Moffitt

The novel chimeric monoclonal antibody ensituximab demonstrated modest clinical activity and was found to be well tolerated in patients with heavily pretreated, refractory colorectal cancer (CRC), according to results from a phase 2 study that were published in 

“This drug is well tolerated, which is a good start, but we could do better in terms of efficacy,” said lead study author Richard D. Kim, MD. “The next step is to combine it with other agents, such as interleukin (IL)-15, to make it synergistic and possibly induce responses and keep the same safety profile.”

The phase 2 trial enrolled patients with advanced CRC who were refractory to chemotherapy and were treated with single-agent intravenous ensituximab at 3 mg/kg every 2 weeks. Results showed that among 57 evaluable patients, the median overall survival (OS) was 6.8 months. No responses were observed, while the stable disease rate was 21%. There were treatment discontinuations due to drug-related adverse effects (AEs).

, Kim, assistant professor of oncology, University of South Florida College of Medicine, and medical oncologist, Department of Gastrointestinal Oncology, Moffitt Cancer Center, discussed the phase 2 findings with ensituximab in patients with refractory CRC and how its future likely lies in combination with other therapies.

: What are the treatment challenges regarding patients with chemotherapy-refractory CRC?

: In patients who are refractory to standard chemotherapy, there are currently 2 oral alkaloids available for the treatment of those patients. These include TAS-102 (trifluridine/tipiracil; Lonsurf) and regorafenib (Stivarga). However, in the era of molecular profiling, we are profiling every patient diagnosed with stage IV disease. Through the use of molecular profiling, there are a few mutations that are identified. If you have any kind of mutation, such as 

, those [targets] have come into prime time. [There are treatments for those targets that] we would use now starting in the third-line and, at times, even the second-line setting if the patient fails first-line therapy. We are getting more options than our typical oncolytic based on the profiling of the tumors.

Please discuss ensituximab and the phase 2 study with this drug in this patient population.

Ensituximab in a chimeric monoclonal antibody that targets an antigen called 

, which is expressed in colon cancer and pancreatic cancer, as well. If you look at our data, it is probably expressed 50% to 60% of the time. There was a phase 1 study where we dose-escalated the therapy and found the right dose to be studied in the larger phase 2 study setting.

This phase 2, single-agent study was in patients [with metastatic CRC] who were refractory to standard therapy. All of the patients received oxaliplatin, irinotecan, and bevacizumab (Avastin), and if they were 

 wild-type they received EGFR-directed therapy as well. Some even got oral oncolytics, such as regorafenib and TAS-102, as well.

What we see from this study is that the drug is very well tolerated; there are not many AEs associated with this therapy. There are perhaps a few grade 3 anemias and fatigue, but overall, it is very well tolerated.

We met the endpoint of OS, which was around 7 months. We do not want to compare 1 study to another, but [data showed that this drug] could be slightly better than [data seen in] the phase 3 study with regorafenib or TAS-102. However, there were not a lot of responses; response rates were about 20%, some of which were very durable. Based on our phase 2 study, which is about 50 patients, it shows that there may be some modest activity as a single agent and we can take advantage of that because it is well tolerated.

Moving towards the future, single-agent ensituximab is probably not the answer but the combination of it with another agent, such as IL-15, [is promising]. There are some preclinical data suggesting that IL-15 and ensituximab could be synergistic by working through natural killer cells. In the future, trying to combine different agents is where we are going. Single-agent ensituximab is well-tolerated and has modest activity, but we could do a better job by combining it with different agents.

What was the rationale for this phase 2 trial?

The rationale for this study was that this drug is a chimeric monoclonal antibody that targets 

. This is a biomarker-driven study, which is what we want to do these days. All of the patients who enrolled in the study were eligible if they were positive for 

, and they had to be positive for it for more than 20% of the study duration. We screened more than 200 patients and about 50% of them were positive and enrolled in the study. That is the rationale of using this drug as a single agent and in this biomarker-specific patient population.

What was surprising was that this was a highly refractory patient population. Some patients received more than 3 or 4 lines of therapy. Despite that, and not seeing a response rate per RECIST criteria, there were quite a few patients who had stable disease. That is a key point.

