Laura Martin

One of the most promising findings in glioblastoma presented the 2015 ASCO Annual Meeting included an update on the overall survival (OS) benefit from the ReACT trial, a phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma.

Three phase II studies of rindopepimut in newly diagnosed, resected, epidermal growth factor receptor variant III (EGFRvIII) glioblastoma previously demonstrated encouraging progression-free survival (PFS), OS, and safety. Prior compassionate use experiences also demonstrated that similar results might be possible in relapsed patients.

The ReACT trial, presented at ASCO, showed this to be true.

After 6 months, PFS was 27% in the rindopepimut plus bevacizumab arm versus 11% in the bevacizumab plus placebo arm (

= 0.048) in patients who had relapsed and were bevacizumab na&iuml;ve.

Overall survival was 24% in the rindopepimut/bevacizumab arm compared with 17% in the bevacizumab/placebo arm. Median OS was 12 and 8.8 months in the rindopepimut/bevacizumab arm and bevacizumab/placebo arm, respectively.

spoke with David Reardon, MD, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, president of the Society for Neuro-Oncology, and lead author on the ReACT trial to better understand the significance of these results. In the interview, Reardon also speaks about another ongoing trial with potential, which looks at MEDI4736 for newly diagnosed patients with glioblastoma.

What are the most significant findings from the ReACT trial?

This [trial] is looking at a novel vaccine therapy for patients with recurrent glioblastoma called rindopepimut. It is a peptide-based vaccine targeting the EGFRvIII. This is a mutant growth factor that is found in approximately 30% of glioblastoma tumors. It is a tumor-specific antigen, meaning it&rsquo;s not expressed on any normal cells in the body; it&rsquo;s only present in a glioblastoma tumor. The vaccine targets that unique tumor-specific expression profile. The study that we presented at ASCO looks at rindopepimut plus bevacizumab versus bevacizumab plus placebo. This is a randomized placebo-controlled phase II study. The results that we&rsquo;ve seen with this vaccine are somewhat surprising. We did not expect much activity in the patients with recurrent disease, because they are heavily pretreated and their immune system is weakened. We were surprised to see that the vaccine showed impressive therapeutic benefit, even in patients with recurrence. Patients who had received the vaccine compared with placebo had a statistically significant survival benefit. This is the first immunotherapy of any kind that has been tested in a randomized clinical trial for glioblastoma to show a survival benefit. Patients who received the vaccine also had an improved progression-free survival as well as an improved radiographic response rate. We saw efficacy with the vaccine across the spectrum of different outcomes parameters, but most importantly, there was a demonstration of a survival benefit.

Surprisingly, the patients also had a very robust antibody response to the vaccine. That immune response correlated with and predicted survival benefit. So we may also have a biomarker to go along with the development of this therapeutic that can help guide us in understanding which patients are achieving the most benefit.

Was there any significant toxicity associated with the vaccine?

The vaccine is very well tolerated. There were no major side effects other than grade 1 or 2 skin irritation at the point of injection. This is typically no longer an issue a few days after the injection. So in addition to being something that has a therapeutic benefit, the vaccine is also very well tolerated without any significant side effects. There are not many cancer therapies that can offer that for our patients.

What is the current standard of care for this patient population, and does this study have the potential to change that?

There really is no effective therapy that has been shown to improve survival in patients with recurrence. Based on its radiographic response, the US Food and Drug Administration (FDA) approved bevacizumab. Unfortunately the benefit of bevacizumab in terms of survival is pretty limited. There are salvage chemotherapies that have also shown a very limited benefit. But we really don&rsquo;t have any effective therapies to offer these patients. So this vaccine is a very exciting advancement, both in terms of providing proof of concept in immunotherapy and also because it provides a treatment option for a population where there is really nothing available.

What other studies are you excited about in glioblastoma?

There is an ongoing clinical trial that is looking at a novel therapeutic MEDI4736 that is blocking PD-LI for newly diagnosed patients with glioblastoma. This is one of the first clinical trials launched to look at immune checkpoint blockade focusing on PD-1 and PD-L1 signaling for this indication. This is a very innovative trial design with three noncomparative cohorts of patients.

In one cohort of patients, their tumors lack MGMT methylation, and we know that these patients have a very poor response to chemotherapy. For these patients we are dropping the chemotherapy and adding a novel immune checkpoint inhibitor MEDI4736 with the standard radiotherapy, which we hope will improve their outcome.

