Brielle Urciuoli

In the frontline treatment of patients with advanced melanoma, the PD-1 inhibitor pembrolizumab (Keytruda) continues to be a promising immunotherapy option, according to a presentation by Eric Whitman, MD, at the 14th Annual International Symposium on Melanoma and Other Cutaneous Malignancies.

Whitman, medical director of Atlantic Health System Cancer Care and director of the Atlantic Melanoma Center, cited the final results from the phase III KEYNOTE-006 study, which randomized 834 patients with unresectable stage III or stage IV advanced melanoma to 4 cycles of ipilimumab (Yervoy) at 3 mg/kg every 3 weeks (n = 278); 10 mg/kg of pembrolizumab every 3 weeks (n = 277); or 10 mg/kg of pembrolizumab every 2 weeks (n = 279).

Patients enrolled on the multicenter, open-label, randomized study previously received either 0 or 1 prior lines of therapy, excluding immunotherapy with CTLA-4, PD-1, or PD-L1 inhibitors. Of the overall patient population, 65.8% did not receive prior systemic treatment for their advanced melanoma. About 80% of the patients involved had positive PD-L1 staining, 18% had negative staining, and 2% of the population was unknown. Patients also had an ECOG performance status of 0 or 1.

Results from the trial showed that overall survival (OS)  which was a primary endpoint &ndash; was superior in both pembrolizumab arms compared with the ipilimumab arm. The 12-month OS rate was 74% for patients who had pembrolizumab every 2 weeks, 68% for patients who had pembrolizumab every 3 weeks, and 59% for patients receiving ipilimumab. At the 2-year mark, both pembrolizumab arms had a 55% OS rate versus 43% for those in the ipilimumab arm. The median OS at 2 years was not reached for either pembrolizumab treatment arm compared with 16 months for the ipilimumab arm (HR, 0.68; 95% CI, 0.53-0.87 for pembrolizumab every 2 weeks vs ipilimumab;

= .0009 and HR, 0.68; 0.53-0.86 for pembrolizumab every 3 weeks vs ipilimumab;

The overall response rate (ORR) was 37% for patients receiving pembrolizumab every 2 weeks, 36% for the every-3-week regimen, and 13% with ipilimumab (

<.001). The complete response (CR) rates were 12%, 13%, and 5%, respectively.

Based on the primary findings of this trial, the FDA approved pembrolizumab in December 2015 for the frontline treatment of patients with advanced melanoma, regardless of whether or not they harbor a

"The two different doses of [pembrolizumab] don't seem to matter," Whitman said, but added that this dosage information is essential for physicians to know when prescribing to their patients.

"There's an obvious survival benefit," Whitman added. "You can't underestimate this. When you're going to talk to a patient&hellip;there is nothing better than to be able to say, 'Statistics show that treating you with this is better than not treating you with this or treating you with the alternative examined in the trial. You have a reduced risk of dying. And, that is why they're sitting in your office-they're talking about how they want to live."

Aside from the efficacious outcomes with pembrolizumab, the safety profile is acceptable; however, Whitman emphasized commonly reported adverse events (AEs) such as diarrhea, colitis, and pneumonitis that are associated with the PD-1 inhibitor that need to be reported to physicians as early as possible.

"I tell patients they will get some side effects and likely be able to deal with them," Whitman said, referring to other side effects, such as fatigue and rash. "But there are side effects that they need to tell us about, because if you allow them to go on, patients will end up in the hospital-or worse, with one of my surgical colleagues."

Not only will early intervention help decrease the chance that the diarrhea, colitis, and pneumonitis will become grade 3/4 AEs, but also, treatment could be altered to stop the side effects, Whitman explained.

"Patients think that the worst thing that's going to happen to them is their treatment being stopped. If, for any reason treatment is stopped, they may think they're going to die," Whitman said. "However, by working with immunotherapy, we know that is not the case. It may only take 1 or 2 doses for the patient to live. The immune system will figure it out."

