With additional JAK inhibitors under exploration in the myelofibrosis pipeline, such as momelotinib and pacritinib, FDA-approved options continue to be utilized heavily in the paradigm, explained John O. Mascarenhas, MD.

Most recently, a rolling submission of a new drug application has been initiated for pacritinib as a treatment of patients with myelofibrosis who have severe thrombocytopenia, which is defined by having 50 x 109/L platelet counts. The application will be supported by findings from the phase 3 PERSIST-1 (NCT01773187) and PERSIST-2 studies (NCT02055781).

Combination approaches are exploring the potential safety and efficacy of JAK inhibitors, such as ruxolitinib (Jakafi) and fedratinib (Inrebic) with other novel agents, such as venetoclax (Venclexta) or the BET inhibitor CPI-0610.

In an interview with OncLive,&#8239;John O. Mascarenhas, MD, a clinical investigator in myeloproliferative neoplasms, associate professor of medicine at the Icahn School of Medicine, and director of the Adult Leukemia Program at Mount Sinai Hospital, discussed how the positioning of JAK inhibitors in myelofibrosis has shifted, and also pointed to new agents under investigation.

: What are some of the most exciting, recent updates in myelofibrosis?

Myelofibrosis is a hematopoietic stem and progenitor cell malignancy. It's a complex disease, as it often results in multiple hematologic issues. Anemia is one of the major issues, as well as thrombocytopenia, increase in blasts, and transformation to acute leukemia, and patients often have a significant spleen and symptom burden. 

To that effect, JAK inhibitors, such as ruxolitinib and now fedratinib as of August 2019, have been fundamental in addressing certain aspects of these diseases like spleen and symptom [burden], but don't&#8239;effectively, unfortunately, address anemia or reliably alter the natural history of the disease.

For those reasons, [these burdens are] still an intense, and in some cases, urgent unmet need that's being addressed by ongoing clinical trials to evaluate therapies that could be used in the salvage setting. [This would be optimal for] patients who fail the JAK inhibitor, in which we know that the outcomes of those patients tend to be poor. 

We have drugs like CPI-0610, which is a BET inhibitor, as well as venetoclax, which is a BCL-2 inhibitor, with phase 2 data that suggest activity both from the spleen and symptom [burden] standpoint—also from a bone marrow fibrosis reduction and anemia standpoint in a subset of patients. These could be used as monotherapy and also as add-on strategies for patients with myelofibrosis who have failed ruxolitinib, for example. These drugs are now being taken into the frontline setting to be added to ruxolitinib. Once they have demonstrated a safety profile and efficacy in the second-line setting, there is a tendency to evaluate whether there could be effects upfront.

Now there are randomized phase 3 studies that are opening and enrolling across the country comparing for example, CPI-0610 plus ruxolitinib to placebo/ruxolitinib in patients with treatment-naïve or JAK inhibitor—naïve MF, with the hope that we will replicate what was seen in the phase 2 setting in terms of deeper spleen and symptom responses, bone marrow fibrosis reduction, and mitigate the anemia that is usually with JAK inhibitor therapy. Ultimately, we're hoping that these novel agents, whether it's a BET inhibitor or BCL-2 inhibitor, will improve the outcomes and natural history of these diseases.

One other novel drug that fits in this discussion is imetelstat, which is a telomerase inhibitor. It's an intravenous drug given every 3 weeks. It is associated with myelosuppression, but in phase 2 data, it does appear to have the potential to prolong survival, which is an important end point. The phase 3 study of imetelstat versus best available therapy is now going to be activated and will accrue patients who failed ruxolitinib, where the primary goal is extension of life and improved survival.

For me, as an investigator in this field, it's really exciting to see the field move forward and see these end points evolve. The goals of therapy go beyond, for example, speed and symptom which are not unimportant, but importantly, to try to change the natural course of this diseases.

How would you describe the significance of pacritinib in myelofibrosis?

Pacritinib is an important drug and potential agent available in the commercial space; it's the sole JAK2 inhibitor, of the many that have been evaluated, that appears to have the least amount of myelosuppression as it relates particularly to thrombocytopenia. Patients with platelet counts less than 50,000, which is defined as extreme thrombocytopenia, are an unmet need. 

We can't effectively and safely deliver the current JAK inhibitors that are approved, and in fact, there are very therapies for these patients. These patients are typified by a myelodepleted phenotype, so they don't always have large spleens, but they usually are characterized by low blood counts and poor outcomes.

Pacritinib, at least in the randomized, phase 3 PERSIST-2 study, showed efficacy at 20 mg twice daily in both spleen and symptom improvement in these low platelet patients. The PAC203 was a dose-finding phase 2 randomized study looking at 3 different dose levels: 200 mg twice daily, 100 mg twice daily, and 100 mg once daily. The importance of that study was to document and confirm that the drug can be delivered safely. The 200-mg twice daily dose is effective in almost 17% of patients in achieving spleen volume reduction, without incurring significant thrombocytopenia. These are patients with less than 50,000 platelets. The niche for pacritinib is patients with myelofibrosis who have less than 180 days of prior JAK2 inhibitor therapy that have a platelet count below 50,000.

