BTK inhibitor–naïve patients with relapsed/refractory marginal zone Lymphoma (MZL) achieved rapid and durable responses with single-agent parsaclisib, as demonstrated in the CITADEL-204 trial (NCT03144674). According to lead study author Tycel Phillips, MD, this could potentially be a groundbreaking advancement in the limited MZL treatment paradigm, though additional research is needed.

In the open-label, phase 2 CITADEL-204 trial, investigators sought to determine the safety and efficacy of parsaclisib in adult patients with MZL who received at least 1 prior line of systemic therapy but were BTK inhibitor-naïve. One hundred BTK inhibitor–naïve patients were randomized 1:1 to receive 20 mg of parsaclisib once daily for 8 weeks followed by either 20 mg of parsaclisib once weekly or 2.5 mg daily, continuously. The daily-dosing group was selected as the preferred regimen, and all subsequent patients were enrolled to that cohort.

The primary end point was objective response rate (ORR); overall survival (OS), safety, and tolerability were key secondary objectives.

By independent review, results showed that the ORR was 57.0% (46.7-66.9) in all treated patients and 56.9% (44.7−68.6) in the daily-dosing group. The ORR was 70.0% (60.0-78.8) in all treated patients and 68.1% (56.0-78.6) in the daily-dosing group via investigator assessment. Similar rates of response were observed in patients with nodal, extranodal, and splenic MZL.

Treatment-emergent AEs occurred in over 10% of patients and included diarrhea, cough, rash, anemia, nausea, pruritus, and constipation.

From this research, we learned that parsaclisib appears to be safe, tolerable, and effective in patients with MZL. In addition, the results that we have seen thus far seem to be favorable when compared with ibrutinib (Imbruvica),” Phillips said. “True to the design of the molecule, we did notice a marked decrease in transaminitis when compared with some of the other delta inhibitors in the space. Ultimately, this could be a very exciting advancement for patients with MZL.”

Phillips, an associate professor of hematology, medical oncology, and internal medicine at the University of Michigan Cancer Center, highlighted the key findings of the phase 2 CITADEL-204 trial.

 What is the current outlook for patients with MZL?

 Notably, MZL is a low-grade lymphoma. For the longest time, the only approved agent was single-agent rituximab (Rituxan). Since then, many of the treatment options have piggybacked off of follicular lymphoma.

Over the past 2 years, there were regulatory approvals for ibrutinib (Imbruvica) and the combination of rituximab and lenalidomide (Revlimid). To date, these are the only therapies that have received a true FDA approval for the management of patients with MZL. Since this is a smaller niche of patients, they tend to respond well to the therapies available.

What prior research led to theCITADEL-204 trial in MZL?

Parsaclisib is a second-generation PI3K inhibitor that was specifically designed to reduce the incidence of transaminitis, which could be noted as a class effect for this treatment. The treatment dose was found to be 20 mg; however, several other doses were explored as well. This research also explored parsaclisib in combination with a JAK inhibitor. For the most part, the treatment was well tolerated in patients.

To mitigate some of the class effects, they did make some alterations to the dosing of the regimen in the original phase 1/2 study. Notably, most patients derived the best response within the first 8 weeks of treatment. After this, they adjusted the treatment and had patients go on a quasi-maintenance therapy; therefore, patients received 20 mg of parsaclisib once weekly, instead of daily dosing. With the switch to maintenance, they did notice a decrease in several AEs, such as such as rash, pruritus, and pneumonitis. However, they needed more information, including the optimal dose of maintenance for this patient population. After this research, there were several copycat trials in patients with MZL, follicular lymphoma, and mantle cell lymphoma.

What was learned from theCITADEL-204 trial? What are the next steps of this research?

This trial evaluated patients with relapsed/refractory MZL who received at least 1 prior line of therapy. Since there was already an approval for ibrutinib in patients with MZL, the study was designed to evaluate the role of parsaclisib in patients with ibrutinib-naïve MZL or those who were relapsed/refractory to ibrutinib. The vast majority of patients on our study were enrolled to the ibrutinib-naïve arm. There were some enrollments to the ibrutinib-exposed arm; however, enrollment was much slower. As such, most results that were presented during the 2020 ASH Annual Meeting & Exposition came from the ibrutinib-naïve arm.