As a single agent, this drug has a modest activity that we could move forward with. The next step is to combine it with IL-15, which works with NK cells. That is where we are heading at this time and we will see how that goes in the same patient population, who are also positive for 

What is the importance of molecular testing and when should it be done in this patient population?

My recommendation is that unless a patient is enrolled in a study, every patient with advanced CRC should get genetic profiling done at the beginning [of their treatment course] because once we have the genetic profiling done, we have a plan for the patient. For example, if they have a positive 

 status or are [mismatch repair deficient, there are drugs available to target those]. Therefore, all patients with stage IV colon cancer should get genetic testing upfront.

What is your take-home message regarding this research?

This is the first step. As you know, refractory colon cancer is a highly unmet area but we have come a long way. We now have a lot of options available but we could do a better job. One thing is that trying to maintain a good safety profile and improve outcomes [is essential].

Beyond this research, what other exciting efforts are being made in this space?

One of the hot areas that are going on right now is immunotherapy. We know that only 5% of patients are mismatch repair deficient. Therefore, those are our only patients that will respond to a single-agent checkpoint inhibitor. Now, there are a lot of ongoing research efforts to convert a cold tumor to a hot tumor by either combining it with another TKI or an immunotherapy agent. That is the future.

There were some provocative data presented at the 2019 ASCO Annual Meeting from a group from Japan, which showed an objective response rate of 30% with the combination of regorafenib plus a checkpoint inhibitor. Those are exciting data and a similar phase 1b trial us ongoing at Moffitt Cancer Center; we are trying to duplicate it.

Kim RD, Azad NS, Morse MA, et al. Phase II study of ensituximab, a novel chimeric monoclonal antibody, in adults with unresectable, metastatic colorectal cancer [published online ahead of print, June 2, 2020]. 

Articles

The novel chimeric monoclonal antibody ensituximab demonstrated modest clinical activity and was found to be well tolerated in patients with heavily pretreated, refractory colorectal cancer.

Ensituximab Shows Modest Single-Agent Activity in CRC, Combinations to Be Explored

Manish Kohli, MD, vice chair, Department of Genitourinary Oncology, Moffitt Cancer Center, discusses the use of enzalutamide (Xtandi) and apalutamide (Erleada) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

In the phase 3 ENZAMET study, investigators evaluated the combination of enzalutamide with docetaxel in men with mHSPC. The seizure rates, in addition to the neuropathy and fatigue rates, were higher with the combination. As the data mature, it will be important to assess the risk-benefit ratio of adding another agent to the mix, says Kohli.

Apalutamide is another option based on the results from the phase 3 TITAN trial. The interim results from the trial are comparable with abiraterone acetate (Zytiga) and docetaxel, says Kohli. Though, there were some extra adverse effects (AEs), such as pruritus and rash, which were not seen with the other drugs. However, each agent has a different set of AEs. The decision of which agent to pursue largely depends on tolerability, concludes Kohli.

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Manish Kohli, MD, discusses the use of enzalutamide (Xtandi) and apalutamide (Erleada) in patients with metastatic hormone-sensitive prostate cancer (mHSPC).

Dr. Kohli on the Use of Enzalutamide and Apalutamide in mHSPC

In the phase 3 ENZAMET study, investigators evaluated the combination of enzalutamide with docetaxel in men with mHSPC. The seizure rates, in addition to the neuropathy and fatigue rates, were higher with the combination. As the data mature, it will be important to assess the risk-benefit ratio of adding another agent to the mix, says Kohli.

Apalutamide is another option based on the results from the phase 3 TITAN trial. The interim results from the trial are comparable with abiraterone acetate (Zytiga) and docetaxel, says Kohli. Though, there were some extra adverse effects (AEs), such as pruritus and rash, which were not seen with the other drugs. However, each agent has a different set of AEs. The decision of which agent to pursue largely depends on tolerability, concludes Kohli.

The recent approval of isatuximab-irfc (Sarclisa) combined with pomalidomide (Pomalyst) and dexamethasone offers adults with multiple myeloma whose disease has progressed after standard therapy a tolerable new treatment option.

On March 2, 2020, the FDA approved the triplet for adults with multiple myeloma who received ≥2 prior therapies including lenalidomide (Revlimid) and a proteasome inhibitor.