It's a niche; it's a special niche, and it's an unmet need. I would define it as an urgent unmet need, as we can't effectively treat these patients with current available therapies. This randomized phase 3 study will hopefully provide us with the data to allow us to have commercial access to the drug.

I personally think this drug should be approved already based on the studies that have been done, and the data that's at hand, because we owe it to our patients with low platelets to provide them with some at least palliative benefit with spleen and symptom burden. I look forward to the PACIFICA study, and I'm very hopeful that the study will allow us to confidently move that drug from clinical trial testing to commercial use.

Do other novel JAK inhibitors or potential combination strategies in the pipeline look particularly hopeful?

There is more room for other JAK inhibitors. Ruxolitinib and fedratinib are welcomed in this space. Pacritinib would fill the niche of 50,000, but there's really also this unmet need of anemia, which is frequent at presentation and expected through the course of the disease.

Momelotinib, which is a JAK1/2 inhibitor that also appears to inhibit activating receptor signaling and hepcidin expression, has been shown in phase 2 testing to have an anemia response, which we don't see with the other JAK inhibitors. This is important because for those patients we see with anemia as part of their picture and have spleen and symptom burden, it would be advantageous to be able to deliver the benefits of JAK inhibition without the detriments of anemia and actually improving anemia in patients.

That's what the MOMENTUM study is designed to do, and that's a randomized phase 3 study testing momelotinib versus danazol. It's a double-blinded, placebo-controlled study, and the primary end point is symptom improvement, but a key secondary end point is anemia response, so I'm hopeful that study, importantly, will hit its primary end point and allow for secondary end point assessment and join the armamentarium so that we have multiple options for our patients and can cycle JAK inhibitors as well.

The problem we have in myelofibrosis is that it is a disease where you have both a clonal hematopoietic stem cell disorder in the context of a microenvironment in the bone marrow and spleen that are also corrupted. Trying to address both or finding 1 agent to address both is probably unrealistic, so it needs combination therapies, which, as we discussed, with BET inhibitors or BCL-2 inhibitors, or multiple other drugs that are in testing right now that are usually combined with the backbone, which is a JAK inhibitor at this point. However, I do think that paradigm will change, and you will see various combinations of therapies, hopefully, that are informed by preclinical studies that suggest that the 2 agents work well in combination because that's the way we will move the field forward.

It is a complex disease, and it's hard for patients to wrap their heads around the disease because it is a blood cancer, but it often results in bone marrow failure. It's hard to explain to patients what's driving it and how to address it and the complex issues that surround it because most patients are either older in age or have significant comorbidities and are not amenable to hematopoietic stem cell transplantation, which is the only curative option. 

For most of these patients in whom we know that the median survival can range anywhere in low-risk patients from 10 to 15 years, to high-risk patients in whom the survival can be 1 to 2 years, it's very hard to predict for a given individual how they will behave and how to approach their disease. The older and sicker they are, the more complicated that is in balancing risks and benefits of the disease versus the therapies that we can offer.

Do you have any final thoughts to share regarding this research?

I encourage physicians in the community and patients alike to consider referral to tertiary centers where clinical trial options are available because this is really how we move the field forward. If it weren't for those brave folks who enrolled on the COMFORT studies, we wouldn't have ruxolitinib approved today, or similarly, for the JAKARTA studies, we wouldn't have fedratinib available. I'm hoping we'll continue that momentum and deliver more effective drugs, but really, it's a union between academia, pharmaceutical industry, and patients.

TI BioPharma initiates rolling submission of new drug application (NDA) for pacritinib in myelofibrosis patients with severe thrombocytopenia. News release. CTI BioPharma, Inc. October 13, 2020. Accessed November 9, 2020.&#8239;https://bit.ly/3iSx8WU

Articles

With additional JAK inhibitors under exploration in the myelofibrosis pipeline, such as momelotinib and pacritinib, FDA-approved options continue to be utilized heavily in the paradigm, explained John O. Mascarenhas, MD.
 

JAK Inhibitors Build Momentum in Myelofibrosis Treatment

Subgroup analyses from the phase III CheckMate-067 trial identified potential biomarkers in patients who achieved a complete response (CR) with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) but later progressed, according to Georgina V. Long, BSc, PhD, MBBS, FRACP.1 Now, investigators are working to answer more questions about this group of patients.

“We are planning to try and understand more about the patients who are doing really well at 5 years,” said Long. “We are doing what we call a regression analysis to understand what major features at baseline play into why or why not a patient will be alive at 5 years.”

In CheckMate-067, patients with previously untreated stage III or IV melanoma were randomized 1:1:1 to receive either the combination of nivolumab and ipilimumab followed by nivolumab; ipilimumab alone; or nivolumab monotherapy.

Five-year outcomes data presented at the 2019 ESMO Congress showed that at a minimum follow-up of 60 months, the nivolumab-containing arms continued to demonstrate improved overall survival (OS), progression-free survival, and response compared with ipilimumab alone.2 Furthermore, descriptive analyses showed that median OS was not reached with the combination, 36.9 months with nivolumab alone, and 19.9 months with ipilimumab alone.