The second cohort of patients has recurrent disease. These patients have progressed after standard of care therapy. These are patients that were na&iuml;ve to single-agent bevacizumab, which is the standard of care for recurrent patients in the United States. They will receive MEDI4736 as a single-agent therapy.

The third cohort consists of patients who are the most refractory and heavily pretreated. Patients in this cohort have progressed on bevacizumab and radiation. They will receive MEDI4736 and bevacizumab.

All three arms of this study are currently enrolling patients. There are six centers participating in this study. We look forward to results in the next 6 to 12 months.

Immunosuppression is a key factor associated with this cancer. We hope by blocking one of the key mediators of P1 and PDL-1 signaling with MEDI4736, we can provide a therapeutic benefit for these patients. We know that PDL-1 is almost ubiquitously expressed in these tumors, so the target is certainty present.

Articles

Targeted Oncology spoke with David Reardon, MD, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, president of the Society for Neuro-Oncology, and lead author on the ReACT trial to better understand the significance of the study results for patients with glioblastoma. 

Reardon on ReACT: First Immunotherapy to Show Benefit in Glioblastoma 

The treatment of patients with ovarian cancer has evolved from an approach focused on chemotherapy and surgery to one involving targeted therapies and monoclonal antibodies. Chief among the recent approvals in ovarian cancer were the VEGF inhibitor bevacizumab (Avastin) and the PARP inhibitor olaparib (Lynparza).

Bevacizumab gained approval in November 2014 in combination with chemotherapy for patients with platinum-resistant recurrent ovarian cancer. This decision was based on a 62% improvement in progression-free survival experienced by patients treated with bevacizumab compared with chemotherapy in the phase III AURELIA trial.

Shortly following this decision, in December 2014, the FDA approved olaparib along with a companion diagnostic to detect

mutations for the treatment of women with BRCA-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy. This accelerated approval was based on a 34% objective response rate seen in patients with BRCA-positive ovarian cancer in a single-arm phase II study.

Can you highlight some of the changes seen in the treatment of ovarian cancer in recent years?

To gain insight into the evolving field and remaining challenges,

interviewed Robert C. Bast, Jr, MD, vice president of Translational Research at the University of Texas MD Anderson Cancer Center. Bast highlighted the approval of bevacizumab as a major advance for patients with ovarian cancer; however, he added that early detection remained a significant challenge to improving outcomes.

: Care of patients with ovarian cancer really has evolved. For the last 15 years, a combination of carboplatin and paclitaxel after cytoreductive surgery has been the standard of care. We have tried to periodically add other conventional drugs and it has not improved outcomes. At the present time, bevacizumab has improved progression-free survival, but has only improved overall survival in a subset of patients. Bevacizumab is probably the major advance in community care after carboplatin and paclitaxel.

One of the most exciting things in the last few years has been the focus on better surgery. We have known for a while that taking out as much of the tumor as possible improves outcomes for patients, probably by influencing the effect of the chemotherapy. As we look retrospectively at different studies, we have found that if the disease can be completely resected, the results will be better. This is the case for any solid tumor. Our usual resection rate is about 30%, and we can identify a subset of patients with a 90% resection rate.

Where do you see treatment going in the future?

For the individuals who are not resected upfront, three cycles of chemotherapy reduce the disease enough that, post-operation, an 80% complete resection rate can be achieved. In other studies, upfront complete resection is correlated dramatically with improved outcomes. We don&rsquo;t know if three cycles of chemotherapy followed by resection will have results as good as upfront resection; however, with this strategy, the tumor can be completely removed for 80% of an individual. That is very promising.

About half of high-grade serous ovarian cancers have the

mutation. Only about 20% have germline or somatic mutations of

. There are problems with homologous repair in about 30%. Tests are being done to identify those individuals. Olaparib [which is approved for advanced ovarian cancer] and other PARP inhibitors, in combination with other targeted therapies, are currently being evaluated at different centers including MD Anderson.

With the new agents recently approved, what is the biggest challenge in the treatment of ovarian cancer?

The other possibility is PI3 kinase activation. About half of high-grade serous ovarian cancers have abnormalities in activation of PI3 kinase. There are combinations of PI3 kinase pathway inhibitors that are being investigated. There are severe toxicities from those combinations at this point, so we are going to have to determine how we can improve the therapy index going forward.

