Andrew Wei, MBBS, PhD, an adjunct associate professor at Australian Centre for Blood Diseases at Monash University, discusses the results from the phase 3 QUAZAR AML-001 Maintenance Trial of CC-486 for patients with acute myeloid leukemia (AML) in the first remission after intensive chemotherapy.

Elderly patients receiving chemotherapy can suffer severe toxicities, which makes further consolidation therapy difficult. Wei and his colleagues investigated how the number of consolidations—0, 1, or 2 or more—affected patients’ response to CC-486 or placebo. The study drug and placebo were each given at 300 mg for 14 days per cycle until disease progression. Wei says that patients who had not received any consolidation had improved overall survival with CC-486 from 11 months to 23 months.

Patients receiving CC-486 also had better survival than those receiving placebo regardless of the amount of consolidation. According to Wei, patients who received 2 or more cycles of consolidation seemed to do the best, with a median overall survival of 29 months. These findings show that patients who are treated with CC-486 have an improved relapse-free and overall survival no matter how many cycles of consolidation they received, he concludes.

Videos

Andrew Wei, MBBS, PhD, discusses the results from the phase 3 QUAZAR AML-001 Maintenance Trial of CC-486 for patients with acute myeloid leukemia in the first remission after intensive chemotherapy.

CC-486 Improves Overall and Relapse-Free Survival in Patients With AML

Jesus G. Berdeja, MD, director of Myeloma Research at Sarah Cannon Research Institute, discusses the findings from the phase 2 results of ciltacabtagene autoleucel (cilta-cel; JNJ-68284528) as treatment of patients with relapsed/refractory multiple myeloma in the CARTITUDE-1 study (NCT03548207).

Researchers were gratified by the results seen in this study, says Berdeja, especially in regard to the response rates. The objective response rate was 97% with 57% of patients achieving a stringent complete response and 92% a partial response or better.

According to Berdeja, the median progression-free survival had not been reached yet, but at 12-months, 76.6% of patients remained in remission in the study.

Jesus G. Berdeja, MD, discusses the findings from the phase 2 results of ciltacabtagene autoleucel as treatment of patients with relapsed/refractory multiple myeloma in the CARTITUDE-1 study.

CARTITUDE-1 Study Demonstrates Promising Response Rates in Relapsed/Refractory Myeloma

Anne Chiang, MD, associate professor, Medical Oncology, Yale School of Medicine, discusses hard-to-treat lung cancer and how due to recent lung cancer innovations and treatment options, the tumor is becoming increasingly heterogeneous. 

The discussion, which was held at the 2020 New York Lung Cancer Symposium, examines a series of case studies on challenging cases of lung cancer. According to Chiang, a better understanding of generic mutations combined with more treatment options has led to a more interesting conversation around hard-to-treat lung cancer.

Of the cases discussed by 4 different medical oncologists, 2 of the patients had different histologies in 2 different legions of the lungs. Other cases focused on how you continue to treat difficult cases over time and continue to effectively manage the tumor.

According to Chiang, both liquid and tissue biopsies should be utilized over the course of treatment. This will give care providers a clear idea of how the tumor progresses over time and develops resistance. Once care providers have a better idea of how the tumor is becoming resistant to certain treatment options, a more personalized plan can be created for the patient.

Considering Mutations and Resistance in Lung Cancer to Improve Precision Medicine

Amitkumar Mehta, MD, an associate professor at the University of Alabama at Birmingham Comprehensive Cancer Center, discusses the toxicity profile of the first-in-class PI3Kδ inhibitor parsaclisib, according to findings from this agent in the phase 2 CITADEL-205 clinical trial (NCT03235544) of relapsed/refractory mantle cell lymphoma (MCL).

Parsaclisib is a highly specific PI3Kδ inhibitor compared with the other PI3Kδ inhibitors, and it was designed to reduce transaminitis as a side effect, says Mehta. This study aimed to explore the efficacy and safety of this therapy.

Overall, the occurrence of transaminitis was very low, especially in terms of grade 3/4 toxicity, which occurred in about 3% to 4%. Diarrhea was observed, which is a known class side effect, according to Mehta. Grade 3 or higher diarrhea occurred in about 13% of patients in the study, and for about half of the patients, this was reason for discontinuation.