Subgroup analyses presented at the 16th International Congress of the Society for Melanoma Research (SMR) showed that patients who were alive at 5 years were an enriched population who were more likely to have achieved a CR, have a normal level of lactate dehydrogenase (LDH) at baseline, and have a low number of metastatic sites. Of all patients alive at 5 years in all treatment groups, 61% to 65% had ≥1 poor prognostic factor and 24% to 28% had ≥2 poor prognostic factors.

 during the conference, Long, co-medical director of Melanoma Institute Australia (MIA), chair of Melanoma Medical Oncology and Translational Research at MIA and Royal North Shore Hospital, University of Sydney, discussed the findings from a subgroup analyses of the CheckMate-067 trial.

: What are the current treatment options for patients with advanced melanoma?

For patients with advanced melanoma, the approved drugs in many countries around the world include 2 types of treatments: immunotherapy and targeted therapy. The targeted therapies include BRAF plus MEK inhibitors for those who carry the BRAF mutation in their tumor, which is about 40% of all patients with advanced melanoma. Immunotherapies work in all patients, whether they are BRAF wild-type or BRAF-mutant. I should clarify that immunotherapies don’t work in all patients, but they are potentially available for all of them. Immunotherapies include checkpoint inhibitors—the anti&mdash;CTLA-4 agents like ipilimumab, and the anti—PD-1 agents, such as nivolumab or pembrolizumab (Keytruda). We also have the combination of ipilimumab with nivolumab as an option for patients.

If a patient has BRAF-mutant disease, there are [targeted] options. If a patient has BRAF wild-type disease, there are 2 options; these include checkpoint inhibitors alone or in combination.

What was the rationale for studying nivolumab plus ipilimumab in advanced melanoma?

We have known for some time that anti—CLTA-4 and anti—PD-1 [agents] can be synergistic. Although they are both checkpoint inhibitors, they act at different time points in the activation of the immune system. Anti–CTLA-4 acts at a rather early time point when we activate T cells against a foreign antigen. Anti–PD-1 is a checkpoint that works later on in the activation of a T cell, [when] the T-cell army is ready to kill the tumor; that checkpoint works to unleash the killing of a T cell.

[CheckMate-067] examined the combination of ipilimumab plus nivolumab versus ipilimumab alone, as well as nivolumab alone versus ipilimumab alone. It was a 3-arm study. The doublet regimen was not powered to compare with nivolumab, although we have done these descriptive analyses.

We now have 5-year OS data for this randomized, 3-arm trial. They showed that the landmark survival at 5 years remains high for the combination of ipilimumab and nivolumab at 52%. The 5-year OS with nivolumab alone is 44%, and ipilimumab is lower at 26%. With the analysis that we presented, we tried to understand who the patients alive at 5 years are. What are their features? Is there anything in the clinic that will tell us if patients are more likely to be alive at 5 years or not?

What were the results from this subgroup analysis?

When we looked at the descriptive analysis of subgroups, those alive at 5 years are an enriched population who were more likely to have had a CR, a more normal LDH at baseline, and a lower number of metastatic sites. Patients who achieve a CR, have low-volume disease, and a normal LDH at baseline tend to do better on all of our drugs. Indeed, we see this with the combination of ipilimumab and nivolumab, as well as with nivolumab alone. That was 1 finding from the study. That doesn’t mean if patients have poor prognostic features that they won’t be alive at 5 years; they can, but it’s enriched for patients [with those other factors].

The other thing we looked at in this study is how well patients do, based on their response. We found that of patients who had a CR, 80% remained in CR at 5 years; that was the same for [those who received] nivolumab. Seventy-nine percent of patients who achieved a CR on nivolumab alone had not progressed and remained in CR at 5 years.

We then delved into who the 20% of patients who progressed after a CR were. We saw some features that were, again, associated with a poor prognosis; [for example] patients who had N1c melanoma in organ sites, for instance, outside the lung. Also, patients who had noncutaneous melanoma or acral melanoma were more likely to progress after a CR. Although these are small numbers, we saw all of those same poor prognostic features.

We also delved into things like stopping treatment early and [using] lots of corticosteroids [to manage] toxicities, [to see if they] had an impact on whether [a patient] progressed after a CR. We are now looking into that further, as there may be a relationship between corticosteroids and duration of treatment, and how well a patient maintains a CR.

Those are the main findings of the trial. Five-year OS is excellent, particularly with nivolumab plus ipilimumab (52%) and nivolumab alone (40%). The patients who are surviving to 5 years are enriched for good prognosis, and in those who have a CR, the vast majority remain in CR up to 5 years. Twenty percent of patients have progressed, and they tend to be those with poorer prognostic features at baseline.

What does the toxicity profile look like with this combination?

We do see [more] toxicity with the combination compared with nivolumab monotherapy. With the combination, we see a rate of grade 3/4 TRAEs of just under 60%. Many of those events are reversible with corticosteroids. The ones that are not reversible tend to be the endocrinopathies, such as thyroid, hypopituitary, and rarely, type 1 diabetes. However, these events can be managed with replacement drugs, such as thyroid hormone, corticosteroids, or insulin for the diabetes. All of [those events] can impact quality of life.