Moreover, according to findings from the KEYNOTE-006 trial, a greater exposure to pembrolizumab was not associated with higher toxicity. Grade 3/4 toxicities were seen in 17% of patients on the pembrolizumab arm compared with 20% on the ipilimumab arm.

Overall, Whitman said physicians must educate typical immune-related AEs to patients, which differ from those associated with chemotherapy as it has a very different mechanism of action.

"What we are really trying to do with this drug is teach your immune system to do what it failed to do: recognize and kill the melanoma," he said.

Pembrolizumab continues to be explored in other settings in melanoma. For example, the PD-1 inhibitor is being explored in combination with the IDO1 inhibitor epacadostat in the phase III (KEYNOTE-252 / ECHO-301) trial in patients with metastatic or unresectable melanoma. Phase I findings in the KEYNOTE-037 trial exploring this regimen showed that the combination demonstrated an ORR of 56% with a CR rate of 13%.

Another combination involves pembrolizumab with talimogene laherparepvec (T-VEC; Imlygic), early results of which were seen from the phase I MASTERKEY-265 study. Here, the regimen had an ORR of 62% with a CR rate of 33%. The median PFS has not yet been reached.

The KEYNOTE-034 trial continues to assess pembrolizumab and T-VEC (NCT02263508), along with a phase III expansion cohort of the MASTERKEY-265 trial (NCT02263508).

Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).

. 2017;390(10105):1853-1862. doi: 10.1016/S0140-6736(17)31601-X.

Hamid O, Gajewski TF, Frankel AE, et al. Epacadostat plus pembrolizumab in patients with advanced melanoma: Phase 1 and 2 efficacy and safety results from ECHO-202/ KEYNOTE-037. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 1214O.

Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intramoral T cell infiltration and improved anti-PD-1 immunotherapy.

. 2017. doi: http://dx.doi.org/10.1016/j.cell.2017.08.027

Articles

Eric Whitman, MD, discusses data for pembrolizumab in the frontline treatment of advanced melanoma and ongoing research with the agent in other settings of the disease.

Expert Discusses Long-Term Efficacy of Pembrolizumab in Melanoma

A recent warning issued by the FDA advised that breast implants may increase an individual&rsquo;s risk of developing anaplastic large cell lymphoma.

The warning follows on a statement released by the FDA in 2011 suggesting a potential link between breast implants and the rare lymphoma. The issue was subsequently researched and in 2016, the World Health Organization (WHO) recognized the correlation.

&ldquo;Since 2011, we have strengthened our understanding of this condition and concur with the World Health Organization&rsquo;s designation of breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) as a rare T-cell lymphoma that can develop following breast implants,&rdquo; the FDA reported in a statement.  &nbsp;

An estimated 10 to 11 million women worldwide have breast implants, according to the American Society of Plastic Surgeons and the Plastic Surgery Foundation. When BIA-ALCL occurs, it has been identified most frequently in patients undergoing implant revision operations for late onset, persistent seroma, the FDA noted. The exact number of cases remains difficult to determine due to significant limitations in worldwide reporting and lack of global implant sales data.

There have been 359 medical device reports (MDRs) of BIA-ALCL, which included 9 deaths. Of the 231 in this group that did provide information on the implant surface, most reported the implants involved were texturized, according to the FDA reported. Further, 312 of the cases provided information on the fill type. Of those cases, 186 of the implants were silicone, while the other 126 were saline.

There are currently no known risk factors, and further investigation is warranted.

&ldquo;Additional research is critical to identify patients at risk of developing this disease, characterize the early signs and symptoms, and determine best practices for treatment,&rdquo; the American Society of Plastic Surgeons and the Plastic Surgery Foundation said in a statement, noting that common symptoms include spontaneous seroma or effusion after about a year of implantation.

The FDA recommends that healthcare practitioners continue to provide their patients with breast implants routine care and support, because BIA-ALCL is very rare: &ldquo;Because it has generally only been identified in patients with late onset of symptoms such as pain, lumps, swelling, or asymmetry, prophylactic breast implant removal in patients without symptoms or other abnormality is not recommended.&rdquo;

When BIA-ALCL does occur, however, it happens most often in patients undergoing implant revisions for seroma; thus, clinicians should be aware of the risk when presented with a patient with late-onset, persistent, peri-implant seroma, and refer her to an appropriate specialist for further evaluation.