Mehta says physicians have learned to be proactive about this side effect. If a patient has diarrhea, physicians should act quickly to manage it.

Amitkumar Mehta, MD, discusses the toxicity profile of parsaclisib in the phase 2 CITADEL-205 clinical trial of relapsed/refractory mantle cell lymphoma.

Evaluating the Toxicity Profile of Parsaclisib in Mantle Cell Lymphoma

Overview of RAI-Refractory DTC

Phase 3 SELECT Trial

Dosing of TKI Therapy for RAI-Refractory DTC

Managing Adverse Events in RAI-Refractory DTC Therapy

RAI-Refractory DTC: Patient Education of Systemic Therapy

Future Treatment Landscape of RAI-Refractory DTC

Steven Sherman, MD, FACE, provides insight on the treatment of radioactive iodine-refractory differentiated thyroid cancer and the management of adverse events.

Differentiated Thyroid Cancer with a Focus on Adverse Event Management

Kerry Rogers, MD, hematologist/oncologist, assistant professor, Department of Hematology, The Ohio State University Comprehensive Cancer Center–James, discusses the findings observed in the phase 1b study of ianalumab (VAY736) in combination with ibrutinib (Imbruvica) as treatment of patients with chronic lymphocytic leukemia (CLL) on ibrutinib therapy.

This therapy was tolerable, which was not surprising as antibodies are generally tolerable, Rogers says. One surprising finding, however, was the number of patients that had elimination of their CLL and were able to stop treatment. Despite this being a phase 1 study, many patients were able to achieve this, according to Rogers. The study was not powered to detect this, but it was great to see that level of efficacy early on, Rogers says.

Kerry Rogers, MD, discusses the findings observed in the phase 1b study of ianalumab in combination with ibrutinib as treatment of patients with chronic lymphocytic leukemia on ibrutinib therapy.

Ianalumab Produces Encouraging Early Activity in Phase 1 Study of CLL

John H. Strickler, MD, medical oncologist, Duke Cancer Center, Duke Health, discusses dosing of regorafenib (Stivarga) in colorectal cancer.

Treatment with regorafenib in patients with colorectal cancer often involves dose escalations. The purpose for escalating the dose of this drug is to ensure that patients receive a dose that provides the best quality of life.

Efficacy is typically not sacrificed when patients are given a lower dose of regorafenib and are gradually escalated to a higher dose, says Strickler. In addition, there is no data to suggest that a higher dose of regorafenib improves efficacy. Strickler recommends focusing on the tolerability of the agent when deciding on escalation or even de-escalation, if needed. 

John H. Strickler, MD, discusses dosing of regorafenib in patients with colorectal cancer. 

Finding the Optimal Dose of Regorafenib in Colorectal Cancer

A phase 2 clinical trial (NCT03222609) demonstrated encouraging results with the addition of navitoclax to the JAK inhibitor ruxolitinib (Jakafi) in patients with myelofibrosis (MF) who were no longer receiving benefit from prior ruxolitinib. This add-back strategy induced clinically meaningful improvements in spleen volume and total symptom score, which were independent of high-molecular-risk mutations or high numbers of total gene mutations at baseline.

Preclinical studies demonstrated that dual inhibition of Bcl-1/Bcl-xL and JAK2 could enhance malignant cell death compared with JAK2 inhibition alone, and this combination is thought to overcome acquired resistance to single-agent JAK inhibitor therapy. This study aimed to explore the clinical responses of navitoclax plus ruxolitinib in this patient population.

These findings were presented during the 2020 American Society of Hematology (ASH) Annual Meeting, which explored the results of 34 patients who had been enrolled and received at least 1 dose of the combination regimen as of the data cutoff date. The single-arm open-label study included patients with either primary or secondary MF with splenomegaly who either failed ruxolitinib or had a suboptimal response after 12 weeks of continuous treatment.

, Naveen Pemmaraju, MD, associate professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the potential role of an add-back strategy as treatment of patients with MF who no longer benefited from prior ruxolitinib.

: What is the prognosis like for patients with MF, and what options are available after these patients fail ruxolitinib?