[The combination] is certainly more toxic, and we see fewer grade 3/4 TRAEs with nivolumab alone. Less than 20% [of patients] experience grade 3/4 TRAEs, but it is a similar pattern in that most of the TRAEs are reversible with the cessation of treatment. Sometimes you need steroids to reverse those events, but the endocrinopathies are not reversible. However, [in those cases], you are able to replace the hormone.

What will you be looking into next with this combination?

One next step is to understand, who the patients are who have a CR or partial response and progress by 5 years. Why are they progressing? [We need to understand this] particularly in the those with CRs, because we usually associate a CR with a cure. We believe we are curing the majority of patients, but 20% are still progressing and we need to understand why. We see that these patients have poorer prognosis at baseline compared with those who have achieved a CR and have not progressed. However, we need to understand that a bit more.

Looking ahead, where do you see the field headed?

We have done well. We have come from seeing a 5-year OS rate of less than 5% 10 years ago to now, over 50% with the combination, although [that benefit] comes with toxicities. Our next step is to raise that bar higher. We do want to work towards seeing a 100% [survival rate] and 0 deaths from melanoma. The platform we believe is most exciting in the melanoma field is the neoadjuvant platform. Here, we can assess doublets and triplets of novel therapies within 6 weeks and have a pathologic response readout, which we have already correlated with relapse-free survival for immunotherapies. With that benchmarked, we can make a decision about whether we should further explore combinations and triplets.

Some exciting combinations are coming up. We know that tumor-infiltrating lymphocyte therapy after PD-L1 progression seems to have activity. We are looking at other targets as well; VEGF may complement our checkpoint inhibitors. Many intralesional treatments on the innate immune system are under investigation. There is a lot of activity in this space and we hope to achieve 0 deaths from melanoma [in the future].

1. Long GV, Hodi SF, Chiarion-Sileni V, et al. Characteristics of long-term survivors and subgroup analyses with combination nivolumab plus ipilimumab for advanced melanoma (CheckMate 067). Presented at: the 16th International Society for Melanoma Research Congress; November 20-23, 2019; Salt Lake City, UT.

2. Larkin JMG, Chiarion-Sileni V, Gonzalez R, et al. 5-year survival outcomes of the CheckMate 067 phase III trial of nivolumab plus ipilimumab (NIVO+IPI) combination therapy in advanced melanoma. Ann Oncol. 2019;30(suppl 5):mdz394.065. doi: 10.1093/annonc/mdz394.065.

This article was originally published on OncLive as, "

Expert Highlights Potential Markers of Nivolumab/Ipilimumab Response in Melanoma

Subgroup analyses from the phase III CheckMate-067 trial identified potential biomarkers in patients who achieved a complete response (CR) with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) but later progressed, according to Georgina V. Long, BSc, PhD, MBBS, FRACP.1 Now, investigators are working to answer more questions about this group of patients.
 

Predicting Immunotherapy Response in Melanoma

The FDA has granted fast track designation to the potent reversible LSD1 inhibitor SP-2577 (seclidemstat) for the treatment of relapsed/refractory patients with Ewing sarcoma.

Currently, the agent is being evaluated in an ongoing, open-label, nonrandomized phase I trial (NCT03600649) in patients with Ewing sarcoma. In the study, researchers are aiming to find an optimal dose of SP-2577 using an accelerated dose-escalation followed by a conventional 3+3 dose escalation phase, in an effort to reach the maximum-tolerated dose (MTD). A total 50 patients will be enrolled until April 2020.

“Securing FDA Fast Track Designation for Seclidemstat in Ewing sarcoma is an achievement for Salarius in the ongoing development of the drug and recognition that there is an unmet need to bring much needed hope to patients and their families suffering through this devastating disease,” said David Arthur, president and chief executive officer of Salarius, in a statement. “Coupled with Seclidemstat’s previously granted Orphan Drug Designation and Rare Pediatric Disease Designation by the U.S. Food and Drug Administration, we feel well positioned to take advantage of the FDA’s expedited programs for drug development and review.”

SP-2577 is a first-in-class oral, small molecule that is designed for the reversible inhibition of LSD1. SP-2577 could offer more efficacy to patients with Ewing sarcoma, as well as more flexible dosing and fewer toxicities.

In the trial, patients receive SP-2577 orally twice daily. The primary endpoint of the trial is to define the safety and tolerability of the LSD1 inhibitor, assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Secondary endpoints include identification of a MTD, characterization of the pharmacokinetics, and efficacy—in terms of overall response rate, duration of response, and progression-free survival.

To be eligible for enrollment, patients must have a histologically confirmed diagnosis of relapsed/refractory Ewing sarcoma and had received ≥1 prior treatment. Patients must be at least 12 years or older, as well as Karnofsky ≥70% for over ≥16 years old and Lansky ≥70% for under 16 years old. Their ECOG performance status should be either grades 0 or 1, and their life expectancy should be greater than 4 months, among other inclusion criteria.