The agency further suggests that clinicians develop an individualized treatment plan in coordination with any impacted patient's multidisciplinary care team and &ldquo;consider current clinical practice guidelines, such as those from the Plastic Surgery Foundation or the National Comprehensive Cancer Network when choosing your treatment approach.&rdquo;

The FDA recommended that individuals considering implants talk to their healthcare provider about the risks and benefits of textured- versus smooth-surface implants. Individuals who already have breast implants do not need to drastically change their healthcare or follow-up routines, according to the FDA. They should continue to monitor the implants according to their physician&rsquo;s instructions and, if their implants are silicone-filled, have frequent MRIs, as instructed by their providers.

FDA Warns Breast Implants May Increase Risk for ALCL

Some exciting progress is being made in the treatment landscape of ovarian cancer, says Kathleen N. Moore, MD, associate director of Gynecologic Oncology at the Stephenson Oklahoma Cancer Center.

at the 2017 Society for Gynecologic Oncology Annual Meeting, Moore discussed the use of PARP inhibitors such as niraparib for the treatment of ovarian cancer  advances that could be practice changing, she says.

Can you give an overview of the randomized double-blind phase III NOVA trial of niraparib maintenance therapy?

It's a study trying to answer the question whether maintenance PARP inhibitor, in this case the PARP inhibitor niraparib, improves progression-free survival (PFS), and then there's a number of other endpoints: overall survival (OS), time to first subsequent therapy, chemotherapy-free interval, and a number of quality of life measures, as well. But the main question is: does the use of niraparib improve survival endpoints in what we call maintenance therapy following chemotherapy for patients with recurrent ovarian cancer who are considered sensitive to platinum?

It's an interesting study in that it allowed really any ovarian cancer patient who had high-grade serous or high-grade endometrioid tumors, irrespective of whether or not they had a germline

mutation. But, within the main study, there were actually 2 independently powered studies. One study for patients with a known germline

mutation; they were randomized in a 2:1 fashion to niraparib or a placebo. So, patients could get really any sort of platinum-based chemotherapy that their physician felt was the best choice for them. They had to either be in a complete response (CR) or in a very good partial response (PR), meaning they had less than 2 cm of visual disease on CT scans.

The other independent study was the same design: 2:1 randomization, for patients without a germline

mutation. Within that group there were a number of exploratory studies done within certain subgroups.

The primary results were presented at ESMO in 2016 and were just remarkably positive for the initial endpoint, which is PFS. So, in the germline

mutation group, there was a hazard ratio of .27 in favor of use of niraparib. And then in the germline

mutation, there was also a very statistically significant hazard ratio as well. The exploratory end points of that trial were to look within that germline-negative group and try to characterize them further. That was presented in the main presentation when they found patients with somatic

mutations, and found small numbers, which we expect. But in that small group of patients, that hazard ratio was almost identical, if not identical, to that of the germline

mutation patients. So, they seem to gain the same degree of benefit from the use of niraparib as did their germline

And then there were subgroups that looked at patients who had something called homologous recombination deficiency, and this was measured by the myriad test. Basically what that means is that there's evidence in the tumor that that tumor at some point in the life cycle of that patient had difficulty repairing double-stranded DNA breaks. It doesn't tell you why that is, or whether or not that status is still present, but it tells you that that tumor at least at some point couldn't fix itself. So, they've divided patients into what we call HRD-positive, excluding those somatic

patients who are certainly HRD-positive, so they were analyzed separately. Really the surprising thing, I think to everyone, was that both groups benefitted significantly. So you wouldn't have really expected the HRD-negative group to benefit, but they had a statistically significant improvement in their PFS by virtue of a hazard ratio.