The approval for the CD38-directed cytolytic antibody was based on efficacy results from the phase III ICARIA-MM (NCT02990338) trial, which showed that treatment with the triplet therapy conferred a significant survival benefit. The median progression-free survival (PFS) was 11.53 months with the regimen versus 6.47 months with pomalidomide and dexamethasone, translating to a greater than 40% reduction in the risk of disease progression or death (HR, 0.596; 95% CI, 0.44-0.81; 

ICARIA-MM’s study population “represents a critical group of patients in multiple myeloma,” according to Ken Shain, MD, PhD, an assistant member of the departments of Malignant Hematology and Tumor Biology and the Chemical Biology and Molecular Medicine program at the Moffitt Cancer Center & Research Institute in Tampa, Florida. In an interview with 

, Shain discussed isatuximab-irfc and its potential to move into different stages of the multiple myeloma paradigm following further clinical investigation.

: Please provide an overview of the patient population.

: In a disease like myeloma that we cannot control forever, we need to continue to develop new drugs and drug combinations to maintain control of the disease so that our patients can live their lives as long as possible. In this randomized phase III study, relapsed and refractory patients, defined by having received and failed 2 or more prior lines of therapy containing both lenalidomide and a proteasome inhibitor [PI], were enrolled. To this end, the study population represents a critical group of patients in multiple myeloma.

What is the agent’s mechanism of action?

Isatuximab is a monoclonal antibody that targets a protein called CD38 on the surface of multiple myeloma cells. Importantly, myeloma cells express this protein more than any other cell in the body, so it has become a very exciting target with an excellent therapeutic index in multiple myeloma. We have learned, both from isatuximab and from daratumumab [Darzalex], that targeting CD38 in myeloma is very effective in attacking myeloma cells.

Isatuximab targets and kills myeloma cells in a number of ways, including directly via apoptosis, which appears to be unique to isatuximab as a CD38-targeting agent, and indirectly through antibody-dependent cell-mediated cytotoxicity, complementdependent cytotoxicity, and antibody-dependent cellular phagocytosis. It may also function in an additional immunomodulatory capacity. Thus, isatuximab has a multifaceted way of helping us attack myeloma cells. This is likely why it works well in combination with other agents such as pomalidomide and dexamethasone.

What do we know about the agent’s tolerability?

Tolerability is always critical, and so to get to a phase III study, isatuximab has gone through phase I trials, in which we have identified a tolerable dose, as well as a phase II study where an effective dose was selected. In the context of ICARIA-MM, isatuximab is a very well-tolerated drug, with the exception of infusion reactions. Approximately 38% of individuals experience an infusion reaction. Importantly, infusion reactions are expected with this class of agents and are generally relatively minor.

We also know that isatuximab will have some potential toxicities when given in combination with drugs like pomalidomide and dexamethasone.

However, isatuximab is very well-tolerated therapy that did not add significant toxicities to pomalidomide and dexamethasone outside of infusion reactions. Regardless, it is critical for us to be mindful of toxicities and carefully monitor our individual patients because they may experience some additional toxicities.

How does the agent fit into the current treatment paradigm?

This is a question that we all will continue to strive to understand. We are always striving to improve our armamentarium; having more agents to control disease for longer periods is going to be important for our patients. I think isatuximab will initially be used primarily in later lines of therapy. Pomalidomide had been generally used in that setting but also has a critical role in combination with other CD38 antibodies earlier in therapy. That will create a space later in therapy to reuse this class of drugs in those 2 or 3 prior lines of therapy population.

What are the next steps for isatuximab-irfc?

Whenever we have a new agent approved, it allows us to start testing it with other drug combinations and in other disease settings. We will continue to ask questions and study its use in earlier relapse, maintenance therapy, and the newly diagnosed setting. Further, additional combination studies are being carried out and will continue to be carried out with other classes of drugs like PIs and selective nuclear export inhibitors. Answering these questions will provide our next steps.