Patients who have not recovered to grade 2 or baseline from adverse events from previous therapies and patients who are receiving any other investigational agents are unable to be included in the study. Additionally, those with a prior LSD1-targeted therapy, systemic anti-cancer therapy, immunotherapy, palliative radiotherapy, or long-acting myeloid growth factor within a certain amount of time cannot be included on trial, among other exclusion criteria.

“Ewing sarcoma is a rare and deadly bone cancer that most often strikes children and young adults and for which there are no targeted therapies approved. SP-2577 has demonstrated a potential to address this considerable unmet need, and we look forward to rapidly advancing its development so that it soon may be available to those patients most in need,” said Damon Reed, MD, director of the Adolescent and Young Adult Program at the Moffitt Cancer Center and principal investigator of the Salarius Ewing sarcoma clinical trial, in a statement.

Fast track designation is designed to expedite the process of developing and reviewing drugs that have the potential to treat serious or life-threatening conditions, ultimately helping to fulfill unmet medical needs. 

Salarius Pharmaceuticals Receives FDA Fast Track Designation for Lead Drug Candidate, Seclidemstat, in Relapsed or Refractory Ewing Sarcoma. Global Newswire website. https://bit.ly/2LZ3AcD. Published December 16, 2019. Accessed December 17, 2019.

This article originally appeared on OncLive as, "

FDA Grants SP-2577 Fast Track Status for Ewing Sarcoma

PARP inhibitors, which have approved indications in breast and ovarian cancer, are expanding to additional treatment paradigms, including pancreatic cancer.

Data from the phase III POLO trial presented at the 2019 ASCO Annual Meeting showed that the PARP inhibitor olaparib (Lynparza) significantly improved progression-free survival (PFS) compared with placebo among patients with germline BRCA-mutated metastatic pancreatic cancer. The median PFS with olaparib was 7.4 months compared with 3.8 months with placebo (HR, 0.53; 95% CI, 0.35-0.82; P = .0038).1,2

, POLO study investigator Michael J. Hall, MD, Fox Chase Cancer Center, discussed the emergence of PARP inhibition in the armamentarium for patients with pancreatic cancer.

OncLive: What was the rationale for looking at a PARP inhibitor as maintenance in this setting

Hall: Pancreas cancer is 1 of the most dismal tumors in all of oncology, particularly in gastrointestinal oncology, and what we have discovered over the years is that the only option to control disease once it spreads outside of the pancreas, which is 80% of patients when they present, is to use big time multiagent chemotherapies that are toxic. What’s challenging about that is you’re already taking someone who is often very sick from the disease, and to be able to extend their life sometimes by 6 to 8 months, you’re giving them very toxic chemotherapies. That’s not necessarily something that’s attractive to a patient. They want extended disease-free survival and QoL; they want to have both.

The idea behind this was that there were some preliminary data several years ago that showed that in [patients with] pancreas tumors that have a germline BRCA mutation, and at that point we knew the range was maybe 5% to 15%, we knew that those tumors responded differently than the other pancreas tumors. They seemed to be especially sensitive to platinum-based agents. Talia Golan, MD, who is the senior author on the study, had a paper in the Journal of Clinical Oncology that showed that platinum agents were great in this subgroup of patients with pancreas cancer.

Over time, we understood it was the deficiency in homologous recombination and BRCA that was driving this sensitivity, so when the PARP inhibitor class of agents was developed, naturally this became something [of interest]. I think a lot of people first looked at pancreas cancer and said there is no way an oral agent will ever be able to control this disease if FOLFIRINOX can only hold off PFS by a few months, how can this oral agent ever do this? That was a real gamble. I think there were a lot of naysayers that felt it probably wouldn’t work. The trial was born of that. How was this trial designed?

To get on this trial, there were a few different steps. First, you had to undergo germline BRCA testing. I’ll talk a little later on in regard to germline versus somatic, but over 3000 people worldwide were screened for this study to find the roughly 90 patients that went on the olaparib arm and the roughly 60 patients who went on the placebo arm. That was the first part.

Among that group, you had to be a responder to platinum therapy. We know that’s a big part of understanding who is going to respond to PARP inhibitors, so on this trial you actually had a choice of whether it was platinum-based like oxaliplatin, some were on gemcitabine, but frankly most people were on a modified FOLFIRINOX regimen since that is the standard US regimen. You had to be a responder on that for at least a particular amount of time. Once you were a responder for at least 16 weeks or more showing a response, your doctor could actually leave you on that regimen as long as they wanted and as long as you continued to respond, but there was a minimal requirement to demonstrate response.

Once that response was demonstrated, then people were randomized 3:2 to olaparib versus placebo. Everyone asks why 3:2, but that’s because the developers of the trial knew it was not going to be attractive to someone who had an aggressive disease to consider being randomized to placebo, so we tried to make the numbers a little better to go on the study drug. We ultimately randomized around 90 patients to the olaparib arm and around 60 patients to the placebo arm.

What were the findings that were presented at ASCO from the POLO trial?

Hall: PFS was our major endpoint. What we saw and what we presented was that we saw a nearly doubling of PFS with a hazard ratio of progression of 0.53, which I think blew everyone away. The P value is very nice, and it demonstrates this is something that works.