Questions that investigators still have are: What's the impact on subsequent therapies? Should a patient receive a PARP inhibitor in the maintenance setting? Does it impact OS? If it improves your PFS, but then you can't get subsequent therapies, that would be an important thing to know. At this meeting, some preliminary data on that was presented, at least the data for the treatment chemotherapy-free intervals. The time from completion of chemotherapy to the next needed chemo, and then what's called the time to subsequent therapy, which is the time from the beginning niraparib to the time of beginning subsequent therapy. So there's the same kind of continuum, but those showed equal improvement, as did the PFS, which is to be expected. I think what we're really going to want to see is what happens when you treat someone again, and then how long they survive after that or what their response is there.

I think the other big question is what we do about the HRD-negative group. They seemed, at least by the myriad test, to benefit. Not as much, but the benefitted. And we want things that benefit our patients, so it would be a reasonable thing to offer our patients if it's approved effective. But it raises the question of whether or not we need a better test to really pick patients who truly should or should not get any PARP inhibitor, much less niraparib in this setting. So I think we're still working on that as well.

For the maintenance treatment with niraparib, what ultimately, do these results mean?

The studies that are resulting now in the maintenance setting, really have the potential to be paradigm-shifting for our patients. And practice patterns differ, some people will give 6 cycles and stop, some do 8. Some, if they don't have a CR, will just continue it indefinitely. So, either way, if you do 6 or 8 and then stop and watch someone, it should be similar to the placebo arm. Or if you continue someone on chemotherapy indefinitely, at some point patients are going to be re-exposed to chemotherapy again when they recur, they're just going to keep right on being exposed to it until they progress.

So it's chemotherapy, it's infusions, patients have to come in, they have to have pre-medications, there's the physicians visits, travel, you're constantly being reminded that you're a patient and coming in and having a variety of medications infused into your body. Depending on the medications given, there's hair loss or neuropathy or other sorts of toxicities. And so, if we believe that PARP inhibitors have a role here, then if you're someone that treats to complete response, if you knowand the data pretty clearly shows us  even in complete response, that those patients actually recur or can recur relatively quickly. The median time to progression for the whole group is about five to six months for placebo, and probably there are those who had complete response that was longer, but it doesn't look like it's years.

And so if we believe in the maintenance strategy, then you can put someone on an oral therapy, which after an initial time of pretty close supervision for all the drugs  for niraparib, we're watching for thrombocytopenia with rucaparib, we're doing some initial tests to just make sure their liver functions. It's not clinically relevant unless it gets too high. With olaparib, we're looking for anemia. So you kind of have to watch people a little closely in those first one or two cycles. Then, once you have someone on a stable kind of regimen, they're tolerating things, not having nausea, then you have someone that can be home and be doing fine, checking labs, and be frequently sent in for physician visits. This is not to say no physician visits, because we do need to keep an eye on our patients, but there's no reason to see someone every three weeks on an oral agent doing well. They don't need to come into the infusion center or come in and wait in your waiting room. Once they're stable and doing well and you're monitoring them from a symptom and lab standpoint, you kind of stretch things out and they can have a little bit of their life back.

What are some major takeaways from this study?

I think one of the most hopeful things is just that finally we are developing drugs of importance for patients with ovarian cancer -- good drugs with reasonable side effect profiles that may have meaningful prolonged survival for a meaningful amount of time. We're not just talking a couple of months.

Behind this first wave of PARP inhibitors, there's whole pipeline in almost every pharmaceutical company, of different but similar agents that work just in a different way, but then with the same DNA response pathway which may be very effective drugs when PARP inhibitors stop working or drugs that work with the PARP inhibitors so that people get a better response or work in different subtypes.

There's just quite a wave of very exciting new agents coming behind these very effective PARP inhibitors, so clinical trials and clinical trial participation will continue to be really critical. Even though we've had some successes here, we just still have so many questions to answer. We're not curing people yet, we want to cure people, and so there's still a lot of questions to ask. Clinical trials are going to be important in answering these questions, and there's a lot of really exciting agents -- immune agents, DNA agents, targeted chemotherapy, other pathway targeted drugs -- which may have relevance in ovarian cancer. It's a hopeful time for patients to finally have some new, potentially better options with things on the way.