 Patients with MF are experiencing a very new era [of treatments]. Previously we thought of MF as exclusively a chronic disease, but what we're finding out now is patients who failed the only frontline available targeted class, the JAK inhibitors, some of these patients experience very poor outcomes, including overall survival. There have been several studies that have come out from the United States and now Europe that survival among a lot of these patients with MF may be 2 years or less if they experienced clonal evolution after frontline JAK inhibitor ruxolitinib. I think it reminds us that relapsed/refractory MF can be, in fact, a life-threatening condition and a little bit more of an acute than a chronic situation. To frame 2020 as we head into 2021, patients with MF after ruxolitinib or fedratinib, the 2 JAK inhibitors approved, there are no standard approved therapies, so there's no standard approach. The 3 approaches outside of stem cell transplant have been either to change up the JAK inhibitor, to add in or add back a second agent, or change it up completely and go to a novel agent. I think this is the framework for patients with MF after frontline JAK inhibitor failure or suboptimal response.

: What was the rationale for the addition of the navitoclax to ruxolitinib for this study?

 In the background of ruxolitinib failure or suboptimal response, as I mentioned, there are several strategies that 1 can follow. One that's emerging over the last few years is that add on or add back strategy. In this strategy, the concept or hypothesis is to keep the JAK inhibitor on and add in the second agent after a certain period of time to see if there's additive synergistic, combinatorically effect. Several of these strategies are ongoing with bromodomain inhibitors, PI3k inhibitors, hypomethylating agents, and now with Bcl-xL with navitoclax. That's the study that I presented at ASH.

The rationale and background are interesting. It turns out that possibly in MPNs and MF, this pathway of Bcl-xL may be upregulated or overexpressed, and that may be a bit different from some of the other myeloid malignancies where Bcl-2 plays a more prominent role. Everyone is familiar with Bcl-2 with venetoclax (Venclexta), but there is a drug not FDA-approved, known as navitoclax, which targets primarily Bcl-xL. The concept, at least preclinically in the lab, is that if you can administer navitoclax, either alone or in combination with the JAK inhibitor, this may serve to overcome JAK resistance and may work well with the JAK inhibitor to lead to clinical benefit in patients, so that's the preclinical rationale for this study.

: How do high-risk molecular mutations factor into the study before we get into the results?

 What we're learning from several of the groups that are putting together these scoring systems is that outside of the big 3, which is 

, which essentially make up close to 90% or more of the mutations seen in the MPN. There are what's called additional or non-driver major molecular mutations, and some of these have prognostic significance. Some of them include more familiar ones, such as 

, but some of them also include some of these unclear mutations. In the setting of high-risk molecular mutations, a lot of the new scoring systems, for example, the MIPSS70, which has just come out recently, will include several of these, so 

. Several of these mutations are considered high risk, and so those can be plugged into scoring systems or in the clinic, in terms of clinical terms, they may predict for someone who has a higher chance of transformation to leukemia or a less positive outcome.

: What were the results that were presented during the 2020 ASH Annual Meeting?

 At ASH, I was able to be the leading presenter for our group that was looking at this ongoing phase 2 study of ruxolitinib plus navitoclax in patients who have had a suboptimal response to ruxolitinib alone in MF, and so just over 30 patients have been treated. This abstract focused on some novel findings, which are really in the setting of high-risk molecular mutations and cytokine profiling that was built from the beginning.

I think in terms of high-risk molecular mutations, it was notable that more than just over half the patients actually had not only high-risk mutations but also had 2 or more of these mutations, and still, the addition of the navitoclax, by and large, yielded clinical benefit for the majority of these patients. That's very nice to know that even in the presence of high-risk mutations, the combination trial is still working to give clinical benefit.

The second finding is that of cytokines. It's been known that MF has an upregulation of these cytokines, and so we showed that several of the cytokines that were expected from before were elevated, but I think also the new interesting data are that there were a couple of new cytokines that we found that were upregulated in the setting of MF and may be modulated by the combination. I think these new cytokines need to be further investigated, not only on this ongoing study, so it'll be important to see what the significance is because those have not been known, and to also ask other groups around the world to look into their datasets, their studies, and trials to see if they're finding the same thing. The implication would be, can you develop a new broader cytokine panel to build into these studies to see if it correlates with symptom burden, with spleen size reduction, and potentially even other outcomes later on? I think this is an exciting emerging clinical translational correlative work that still needs validation as we move forward.