Another really important part that we have not addressed is whether this agent can be effective in patients who have failed the same class of drugs. With its unique direct apoptotic activity on multiple myeloma cells, can we use this as a subsequent CD38- targeting agent after another monoclonal antibody has failed. Will it have activity in this subset? These are the studies we need to do so that we know whether isatuximab can be used to salvage patients or not.

It will be very important to see how we can move isatuximab and its exciting activity into our armamentarium. It has a shorter infusion than the previously approved CD38 antibody [daratumumab]. This may be one of the factors that will help it find its niche, perhaps among community oncologists who have busy schedules. To this end, isatuximab may be able to help patients get in and out of the clinics more efficiently. The triplet regimen provides an effective therapy that we can use to help our patients without adding untoward toxicity.

Sarclisa [prescribing information]. Bridgewater, NJ: Sanofi-Aventis US LLC; 2020. www.accessdata.fda. gov/drugsatfda_docs/label/2020/761113s000lbl.pdf. Accessed March 2, 2020.

Ken Shain, MD, PhD, discusses isatuximab-irfc and its potential to move into different stages of the multiple myeloma paradigm following further clinical investigation.

Isatuximab Affords the R/R Multiple Myeloma Setting a Tolerable New Alternative

Jeannie Chern, MD, a gynecologic oncologist at Moffitt Cancer Center, discusses challenges with germline molecular testing for patients with ovarian cancer.

The cost associated with germline testing can be prohibitive for patients with ovarian cancer who are undergoing chemotherapy treatment, says Chern. However, some pharmaceutical companies may offer financial assistance so patients can be tested, explains Chern.

A lack of genetic counselors is also a rate-limiting challenge in this space, says Chern. Patients who undergo germline testing should have access to genetic counselors to help them understand whether they harbor an actionable target. Genetic counselors can also offer support and additional resources to a patient who may have a germline mutation, concludes Chern.

Jeannie Chern, MD, discusses challenges with germline molecular testing for patients with ovarian cancer.

Dr. Chern on Challenges Regarding Germline Testing in Ovarian Cancer

Andrew T. Kuykendall, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the addition of fedratinib (Inrebic) to the treatment paradigm in myelofibrosis.

Fedratinib is a relatively old drug that went through extensive clinical trials and was tested in many patients several years ago. After going through phase III clinical trials in ruxolitinib (Jakafi) patients with myelofibrosis, fedratinib was put on hold.

Despite its setbacks, fedratinib experienced a resurgence where the safety signals were reexamined, and researchers took a closer look at its efficacy. Now, fedratinib is approved to treat patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, giving patients the option of a second JAK inhibitor.

Andrew T. Kuykendall, MD, discusses the additionof fedratinib to the treatment paradigm in myelofibrosis.

Dr. Kuykendall on the Approval of Fedratinib in Myelofibrosis

Mitchel Hoffman, MD, gynecologic oncologist, Moffitt Cancer Center, discusses ongoing research regarding neoadjuvant chemotherapy and primary debulking surgery in advanced ovarian cancer.

Historically, primary debulking surgery has been the standard up-front therapy in patients with advanced ovarian cancer, says Hoffman. However, recent trials and guidelines state that neoadjuvant therapy is within the standard of care.

Data from randomized phase III trials have not provided definitive evidence that one approach is better than another, says Hoffman. Rather, these trials have called attention to the importance of patient selection. The TRUST trial (NCT02828618) is evaluating the caliber of primary debulking surgery as well as its relative benefit versus neoadjuvant chemotherapy. Strict criteria will be put in place to control for confounding variables. However, it remains to be seen whether the results will point to a new standard of care, concludes Hoffman.

Dr. Hoffman on Research Regarding Neoadjuvant Chemo and Primary Debulking in Ovarian Cancer

Robert M. Wenham, MD, gynecologic oncologist and chair of the Gynecologic Oncology Program at Moffitt Cancer Center, discusses data with intraperitoneal (IP) chemotherapy, dose-dense chemotherapy, and intravenous (IV) chemotherapy in patients with advanced ovarian cancer.