Over the last two decades, the 5-year survival rate for patients with ovarian cancer has improved significantly. However, we currently are curing no more than 30% of long-term ovarian cancers. That is related both to the persistence of drug-resistant cancer cells, but also to late diagnosis. If you can detect ovarian cancer in stage I or II, when it is still limited to the ovaries or the pelvis, you can cure 70% to 90% of patients with available surgery and chemotherapy. When the disease has spread to the rest of adnominal cavity or farther, as is the case in stage III or IV, the cure rate slips to less than 20%.

At present time, we are only detecting one-fourth of patients with stage I or II disease. One of the goals over the last 20 years has been to develop better early detection. There is currently a trial at MD Anderson where we are detecting stage I or II disease through CA-125 testing each year, which measures the amount of cancer antigen in the blood. When that goes up, we do an ultrasound or another imaging test and if that appears abnormal, then we do surgery.

How far are we from applying these findings to oncology practice?

There is a larger trial, the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS), in which 200,000 women are being studied. Of that 200,000, 50,000 are getting CA-125 testing each year and an ultrasound if their levels go up. That trial will turn out later this year and we are very much excited to find out if that test improves survival by improving early detection. At present time, only about 80% of ovarian cancers express CA-125, so we know we will miss 20% with this test.

At present time there is not a screening test that is approved for ovarian cancer for women at conventional risk for the disease. If the UKCTOCS trial is strongly positive, a community oncologist may consider using a rising CA-125 to trigger an ultrasound and detect early cancer. However, we need to first find out how that trial is going to turn out. Even if that trial is positive, we can do better. Using autoantibodies may improve the screening with CA-125 even further.

The treatment of patients with ovarian cancer has evolved from an approach focused on chemotherapy and surgery to one involving targeted therapies and monoclonal antibodies. 


New Agents Offer Hope in Ovarian Cancer, But Challenges Remain

Updated data from a phase II trial of ibrutinib (Imbruvica) in Waldenstr&ouml;m&rsquo;s Macroglobulinemia (WM) showed a 2-year overall survival (OS) rate of 95% with the BTK inhibitor. Initial results from the study supported the approval of ibrutinib in WM earlier this year.

The follow-up data, which were recently published in

, also showed an overall response rate (ORR) of 91% (median treatment time, 19.1 months) and a median 2-year progression-free survival (PFS) of 69%.

For expert insight on these new findings,

spoke with Steven P. Treon, MD, PhD, first author on the study and director of the Bing Center for Waldenstr&ouml;m&rsquo;s Macroglobulinemia at Dana-Farber Cancer Institute, where the study was conducted.

How significant are these updated results?

This study was the basis for the FDA approval. What we have learned with this follow-up is that the response rate went up in comparison with the data set that was submitted to the FDA. For the first time, we now have a chance to get a sense of what the PFS and OS impact are for the drug. I think this is particularly exciting given that patients, on average, had two prior therapies; about 40% of them were refractory. Taking into context with other available therapies, this is absolutely remarkable.

How does this compare to other therapies used to treat WM?

When you think about other therapies used with previously exposed patients, the response rates vary for single agents from 30% to 40%. The PFS with many of these agents is usually months up to 2 years, on the highest end. When you are looking at this data in comparison to other therapies, it represents a real advance for patients with WM. This is the first and only approved drug for treating patients with WM.

I think the other remarkable part to the story is how this therapy was discovered to be effective. About 3 years ago, we discovered the

mutation as being a highly prevalent mutation in patients with WM. It is seen in over 90% of patients. Rapidly, we were able to figure out

mutation signals and discovered that BTK was actually one of the key pathways that promoted survival of the tumor cells.

We proceeded to look at ibrutinib, and we were able to receive the first-ever breakthrough designation from the FDA for ibrutinib in WM. That designation had not been previously given to any other cancer. It was really the strong scientific evidence that allowed this fast-track approval. In just under 2 years since being given a breakthrough designation, we received FDA approval for ibrutinib in patients with WM and hopefully an approval will be forthcoming in Europe as well. It is now before the EMA.

What is the long-term impact of ibrutinib as a treatment option for WM?

It is changing the paradigm for how we treat patients. It represents the first targeted therapy for WM as opposed to the hand-me-down therapies that we had to rely on before. Previously, we looked at other related cancers and we would borrow those drugs and see if they worked in WM. This represents the first time we&rsquo;ve been able to use a therapy that is an on-target therapy for the tumor based on its mutation profile.