Kathleen N. Moore, MD, discusses the use of PARP inhibitors such as niraparib for the treatment of ovarian cancer &ndash; advances that could be practice changing, she says.

Niraparib Maintenance Results Have Paradigm-Shifting Potential in Ovarian Cancer, Expert Says

Though dabrafenib (Mekinist) and trametinib (Tafinlar) have changed the treatment landscape for melanoma, both as single agents and in combination, resistance to these therapies is still a significant problem for many patients, says Helmut Schaider, MD, an associate professor at the University of Queensland in Brisbane, Australia.

At the 2016 Society for Melanoma Research (SMR) Congress, Schaider presented a study investigating resistance to dabrafenib and/or trametinib. The study identified chronic stress-induced multi-drug tolerant cells (IDTCs) and determined that prolonged activation of adenosine monophosphate-activated protein kinase (AMPK) using aspirin may delay the formation of these cells and prevent permanent drug resistance.

, Schaider discusses why drug resistance may be due to epigenetic changes and not mutation-induced changes, as well as the role of immunotherapy/targeted therapy combinations in combating resistance.

Can you provide an overview of the study you presented at SMR?

I talked about the inference of metabolic proteins on epigenetics. We all know that now there are several options for targeted therapies, but unfortunately resistance is a problem for many of these patients, and then they relapse. We are interested in investigating potential targets that can combine with other agents to prevent this drug resistance.

What is currently being done to achieve that?

The combination of targeted therapy with immunotherapy is showing some promise for the future. There are so many combinations that may become available. But, still we need to think of things like side effects, toxicities, etcetera.

What we [my team of researchers] can contribute is that we are looking into the very early phases of drug resistance. This is the focus of our research. What we&rsquo;re doing is looking into early drug resistance using a cell-based model. Then, we are actually exposing the cell in the cell culture to combination therapy and then we&rsquo;re looking at what&rsquo;s happening to the cellshow they&rsquo;re developing, how they&rsquo;re changing their phenotype, and how they&rsquo;re changing in the epigenetic box. This is important because we think, within the first 2 to 3 months, all of the changes you&rsquo;re seeing are epigenetic changes&mdash;not necessarily mutation-induced changes.

What more needs to be done and what is the end goal?

The final goal would be either to make melanoma a chronic disease or even have the oncologists really be able to eradicate the tumor. What we came out here to do was to have a closer look at the early stage of drug resistance and how we can find some new targets that can be combined with already existing different combination therapies.

What is the mechanism of action in combining immunotherapy with targeted therapies to prevent resistance?

What&rsquo;s happening, especially if you&rsquo;re talking about targeted therapy, is that you have a compound that is directed toward the signaling pathway that is hyper-activated. If you inhibit that, it has been shown in many studies already that this is only working for a certain time and the cancer cell will actually develop new kinds of pathways that they can use for survival. At the same time, what we see if we stress the cells with a BRAF inhibitor or MEK inhibitor and we are introducing stress is an epigenetic profile.

This opens a window where we can either from the beginning&mdash;add another or add another treatment later on, so that the cells cannot adapt to stress. If they&rsquo;re not adapted to stress because they&rsquo;re not changing the epigenetic phenotype, then it could be a good way to get better survival.

This has been tried in the past. However, it depends on how you apply it and which drugs you use in addition to already existing drugs.

Helmut Schaider, MD, discusses&nbsp;why drug resistance in melanoma may be due to epigenetic changes and not mutation-induced changes, as well as the role of immunotherapy/targeted therapy combinations in combating resistance.

Brielle Urciuoli | Authors

Articles

Expert Discusses Long-Term Efficacy of Pembrolizumab in Melanoma

FDA Warns Breast Implants May Increase Risk for ALCL

Niraparib Maintenance Results Have Paradigm-Shifting Potential in Ovarian Cancer, Expert Says

Researchers Exploring Ways to Combat Drug Resistance in Melanoma