During the meeting, we highlighted the responses that were discovered in the first 8 weeks, as well as the AEs that occurred in result of the transition to maintenance therapy. In this study, maintenance therapy was administered at 2.5 mg daily versus 20 mg weekly. This dosing was chosen based on some of the other studies that evaluated this agent. There was a difference in the maintenance dosing due to the response; I don't know if anybody has a better explanation or rationale. Ultimately, the responses were great, the agent was well tolerated, and some of the information that we believed was true, such as the 8-week response, came to fruition. These were some of the key takeaways from this research.

As we gather more data, the new takeaways will be the mature responses, responses that are observed in different MZL subtypes, as well as long-term AE data. Notably, the AEs associated with PI3K inhibitors, in general, are one of the greatest roadblocks. When comparing the data of parsaclisib to some of the other approved agents in this space, there seems to be some similarities. Due to this, we are hopeful that more agents will be approved in the future.

Could you spotlight the significance of this research in the field of MZL?

This is an exciting time for patients with MZL because, historically, very few clinical trials included these patients in their research. Since the CITADEL-204 trial is a very specific study in MZL, if the data is found to be positive in the next steps, this could potentially be a new treatment. Additionally, we are hopeful that this research will help us better understand how to manage the AEs that are associated with delta inhibitors in this space.

Phillips TJ, Corradini P, Gurion R, et al. Phase 2 Study Evaluating the efficacy and safety of parsaclisib in patients with relapsed or refractory marginal zone lymphoma (CITADEL-204). Presented at: 2020 ASH Annual Meeting & Exposition; December 5-9, 2020; virtual. Abstract 338.

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Tycel Phillips, MD, highlighted the key findings of the phase 2 CITADEL-204 trial.

Parsaclisib Yields Encouraging Clinical Activity in Marginal Zone Lymphoma

One-year disease-free survival (DFS) rates in patients with chronic lymphocytic leukemia (CLL) who received ibrutinib (Imbruvica) or placebo after 12 cycles of ibrutinib plus venetoclax (Venclexta) were similar in the minimal residual disease (MRD) cohort in the phase 2 CAPTIVATE trial (NCT02910583), supporting the role of fixed-duration therapy in this patient population.

In this cohort of the multicenter, double-blind, phase 2 CAPTIVATE trial, ​patients with CLL or small lymphocytic lymphoma (SLL) who had confirmed rates of undetectable MRD (uMRD) were randomized to receive ibrutinib or placebo after 12 cycles of ibrutinib plus venetoclax.

Results, which were presented during the 

 showed that the 1-year DFS ​rate in patients who ​had achieved uMRD and received ibrutinib was 100% compared with 95.3% in those who received placebo (

 = .1475). Notably, these findings support the role of fixed-duration targeted ​combination strategies in patients who achieve uMRD status. 

“Ultimately, ibrutinib and venetoclax are complementary in terms of where they act clinically and how they treat patients with CLL. Moreover, there are mechanistic data in the laboratory that shows synergy between the 2 agents,” lead study author William G. Wierda, MD, PhD. “This has garnered a lot of excitement in the CLL space.”

, Wierda, the D. B. Lane Cancer Research Distinguished Professor, section chief of Chronic Lymphocytic Leukemia, center medical director, Department of Leukemia, Division of Cancer Medicine, and executive medical director at The University of Texas MD Anderson Cancer Center, discussed the latest CAPTIVATE findings in patients with CLL.

 What was the rationale for the CAPTIVATE trial in patients with CLL/SLL?

 The rationale was to assess the role of combination targeted therapy, along with the depth of remission, in patients with CLL and SLL. The data that were presented during the 2020 ASH Annual Meeting answered the question of whether a fixed-duration period of treatment is a reasonable approach, along with if patients can expect a reasonable time off treatment, following combined targeted therapy.

What is the synergy between ibrutinib and venetoclax in this patient population?

Ibrutinib is a BTK inhibitor that inhibits a molecule that's downstream of the B-cell receptor–signaling pathway, BTK. It's been approved for several years now, first for relapsed disease and now for frontline treatment. It is broadly approved in CLL. It's very effective and active, including in patients who have been considered high-risk; these patients are defined as those who harbor 17p deletions or 

Venetoclax is also a small molecule inhibitor; it inhibits BCL-2. When CLL cells are exposed to venetoclax and BCL-2 is inhibited with this agent, it pushes the cells into apoptosis and causes CLL cell death. Ibrutinib is very effective at managing this disease.

Clinically, it works very well in shrinking lymph node size. Many of the patients who are responders are partial responders, meaning that there's still some measurable disease, which is usually in the bone marrow or blood. Venetoclax is highly effective at killing CLL cells and is very potent at killing cells in the blood and bone marrow. However, it’s less active when it comes to shrinking nodal disease.

