moving some of these new approaches into curable situations in the future. First, we have to prove that it is active and superior to trastuzumab.

Pegram Sheds Light on Margetuximab in HER2+ Breast Cancer

Although targeted therapies and immunotherapy are revolutionizing oncology, chemotherapy retains a key role in the treatment of advanced prostate cancer, with recent data showing profound benefits with docetaxel in newly diagnosed patients, according to William Oh, MD.

The recent positive findings seen with docetaxel come from 2 randomized trials: CHAARTED and STAMPEDE. In the larger STAMPEDE trial (2962 patients), adding docetaxel to standard hormonal therapy significantly improved survival among men with newly diagnosed, hormone-naïve advanced prostate cancer. The median overall survival (OS) was 81 months with docetaxel plus standard of care (hormonal therapy with or without radiotherapy) versus 71 months with standard of care alone (0.78; 95% CI, 0.66-0·93; 

 = .006). In the CHAARTED study (790 patients), the median OS was 57.6 months with the combination of docetaxel and androgen-deprivation therapy (ADT) versus 44 months with ADT alone (HR, 0.61; 95% CI, 0.47-0.80; 

According to Oh, these results are particularly interesting because docetaxel has already been available for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) for over a decade. He added that there were multiple negative trials involving combining another agent with docetaxel in mCRPC, which preceded the surprising discovery that the addition of the drug early on led to such benefits.

: Can you provide an overview of the role of docetaxel in metastatic prostate cancer?

 at the 2016 Chemotherapy Foundation Symposium, Oh, chief, Division of Hematology and Medical Oncology, professor of Medicine and Urology, Mount Sinai School of Medicine, discussed the continued significance of docetaxel in advanced prostate cancer.

: The role of docetaxel in hormone sensitive metastatic prostate cancer is probably one of the biggest new advances in the last 2 years, based on 2 large randomized trials: CHAARTED from the United States and STAMPEDE from the United Kingdom.

While everyone else in other cancers is looking at targeted therapies and immunotherapy, unfortunately, we’re still in the era of chemotherapy; however, the reason we’re in the era of chemotherapy is that docetaxel has a profound effect when used in newly diagnosed metastatic hormone sensitive prostate cancer.

In both studies the survival benefit was quite dramatic, ranging from up to 20 months of benefit in terms of the added benefit of chemotherapy in the group receiving docetaxel early. It’s 6 cycles of docetaxel given without prednisone within 4 months or so of the initiation of ADT for metastatic prostate cancer.

This was an interesting result because docetaxel, as everyone knows, has been approved for mCRPC for over a decade, and we have been using it in our practice and it has value in the setting for CRPC. Unfortunately, we were never able to enhance that effect in CRPC; in other words, there have been multiple negative clinical trials adding another drug to docetaxel in CRPC.

How has tolerability been with docetaxel in your patients?

This was a bit of a surprise when we found that docetaxel had so much added benefit when used early, and it makes some sense because obviously, we know that there are high-risk metastatic patients who have clones that are going to be resistant to primary hormonal therapy and by using early chemotherapy, we seem to be pushing off the cancer. We’re not curing any of these patients, but we are basically delaying progression enough that there is a significant survival benefit.

Tolerability is very, very important because this is an older group of men. The traditional approach would be ADT alone, which men don’t like but they can tolerate and live sometimes for many years with this treatment. Adding about 4 and a half months of treatment with docetaxel chemotherapy is not a trivial matter.

Now that said, the toxicity in general was very reasonable, and I have been using this now for the past 2 and a half years in my own practice, and I found that it is difficult in some patients but it is mostly neutropenia, fatigue, some fluid retention. These are side effects that we have understood to be related to docetaxel for many years, so I have made adjustments.

Any challenges with docetaxel that are important to tackle in the next couple of years?

For older patients, I might start with a lower dose, I might use growth factor if they are particularly at risk for neutropenia, but I have not had a lot of trouble with giving this treatment. Neutropenia is something that I would focus on, unfortunately it remains an issue, although I wouldn’t use prophylactic growth factor, but there was also differential effect in the 2 studies I mentioned. There was about a 6% rate of neutropenia in the American study but it was about 12% in the UK study, so we don’t fully understand those differences, but we are going to continue to monitor this situation.

I think the biggest question in the next few years is determining whether using these treatments earlier—the treatments that are approved for mCRPC&mdash;will have a more profound impact. That may or may not be true for some of the newer treatments that have been approved for mCRPC, such as abiraterone (Zytiga), enzalutamide (Xtandi), or radium-223 (Xofigo)&mdash;those that are being tested in the same population, and will be tested in randomized trials over the next few years.

What are the key takeaways on these docetaxel findings for community oncologists?

The real question is can we substitute those treatments for the benefit of chemotherapy with docetaxel, but we don’t know the answer yet. We’ll learn more about whether drugs like abiraterone or enzalutamide can be substituted for chemo, but for now, in general, it’s not an option, given the power and the magnitude of the benefit of early docetaxel.

I think this is one of the most profound survival benefits that we have seen in metastatic prostate cancer and that I have seen, basically in my entire career. While I’m very excited about the new treatments in mCRPC, I would strongly urge oncologists to talk to their urological colleagues—who don’t regularly see these patients&mdash;to refer these patients for early chemo.

The other thing I would emphasize is many of these men are older, but they may be very fit, and while some doctors are concerned about giving chemotherapy, for me, there is no upper limit of age for who I would give chemotherapy to. Many of the patients I have been treating recently have been in their 80s, I’ve given chemo to men in their 90s—it all depends on their physiologic age, and you can always give this chemotherapy if you think their risk of dying of cancer is high enough to justify the relative survival benefit.

James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. 

Sweeney CJ, Chen YH, Carducci M. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. 

William Oh, MD, discusses the continued significant of docetaxel in advanced prostate cancer.

Danielle Bucco

Articles

Frontline Ibrutinib Benefit Sustained in Pivotal CLL Trial Update

Pegram Sheds Light on Margetuximab in HER2+ Breast Cancer

Expert Discusses Docetaxel's Continued Significance in Prostate Cancer