There are other endpoints that we are going to be waiting for, so we will be waiting for OS. It’s going to take a while, though, because some of the responders are still responding for a very long period of time. The median duration of response right now is about 24 months. That shows you that for the people where it is working, we are seeing [good responses]. To get the 106 deaths for OS, that may take some time.

We’ve done some subgroup analyses on the PFS, I think the 1 of the high points of that is BRCA1 and BRCA2 responded roughly the same way. We didn’t see any differences in the subgroups, and I thought the other exciting thing was roughly 50% of people had either a partial response or complete response before they went on the study and roughly 50% were at stable disease. Those 2 groups actually responded the same way, which shows you it’s not just about picking out super responders and giving an icing-on-the-cake drug. It’s about demonstrating some response, and then the olaparib takes over on that. That’s super exciting.

Toxicity data was exactly as we predicted. Olaparib had somewhat more toxicity than being on placebo, naturally, but we didn’t see any extremely high rates of grade 3/4 toxicities, so that fit what we were estimating.

We also did some health-related QoL analyses. The punchline of that was that olaparib had no significant decline of health-related QoL compared to being on a placebo or nothing. I think that’s a strong [finding] because the last thing you would want to do is give someone a maintenance therapy, but you just make them sick again. That’s not what we saw, and we are very happy about that.

We need to wait for the rest of the data to come out. We need the rest of the data to mature, so I think that will be exciting. The other question is what about somatic BRCA? We know germline BRCA[mutations are in about] 6% to 7% [of patients], but somatic is probably another 3% to 4% of patients. The FDA approval will first be for the germline as the study showed, but the questions will be asked, and the research will be done looking at somatic BRCA. There are also other genes and mutations in the BRCA family, like PALB2 gene, the CHEK2 gene, ATM—they are all part of the Fanconi anemia pathway. Those are mutations based on some research from other groups, and we know those mutations are common. The question is if we can also get the same response.

There is this bigger group of people that are called the homologous recombination deficient pancreas cancers. The rough number is about 30% of pancreas cancers that are homologous recombination deficient. Can we use olaparib in that group as well? Can we combine olaparib with other agents? I think that’s the future. That’s what we will see at ASCO 2020, 2021.

1. Kindler HL, Hammel P, Reni M, et al. Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial. J Clin Oncol. 2019;37(suppl 18, abstr LBA4). doi: 10.1200/JCO.2019.37.18_suppl.LBA4.

2. Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med. 2019;381(4):317-327. doi: 10.1056/NEJMoa1903387.

PARP Inhibition Arrives in Pancreatic Cancer

PARP inhibitors have shown success in breast and ovarian cancer, and now they may be moving into the pancreatic cancer paradigm, too.

PARP Inhibitors Hit the Pancreatic Cancer Scene

Circulating tumor DNA (ctDNA) monitoring is clinically valid in predicting whether patients with unresectable, metastatic BRAF-mutant melanoma will benefit from dabafenib (Tafinlar) alone or in combination with trametinib (Mekinist), according to findings of a recent analysis that were presented at the 2019 ASCO Annual Meeting.  

At baseline, the presence of ctDNA is linked with poor prognosis in patients with BRAF-mutant melanoma who are receiving therapy with BRAF inhibitors. In the analysis, investigators analyzed 345 patient samples from the COMBI-d trial (NCT01584648) at baseline and at week 4 of treatment. All patients harbored a BRAFV 600E or V600K mutation and were randomized to receive either dabrafenib and trametinib or dabrafenib alone.

Mutation-specific droplet digital polymerase chain reaction (PCR) assays were utilized, and investigators categorized ctDNA data as either positive or negative (±0.25 copies/mL) in this analysis. Moreover, progression-free survival (PFS) and overall survival (OS) were analyzed in all patients. Baseline lactate dehydrogenase (LDH) levels were evaluated as a prognostic factor, although LDH levels are not typically used to guide treatment decisions.

Results showed that baseline ctDNA was detected in 92.7% of patients but was not linked with survival; 201 patients had paired baseline and week 4 ctDNA samples available. Forty percent of these patients became negative for ctDNA at week 4 and experienced a prolonged PFS and OS compared with 60% of patients whose ctDNA remained positive.

An association was discovered between undetectable ctDNA at week 4 and a survival benefit. The prolonged survival was particularly noted in patients with high LDH levels at baseline. For patients with high LDH at baseline, ctDNA monitoring can be useful in predicting treatment outcomes with dabrafenib or dabrafenib plus trametinib.

, lead study author David Polsky, MD, PhD, professor of dermatology at NYU Langone Health, discussed the findings from this analysis in patients with BRAF-mutant, unresectable, metastatic melanoma, as well as the next steps for validating these findings and potentially using ctDNA to help inform treatment decisions.

OncLive: How did you conduct this analysis on ctDNA as a biomarker in unresectable metastatic melanoma?