Patients received single-agent ibrutinib for the first 3 months. Those 3 months of treatment act to debulk the disease, prior to initiating venetoclax and doing the venetoclax ramp-up. We showed and reported a reduction in the high-risk for tumor lysis syndrome [TLS] group of patients. That population significantly decreased with a 3-month lead-in with ibrutinib monotherapy. Patients get 12 cycles of combined ibrutinib and venetoclax and are evaluated for MRD in blood and bone marrow.

At the end of the combination therapy, they're categorized as either confirmed uMRD or persistent MRD. The confirmed uMRD group are randomized to receive either placebo or continue with ibrutinib. The primary end point is the DFS between those 2 groups at 1 year.

Could you spotlight the key findings from the MRD cohort of CAPTIVATE?

The analysis showed that there wasn’t a difference in 1-year DFS rates between the placebo group versus continued ibrutinib. It was 95% for the placebo group and 100% DFS with ibrutinib at 1 year. With those data, this trial supports a strategy of fixed-duration targeted therapy with the combination. There was a reasonable expectation of DFS and progression-free survival, with no additional treatment, once patients are in an undetectable MRD status. Patients with persistent MRD were also randomized. They were randomized to receive ibrutinib monotherapy versus continued combined therapy.

During the 2020 ASH Annual Meeting & Exposition, we reported the uMRD rate with continued treatment, either with ibrutinib alone or placebo. We also reported the safety and tolerability. Notably, there were no significant safety or tolerability concerns on the study.

What challenges did you face with this research?

We are all interested in knowing who the high-risk patients are, who are more likely to respond, and who's more likely to have MRD-negative disease. Unfortunately, the patient numbers are limited so we can't conduct those subgroup analyses and report on factors that correlate with the likelihood of achieving uMRD or longer DFS. This may be possible with further follow-up data, along with combining the analysis with the other cohorts of the CAPTIVATE trial, which was the fixed-duration cohort.

The fixed-duration cohort was a similarly large group of about 150 patients who received only fixed-duration treatment: 3 months of single-agent ibrutinib, followed by 12 cycles of combined therapy. After this, all the patients stopped treatment. In total, there will be more than 300 patients overall where we can hopefully look at subgroup analyses and identify those who are likely to achieve uMRD with 3 cycles [with ibrutinib] plus 12 cycles of combination therapy.

Wierda WW, Tam CS, Allan JN, et al. Ibrutinib (Ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-9, 2020; virtual. Abstract 123.

William G. Wierda, MD, PhD, discusses the latest CAPTIVATE findings in patients with chronic lymphocytic leukemia. 

1-Year DFS Rates Similar Between Ibrutinib and Placebo Following Ibrutinib/Venetoclax in CLL

Progress made in radiotherapy planning and delivery technology has allowed for the safe and effective treatment of an increasing number of patients with lung cancer, according to Katie Keane, MD, who added that patient selection is key to identifying who will benefit most from aggressive local therapies.

“In the stage I disease setting, stereotactic body radiation therapy [SBRT]was developed for patients who were not candidates for resection. Traditionally, patients with stage I lung cancer were managed with a lobectomy; however, about 25% of patients in this setting are medically inoperable,” Keane explained. “For this population, SBRT is the standard of care.”

For patients with unresectable stage III non–small cell lung cancer, data from the phase 3 PACIFIC trial established adjuvant durvalumab (Imfinzi) as the standard of care following chemoradiation. Further findings from an unplanned subgroup analysis showed improved outcomes when durvalumab was initiated within 14 days of the chemoradiation; this may be due to improved performance status in those who were able to begin immunotherapy early or it may be reflective of synergy between immunotherapy and chemoradiation, according to Keane.

“The question is: How can we improve treatment with SBRT?” said Keane. “Ongoing trials are evaluating the addition of immunotherapy to, as well as after, SBRT; [by doing this, they hope] is to improve control rates and distant failure rates. We’re really encouraged by these trials and are hopeful that [these approaches] will improve outcomes for our patients.”

 during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Keane, an assistant professor in radiation oncology at Harvard Medical School, highlighted the evolving role of SBRT in the treatment of patients with stage I lung cancer, the utilization of immunotherapy with chemoradiation in stage III disease, and research evaluating SBRT in those with oligometastatic disease.

: How do you decide whether to use SBRTs or a lobectomy in patients with stage I lung cancer?