The decision between giving IP, IV, or dose-dense chemotherapy has been confounded by clinical trial data, explains Wenham. Three randomized trials—SWOG-8501/GOG-104, SWOG-9227/GOG-114, and GOG-172&mdash;showed about a 20% to 25% improvement in overall survival with IP chemotherapy. However, the approach wasn’t widely adopted because many women aren’t treated at centers that are equipped to deliver IP chemotherapy, says Wenham. Additionally, toxicity concerns were associated with the approach. However, while IP chemotherapy can be more cumbersome to give, it shouldn’t be more toxic than standard approaches, says Wenham.

Although the GOG-252 trial was designed to evaluate IP chemotherapy, it examined dose-dense chemotherapy versus IP chemotherapy in addition to bevacizumab (Avastin). The trial design was similar to that of GOG-262, in which bevacizumab was given in combination with dose-dense and weekly chemotherapy. In the GOG-262 trial, dose-dense chemotherapy was superior to every-3-week administration. However, in the 15% of patients who received every-3-week administration and bevacizumab, patients experienced similar outcomes as those who received dose-dense chemotherapy.

Dr. Wenham on Trials Evaluating IP, IV, and Dose-Dense Chemotherapy in Ovarian Cancer

Andrew T. Kuykendall, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, discusses the toxicity profiles of ruxolitinib (Jakafi) and fedratinib (Inrebic) in myelofibrosis.

Both agents are JAK inhibitors. However, ruxolitinib targets JAK1/2, whereas fedratinib inhibits JAK2 and FLT3, in addition to some other targets, says Kuykendall.

Fedratinib is associated with increased gastrointestinal toxicities including nausea, vomiting, and diarrhea compared with ruxolitinib, says Kuykendall. These adverse events may be mitigated with prophylactic antiemetics or by eating high-fat meals.

Notably, fedratinib comes with a black box warning for encephalopathy. The randomized phase III JAKARTA trial reported 8 cases of encephalopathy, some of which were suspected to be Wernicke’s encephalopathy, says Kuykendall.

The encephalopathy was potentially due to thiamine deficiency. As such, patients receiving fedratinib should have their thiamine levels checked regularly. Additionally, patients should have thiamine repletion before starting fedratinib, concludes Kuykendall.

Andrew T. Kuykendall, MD, discusses the toxicity profiles of ruxolitinib and fedratinib in myelofibrosis.



Dr. Kuykendall on Toxicity Profiles of Ruxolitinib and Fedratinib in Myelofibrosis

Hye Sook Chon, MD, gynecologic oncologist, Moffitt Cancer Center, discusses challenges that are still faced in the maintenance setting in advanced ovarian cancer.

Frontline maintenance strategies are relatively new to the field of ovarian cancer, says Chon. Although PARP inhibitors have been shown to prolong progression-free survival when used as frontline maintenance therapy, the cost-effectiveness, toxicities, and quality of life (QoL) with these agents must also be considered. Typically, at this juncture, patients have already received surgery and chemotherapy, and posing the suggestion to begin maintenance treatment after they believed they were done with therapy is not easy, says Chon.

As long as patients tolerate their chemotherapy relatively well, it’s best to discuss the potential for maintenance therapy sooner rather than later. Patients expect to complete treatment following chemotherapy, but many of them may benefit from maintenance therapy, explains Chon. As such, patients who are counseled on the potential for maintenance therapy during their chemotherapy are less overwhelmed when the time comes for additional treatment, concludes Chon.

Moffitt

Ensituximab Shows Modest Single-Agent Activity in CRC, Combinations to Be Explored

Dr. Kohli on the Use of Enzalutamide and Apalutamide in mHSPC

Dr. Kohli on the Use of Enzalutamide and Apalutamide in mHSPC

Isatuximab Affords the R/R Multiple Myeloma Setting a Tolerable New Alternative

Dr. Chern on Challenges Regarding Germline Testing in Ovarian Cancer

Dr. Kuykendall on the Approval of Fedratinib in Myelofibrosis

Dr. Hoffman on Research Regarding Neoadjuvant Chemo and Primary Debulking in Ovarian Cancer

Dr. Wenham on Trials Evaluating IP, IV, and Dose-Dense Chemotherapy in Ovarian Cancer

Dr. Kuykendall on Toxicity Profiles of Ruxolitinib and Fedratinib in Myelofibrosis

Dr. Chon on Challenges With Maintenance Therapy in Ovarian Cancer