Polsky: This study is investigating ctDNA as a potential biomarker in melanoma; it’s being developed in many other cancer types, but we are particularly interested in how it can be used in monitoring disease activity in patients. We partnered with Novartis to study patients from their dabrafenib/trametinib versus dabrafenib trial, called COMBI-d, which led to the approval for dabrafenib/trametinib combination therapy for patients with BRAF V600E—mutated melanoma. The trial enrolled around 400 patients, equally randomized. We had samples available from 345 patients at baseline and about another 200 patients available at week 4. We measured, using a droplet digital PCR, ctDNA for the BRAF V600E/K-mutant samples. Those were predetermined by the study because it was an inclusion criteria for the study; everybody had to have a BRAF V600 mutation.

What were your findings from this analysis?

Polsky: What we found was that at baseline, the amount of ctDNA was predictive of survival, and this was in contrast to some other studies earlier that had shown, just plus or minus, whether it was present or absent. We had a very high detection rate of 93% of patients had detectable BRAF V600E in their plasma using the platform, which is the highest rate so far to date for a similar type of study. Because of the droplet digital technology, we are able to quantify the amount very precisely. When we analyze the levels as opposed to just the absence or presence, we found that the levels correlated with outcome in a Cox multivariant analysis. That was the first time that’s been done.

We then looked at week 4 samples since that was what was available to us, and we found that the level at week 4 was also predictive of survival benefit. If patients had no detectable ctDNA at week 4, they had an extended PFS and OS, roughly double [that of] the patients who had persistent ctDNA detected at week 4. We think that with additional studies and additional timepoints, this may become a monitoring tool for patients and doctors to help more fine-tune their treatment.

For example, patients who have a persistently positive ctDNA after starting treatment, doctors may want to add an additional treatment, which may have an additional risk of toxicity but also additional benefit. Whereas if patients clear their ctDNA during treatment, they may just stick with what they are on and wait and see if they progress, then add another therapy [as needed]. This is what we are thinking could be the future, but of course additional studies are needed. I think this is a big first step.

Were there any results that really surprised you from this analysis?

Polsky: We were very pleasantly surprised with the detection rate of 93% because previously, detection rates had really varied from 50% in some settings to the high 80s, but rarely over 90%. We were surprised on the upside that we had a 93% detection rate. Otherwise, I would say it panned out the way we were hoping it would pan out.

What additional studies would you like to conduct to further validate these data?

Polsky: We would like to look at additional timepoints. We only had week 4 samples available to us, but certainly samples from week 8, week 12, and etc. [would be useful] to use as a monitoring test. Right now, there isn’t a monitoring test available for patients; LDH is part of the AJCC staging criteria, and we know even in this group that it was predictive of survival outcomes. The ctDNA was independent of LDH with the baseline samples. We are doing some further analysis to try and develop maybe a survival model based on that, but we think it will be even more predictive as we have additional samples available.

Eventually, if it all still looks promising, we would like to do a clinical trial where we can randomize patients to have a treatment decision made, for example, a pre-prescribed second-line therapy built into the trial, then at progression patients switch to another agent and then they can be randomized to [therapy] based on a rise in their ctDNA versus radiographic progression, which is the standard of care. That would be an exciting trial for us to do to see if the marker has clinical utility, not just clinical validity, which is what we have demonstrated so far.

How does this tool fit in with others that are currently available for determining patient outcomes?

Polsky: This was all unresectable metastatic melanoma, so these patients are getting treated and monitored with CAT scans, basically. That’s the standard of care. Another potential application could be using this in conjunction with imaging, so often times at tumor board conferences, we have these indeterminate radiographic findings, and there is a paper out there from the John Hopkins group suggesting that if you add ctDNA into the information available, it can help people better resolve indeterminant findings. That was a very small study, but that’s another potential application that we can try down the road.

Do you have any next steps currently planned for this research?

Right now, this is research-use only. It’s not available for clinical use, but we’ve done a lot of work and have funding from NIH that we use to analytically evaluate these assays. We’re putting out protocols on how to run them, so technically other commercial companies could be running these assays, but you have to go from analytical validation to clinical validation, which is what does it mean when you have 20 copies/mL of mutant DNA? That’s what we are working on now. Clinical utility, of course, is whether or not it changes your management. This is sort of a biomarker development pipeline that’s similar to the drug development pipeline, so we are somewhere in between phase II and phase III, I suppose, with a phase III or phase IV being real clinical utility when we think about the different steps that are needed.

Do you see this technique being applied in any other tumor types?

Polsky: There are other cancers where this is being used, not with droplet digital PCR, but with other technologies. For example, there are clinical trials in colon cancer, stage II colon cancer, where after resection, patients have no other measurable disease but they take a ctDNA measurement of the mutations that are found in the patient’s tumor, and they look specifically for them. If they are still present, these patients who ordinarily would not receive adjuvant therapy are being randomized to either adjuvant therapy or not. Those studies are ongoing, and it’ll be very exciting to see the results, to see if there is a benefit in that population based on the presence of mutations in the ctDNA after surgery.