This is a safe and very effective way to treat patients with minimal toxicity, and it is in contrast to other therapies used to treat patients with WM that created serious side effects. These include, in some cases, debilitating neuropathy, immune suppression, and also risk for secondary cancers. Ibrutinib represents a new targeted therapy and a safe way of treating patients. It really contrasts itself in terms of efficacy and safety compared to existing therapies.

Are there any concerns or challenges with using ibrutinib for WM that oncologists should be aware of?

There are two main areas that are worth emphasizing. For patients who are on warfarin (Coumadin) or another medication that may be an anticoagulant, the use of ibrutinib should be avoided. The second important concern is that if patients have a history of an arrhythmia, they may see reoccurring atrial fibrillation. This does not mean the drug shouldn&rsquo;t be used, but patients with a history of arrhythmia should be approached carefully and, if reoccurring atrial fibrillation occurs, they should stop the drug. Once the patient&rsquo;s rhythm has been restored, they might be able to retry the drug at a lower dose.

Importantly, what we did see in this study is that antibodies that protect against infection, such as IgG and IgA, were not affected by ibrutinib. This is in contrast to other drugs that we used, where IgG and IgA often come down and predispose these patients to an infection. We did not see an infection signal in this study. We did not observe any unexpected infections or incidences of infections.

What are the next steps in studying ibrutinib for the treatment of WM?

mutations are highly prevalent in WM&rsquo;s impact outcome. For patients who did not have the

mutation, which represents 5% to 8% of all patients with WM, there was a low response rate to ibrutinib. We are trying to figure out why that is the case, and we are also trying to study those patients genomically to better understand what permits survival of their tumors so we can develop targeted therapy.

One-third of all patients with WM have the

mutation. This is an interesting mutation because the only cancer that we know of where this occurs, so far, is in WM. It makes the tumor cells less sensitive to ibrutinib, and requires that patients be maintained for longer periods of time on ibrutinib in order to see response. Now, we are trying to use CXCR4 inhibitors along with ibrutinib in order to improve responses in this patient population. We plan on starting a clinical trial, combining a CXCR4 inhibitor with ibrutinib, this year. We received funding from the Leukemia & Lymphoma Society to pursue this study.

Do you think the approval and success shown thus far with ibrutinib will lead the way for other similar therapies for WM?

We think that ibrutinib will open up the doors for other therapies that target the MYD88 pathway. This could include the development of other inhibitors, as well as drugs that can enhance ibrutinib activity. ABT-199, which affects BCL-2, has shown synergistic activity with ibrutinib. We just published a paper on that in the

When a drug is approved for an orphan disease like WM, it also attracts pharmaceutical companies to examine this disease. There is no question that it happened with the approval of ibrutinib. That means there will be more support for clinical trials and the development of new and targeted agents. Just a few years ago, there was very little interest in multiple myeloma. However, when the first drugs were approved, it suddenly opened the door for the development of additional agents. I think this will happen for WM, as well.

Updated data from a phase II trial of ibrutinib (Imbruvica) in WaldenstrÃ¶mâ€™s Macroglobulinemia (WM) showed a 2-year overall survival (OS) rate of 95% with the BTK inhibitor.

Updated Data Show 95% Two-Year Survival for Ibrutinib in WaldenstrÃ¶mâ€™s Macroglobulinemia

Novel combinations and immunotherapies have significantly expanded treatment options for myeloma. Numerous studies, including the ASPIRE and ELOQUENT-2 trials, have shown positive results for triple drug combinations. Additionally research into natural killer cells and monoclonal antibodies has further solidified the potential for immunotherapy to advance myeloma treatment.

, Sundar Jagannath, MD, director of the Multiple Myeloma Program at the Tisch Cancer Institute, professor of Medicine (Hematology and Medical Oncology), Mount Sinai School of Medicine, discusses the latest research advances in myeloma, and how these steps will impact the future treatment paradigm for the disease.

: What recent advances in relapsed myeloma treatment are the most significant?

The last ASH meeting (December 2014) was like a watershed period.  We heard about the ASPIRE trial results. It was lenalidomide and dexamethasone with or without carfilzomib in relapsed myeloma patients. This was the first trial that showed a three-drug combinationa proteasome inhibitor, lenalidomide and dexamethasone&mdash;was better than using lenalidomide and dexamethasone alone.