 To a certain extent, [the decision] depends on what the surgeon is comfortable with. If someone is medically inoperable, my sense has been that using the robot to resect won't necessarily transform someone into an operable state. I believe a lot of [the decision] comes down to a discussion that takes place between the surgeon and the patient regarding the potential risks of surgery, along with the effect on breathing function and overall quality of life.

How have delivery techniques evolved in recent years?

With SBRT in general, advances in radiation have certainly helped quite a bit in terms of increasing the efficacy of the treatment while minimizing toxicity. SBRT is a very high-dose conformal treatment, where the dose of radiation is delivered over only 3 to 5 treatments. Now, we primarily use treatment techniques called volumetric modulated arc therapy and intensity-modulated radiation therapy. Improvements have also been made in terms of technology, which have allowed us to minimize long exposure and the exposure of normal tissue.

The historical way of administering radiation was through beams in the front and the back, and maybe from the side. However, that strategy exposed a lot of normal healthy tissue to the radiation. By using multiple beams from multiple angles, we’re able to concentrate the dose precisely at the tumor, while avoiding the normal healthy structures.

In terms of monitoring the tumor, advances made in respiratory gating have helped, as well. Respiratory gating is a technique where the radiation is only delivered during certain parts of a person's breathing cycle. Typically, the radiation beam is on throughout the entire breathing cycle. However, with respiratory gating, we're only turning the radiation beam on as someone is exhaling; this is particularly beneficial for those with large tumors.

Another area of improvement is, here at Massachusetts General Hospital, we use a technique that helps protect the chest wall and the ribs from radiation. Notably, when you have a tumor right up against the chest wall, there could be a risk of rib fracture and, in the population of patients we treat, that can be pretty significant. As such, we have developed a technique where we minimize the overlap of the planning treatment volume with the chest wall, which results in low rates of chest wall pain or rib fracture.

What was learned from the PACIFIC trial? Do any questions remain?

The PACIFIC trial was an enormous leap forward in this space, especially in terms of dramatic improvements in overall survival [OS] and progression-free survival [PFS] for patients with medically inoperable stage III lung cancer. The question is: How else can we improve and what can we do to improve? To this end, some studies have evaluated concurrent immunotherapy, chemotherapy, and radiation; those published thus far have been phase 1 dose-escalation trials. [However, results have] demonstrated higher rates of pneumonitis than we have seen in PACIFIC, so it's certainly an area where we still need larger trials.

Despite this, we’re encouraged that there is potential and, if we can really increase the overlap between radiation, chemotherapy, and immunotherapy, we [believe that we] could further improve outcomes. The main limiting factors will be the toxicity, so this really needs to be done on a trial where patients are carefully assessed because we know that the risk of pneumonitis is higher when there is an overlap in treatments.

What are some of the differences observed between sequential and concurrent therapy?

The dose of radiation and chemotherapy regimens have been the same. One study looked at concurrent and adjuvant pembrolizumab [Keytruda] while another looked at concurrent and adjuvant atezolizumab [Tecentriq]. The doses of radiation have, in general, been 60 gy and 30 fractions, which is a standard dose. The chemotherapy regimens have also been the same. The difference is that more than 5% of patients have grade 3 or 4 toxicities compared with 3% of grade 3 or 4 toxicities reported on the PACIFIC trial. About one-third of patients experience grade 2 or higher immune-related adverse effects (AEs). We must find the patients who will benefit the most from the overlap without being at increased risk for toxicity.

Is there any insight into which patients may be less likely to develop toxicities like pneumonitis?

In general, if you’re thinking just about the risk of pneumonitis from radiation, we know that the smaller the tumor, the smaller the amount of lung exposed to the radiation; this certainly goes along with pneumonitis risk. When planning radiation, we look at, for example, the volume of normal lung tissue exposed to 20 Gy. If that is 20%, as opposed to 30%, we know there is less risk.

In terms of biomarkers, we don't have any good ones [to understand who is at increased risk of certain toxicities]. Certain patients, in general, are at increased risk of developing pneumonitis, such as those with interstitial lung disease; however, this represents a minority of the overall population. Unlike the metastatic setting, we also don't have a great biomarker for response, such as PD-L1 expression. The ongoing trials have not limited patients based on PD-L1 expression. When considering patients for these studies, our main question is: Is the [care] plan going to put them at a high risk of developing pneumonitis? That would give us pause.

How is the use of radiation expanding in patients with oligometastatic disease?