Syeda MM, Wiggins JM, Corless B, et al. Circulating tumor DNA (ctDNA) kinetics to predict survival in patients (pts) with unresectable or metastatic melanoma treated with dabrafenib (D) or D + trametinib (T). J Clin Oncol. 2019;37(suppl; abstr 9510).

ctDNA Monitoring Carries Clinical Validity in BRAF-Mutant Melanoma

Circulating tumor DNA (ctDNA) monitoring is clinically valid in predicting whether patients with unresectable, metastatic BRAF-mutant melanoma will benefit from dabafenib (Tafinlar) alone or in combination with trametinib (Mekinist).

ctDNA Monitoring Is Important for BRAF-Mutant Melanoma

The cancer death rate declined 27% in the United States from 1991 to 2016, as reported by the American Cancer Society in its 

, in part due to the significant decline in smoking and an increase in advances for early cancer detection and screening.

“The continuous 25-year decline in cancer mortality was good news because rates for several other leading causes of death have been stagnant or even increasing in recent years,” Rebecca L. Siegel, MPH, lead author of the report and scientific director of surveillance research at the American Cancer Society, told 

Siegel added that this progress has translated to “2.6 million fewer cancer deaths during this time period than would have been expected if rates had remained at their peak.”

Data were collected from 47 states and the District of Columbia for this report. Because of the time required for collection and analysis, data lags behind 2 to 4 years. However, the report estimates 1,762,450 new cancer cases and 606,880 deaths will occur in 2019, amounting to more than 4800 new cancer cases to be diagnosed per day. This estimate reflects the contemporary cancer burden based on the most recent data.

Between 2006 and 2015, there were about 2% fewer cancer diagnoses in men while the rate stayed about the same in women. In terms of cancer deaths between 2007 and 2016, the rate decreased by 1.8% in men and 1.4% in women. Cancer made up 22% of all deaths in 2016, making it the second leading cause of death in the United States, following heart disease.

 accounts for the most cancer-related deaths, the most commonly diagnosed cancers in men include prostate, lung, and colorectal cancer (CRC); the 3 most common diagnosed cancers for women are 

Between 1990 and 2016, the lung cancer—related death rate has dropped 48% in men, while this rate has dropped 23% in women from 2002 to 2016. New lung cancer diagnoses have also dropped 3% in men and 1.5% in women between 2011 and 2015.

There was also a 40% decrease in breast cancer—related deaths in women from 1989 to 2016. Among men, the prostate cancer–related death rate decreased 51% from 1993 to 2016.

After an increase in screening and advancements in CRC treatments, both men and women experienced a decline of 53% in CRC-related deaths. However, in adults under the age of 55 years, there was an increase of about 2% in new cases per year since the mid-1990s.

The report also noted that the rate of liver cancer diagnoses is increasing faster than any other cancer. Those infected with hepatitis C virus (HCV) are at the greatest risk; baby boomers, or adults born between 1945 and 1965, make up 75% of HCV-infected patients. 

According to the report, the cancer death rate was 14% higher among blacks than whites in 2016. However, this gap has narrowed from 1993 when the rate was 33%. Several factors affect the differences among racial and ethnic groups, including socioeconomic status (SES). Poverty, for example, has been associated with higher cancer case and death rates.

“People with lower SES have greater exposure to cancer risk factors, like smoking and excess body weight, and barriers to effective cancer prevention, early detection, and treatment,” Siegel commented. “Facilitating access to healthcare has been shown to reduce or even eliminate racial and SES disparities.”

Siegel noted that the most concerning of the widening SES disparities was “especially notable for the most preventable cancers.”

For example, the report demonstrated that in poorer counties, cervical cancer—related deaths were twice as common in women and men experienced 40% more lung and liver cancer–related deaths compared with more affluent counties.

An estimated 11,060 children aged 1 to 14 years will be diagnosed with cancer in 2019; the estimated number of cancer deaths in this age group is 1190. In children, leukemia accounts for the majority of cancer cases, making up 28% of all childhood cancers. Brain and nervous system tumors make up 26% of pediatric cancers, yet they are the most common diagnoses among adolescents (aged 15 to 19 years), accounting for 21% of adolescent cancer cases.

Death rates for children and adolescents have declined continuously for many years, amounting to an overall 65% reduction from 1970 to 2016. Between 2008 and 2014, the 5-year relative survival rate for children rose to 83% from the previous 58% in the mid-1970s and rose to 85% for adolescents from the previous rate of 68%.

Although cancer risk increases with age, adults aged 85 years and older are expected to represent about 140,690 cancer cases (~8%) in the United States in 2019. This group is also estimated to account for 17%, or 103,250, of cancer deaths as well.

However, this age group currently represents one-third of all male cancer survivors and one-fourth of all female cancer survivors. Although this age group is the fastest-growing population in the United States, with the number of adults ≥85 years in the United States expected to nearly triple from 6.4 million in 2016 to 19 million in 2060, they are also the fastest-growing group of cancer survivors, placing greater demand on cancer care needs for an older population.

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019 [published online January 8, 2019]. CA Cancer J Clin. doi: 10.3322/caac.21551.

Cancer Death Rates on the Decline, 2019 Cancer Stats Report Shows

The cancer death rate declined 27% in the United States from 1991 to 2016, as reported by the American Cancer Society in its annual report, in part due to the significant decline in smoking and an increase in advances for early cancer detection and screening.