This was important because, often, we&rsquo;ve all been using bortezomib, lenalidomide, and dexamethasone in newly diagnosed myeloma patients without a clear-cut randomized trial giving us evidence-based medicine that the three drugs are better than the two. More importantly, the complete response rate was very high, the response duration or progression-free survival was better, and there was a trend for improvement in overall survival.

At the same ASH meeting, another study showed that pomalidomide with dexamethasone was also given to relapsed myeloma patients with or without cyclophosphamide. Here, the three-drug combination was again better than the two.  Moreover, the three-drug combination actually showed a trend in improvement in survival, showing that you have to do the best therapy upfront, especially in relapsed patients. If you wait for the patient to relapse again, the patient&rsquo;s general condition is not good and the disease is more refractory, so it is better to use optimal therapy upfront.

The same thing was repeated with pomalidomide, dexamethasone and bortezomib in another trial that was positive. The ELOQUENT-2 trial also came out positive. This looked at the three-drug combination of lenalidomide and dexamethasone with or without elotuzumab. This is an important theme right now.

Based on these studies, how would you best select therapy for a myeloma patient, especially a relapsed myeloma patient?

Only about 10% of patients in the United States participate in clinical trials. Therefore, the evidence-based medicine is generally for a patient population who is fit, healthy, and meets the eligibility criteria for that trial. When you go out into the general population you have comorbidities, patients who are unfit or frail, and you have different prior therapies than shown in these trials.

All of the trials I mentioned before that I was excited about have limitations as to who can participate. The choice of therapy in the general population will depend upon what the previous therapy was. Whether we use the same drugs as the patient has taken before or switch to another combination will depend on how long their prior response duration was. If the patient relapses after 2 years, they could be challenged with the same combination. If a patient progresses on that treatment, then you need to switch to another class of drugs.

How do natural killer cells play a role in the treatment of myeloma?

The importance of natural killer cells came out in the elotuzumab trial when the ELOQUENT-2 became positive. It is clear that natural killer cells are playing an important role because elotuzumab binds to SLAMF7, which is expressed in the myeloma cells, but also in the natural killer cells.  On the natural killer cells, the SLAMF7 has an adaptive protein, so when the antibody binds to it, it actually stimulates the natural killer cells. When elotuzumab binds to SLAMF7 on the myeloma cells, it doesn&rsquo;t have an adaptive protein; therefore, it is not a signaling molecule, it is just expressed in the cancer cells. Here, when the antibody binds, it targets the myeloma cells and the natural killer cells can destroy them. Because of this, you have an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism.

This is also true when we use anti-CD38 monoclonal antibodies. CD38 is highly expressed in plasma cells. When you use anti-CD38 monoclonal antibodies and they bind to the myeloma cells, they also engage the natural killer cells and the CD8 cells and get ADCC mechanism and kill the cells. They could also be directly cytotoxic. These antibodies are also powerful and very effective. For the first time, we realize that we can control myeloma by immune mechanism. The checkpoint inhibitors are soon going to be tried in myeloma, and we are anxious to see how they are going to play in the management of it.

What do you see as the role going forward with immunotherapy for myeloma?

From doing the genome analysis and following the patient from the time of diagnosis through multiple relapses until death, we realize that the immune mechanism is going to play an important role.

Every time a patient presents with newly diagnosed myeloma, they have multiple clones. The current available drugs are only suppressing the predominant clone. Another clone then emerges, which is resistant to the current therapy and you switch treatment, but then the patient develops more mutations and, eventually, the patient dies. The immune mechanism is completely independent of the molecule mutation. It is genome na&iuml;ve. What is happening in the nucleus doesn&rsquo;t matter, because the antibody binds to the cell surface and gets stripped of the cancer cells completely.

Novel combinations and immunotherapies have significantly expanded treatment options for myeloma. Numerous studies, including the ASPIRE and ELOQUENT-2 trials, have shown positive results for triple drug combinations.

Laura Martin | Authors

Articles

Reardon on ReACT: First Immunotherapy to Show Benefit in Glioblastoma

New Agents Offer Hope in Ovarian Cancer, But Challenges Remain

Updated Data Show 95% Two-Year Survival for Ibrutinib in WaldenstrÃ¶mâ€™s Macroglobulinemia

Jagannath Discusses Treatment Triplets, Immunotherapy for Myeloma