: Are there any plans to further that research?

 In terms of future directions, there are actually several that kind of stick out to me in 2021 as we move into this new year. One is while this add back strategy is promising and encouraging, it's still very new. I think the important thing to look out for is toxicities and side effects. With all of these newer agents, there's a potential for thrombocytopenia, so lowering of the platelet counts, which can already happen with the JAK inhibitor. We know about these. We need to monitor doses, regimens, platelet levels, and these are built into these protocols, so monitoring for older and new toxicities, I think, is number 1.

Second is how do we measure success in the post-JAK inhibitor frontline setting? In the frontline setting for JAK inhibitors, we look at things such as spleen and symptom burden. I think these are very important, but as we move into this second-line and beyond setting, I would advocate that we need to consider not only those important factors, but maybe other factors such as progression-free survival, event-free survival, even overall survival because again, as I mentioned earlier, some of these patients have a bit more of an acute course rather than a chronic core, so maybe a course that might be measured in only years rather than decades for many of our patients.

I think a third factor is the scientific understanding of MF itself. As I mentioned, this cytokine [finding], which has been known for a decade or longer, but what are the exact cytokines that are upregulated or downregulated, with the various newer therapies with and without JAK inhibitors? Then to continue the search for novel biomarkers, new clinical translational lab correlates that we can build into studies or find retrospectively. That can give us more clues for a patient's benefit to these newer drugs. I think these are kind of the exciting directions that I see for 2021 in our field.

In an interview with Targeted Oncology, Naveen Pemmaraju, MD, discussed the potential role of an add-back strategy as treatment of patients with myelofibrosis who no longer benefited from prior ruxolitinib.

Adding Navitoclax to Ruxolitinib Shows Potential in JAK-Resistant Myelofibrosis

Kanwal Raghav, MBBS, MD, associate professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses factors that should be considered when deciding on treatment for a patient with metastatic colorectal cancer (mCRC).

Regorafenib (Stivarga) and TAS-102 are both targeted therapies used for the treatment of mCRC. Raghav explains that no rationale exists for the use of one therapy over the other because the clinical trial research supporting these agents was performed in the same patient population. However, there are some differences in how the agents are utilized, says Raghav. For example, oncologists tend to administer regorafenib before TAS-102.

There are other clinical trials for both regorafenib and TAS-102 to determine the activity of the agents in combination with other drugs. Research has already demonstrated the TAS-102 has efficacy in patients who have developed resistance to regorafenib and that regorafenib can be a bridge o TAS-102 therapy. It has also been shown that these agents have different toxicity profiles, and for TAS-102, some may be dose-limiting.

Kanwal Raghav, MBBS, MD, discusses factors that should be considered when deciding on treatment for a patient with metastatic colorectal cancer.

Raghav Discusses the Choice of Regorafenib or TAS-102 in Metastatic CRC

Mark J. Roschewski, MD, staff clinician, associate research clinician, clinical director, Malignancies Branch, Center for Cancer Research, National Cancer Institute, discusses the preliminary results of a phase 2 trial (NCT03789240) of copanlisib (Aliqopa) and rituximab (Rituxan) as treatment of patients with untreated follicular lymphoma.

Roschewski thinks the most interesting data from the trial of copanlisib and rituximab were that all the patients responded and at least had a tumor reduction. The investigators knew the number of patients who would respond was going to be high, and so far, responses have been observed in all of the patients. The median reduction of patient tumors was about 40%, and the responses were rapid. If a patient tumor burden is being reduced by almost 50% after 1 cycle of treatment, that is very good for the patient, according to Roschewski.

To date, the majority of patients who have finished therapy experienced complete response after 6 cycles. Roschewski believes this is the main takeaway from the trial at this point.

In terms of toxicity, many patients experienced rashes, but the rash subsides as patients continue with treatment. No patients have stopped treatment due to toxicity.

Mark J. Roschewski, MD, discusses the preliminary results of a phase 2 trial of copanlisib and rituximab as treatment of patients with untreated follicular lymphoma.