Historically, patients with oligometastatic disease were defined as those who had 1 metastatic site and a stage I tumor; however, the definition has since broadened. It’s an ongoing debate as to who would most benefit from aggressive local treatments. For example, the SABR-COMET study showed really impressive PFS and OS benefit in patients who received SBRT to all sites of metastases along with systemic therapy. Certainly, AEs were associated with aggressive local therapies, thus collaboration between the specialties and careful patient selection is critical. However, this is an area where we are seeing very encouraging results and we’re seeing outcomes improve. [We need to consider] all the potential options for patients, even if they have metastatic disease.

Antonia SJ, Villegas A, Daniel D, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. 

. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697

Katie Keane, MD, highlights the evolving role of stereotactic body radiation therapy in the treatment of patients with stage I lung cancer, the utilization of immunotherapy with chemoradiation in stage III disease, and research evaluating radiation in those with oligometastatic disease.

Emerging Strategies Seek to Build on the Benefit Achieved With Radiation in Lung Cancer 

With the emergence of several BCMA-directed therapies such as monoclonal antibodies, antibody-drug conjugates (ADCs), and bispecific antibodies, outcomes for patients with multiple myeloma have improved significantly, according to Edward A. Stadtmauer, MD, who added that efforts are now focused on ways to improve on the efficacy observed with CAR T-cell therapy.

“BCMA, as a target, is a major development that has truly exploded over the past couple of years. It [has gone beyond] naked antibodies, like daratumumab [Darzalex] and elotuzumab [Empliciti],” said Stadtmauer.“We now have ADCs. Our first FDA approved BCMA-directed immunotherapy was belantamab mafodotin-blmf [Blenrep], which has been very active with low toxicity, except for ocular [effects]. Moreover, a host of BCMA-directed agents, such as the bispecific antibody teclistamab [JNJ-7957], and CAR T-cell products [have also emerged].”

® during the 2020 Institutional Perspectives in Cancer webinar on Hematology, Stadtmauer, section chief of Hematologic Malignancies, and Roseman, Tart, Harrow, and Shaffer Families’ President’s Distinguished Professor, at the University of Pennsylvania, highlighted recent developments with immunotherapy in the multiple myeloma treatment paradigm.

®: What is the current state of immunotherapy in multiple myeloma?

: Over the past 5 years, immunotherapy has become one of the most exciting areas in multiple myeloma treatment. The original immunotherapy [approaches] in this space were the immunomodulating agents like lenalidomide [Revlimid], pomalidomide [Pomalyst], as well as iberdomide [CC-220], which is an investigational next-generation therapy. All these [agents appear] to modulate the immune microenvironment.

In addition, the development of monoclonal antibodies has been particularly exciting, such as the CD38-directed monoclonal antibody daratumumab and the SLAMF7 monoclonal antibody elotuzumab; these have become up-front approaches. Notably, daratumumab is similar to rituximab [Rituxan] in that it improves every [regimen] that it’s added to.

Could you discuss the impact that the subcutaneous (SC) formulation of daratumumab has had on the treatment paradigm? Are there any challenges?

Daratumumab is very active but toxicity could be experienced after receiving the first dose, such as allergic reactions, fevers, shaking, and chills. As a result, this requires pre-medication and slow infusions that can occasionally take up to 8 hours. In addition, the first dose is often split into 2 days. With subsequent dosing, you can usually administer the therapy faster but, traditionally, about 90 minutes is the fastest that it can be infused.

The SC use of daratumumab has truly been a medical breakthrough in that it's utilized with an enzyme that allows the agent to infuse safely and quickly into the SC tissue. Although it’s a 5-minute infusion, it’s still much faster than the intravenous [IV] infusions. Great studies have shown that there is no difference with regard to efficacy between the SC and IV formulations. Moreover, we discovered that there is much less toxicity with the SC infusion. As such, there are advantages with the SC formulation in terms of convenience and toxicity without any loss of efficacy.

You mentioned that BCMA is a very important target in myeloma. Are there any other emerging targets under investigation that you are excited about?

One area of interest is the Fc-directed bispecific antibodies, which was another big headline at the 2020 ASH Annual Meeting & Exposition. This is a bispecific antibody with a different target, where CD3 activates the T cells. High activity was observed [with this kind of agent] in a phase 1 trial; about 60% of patients responded to treatment.

Although we are seeing great activity with agents that target CD38 and BCMA, even in heavily pretreated patients, they still don’t appear to be curative. Therefore, when patients relapse, having other targets to go after will be beneficial. The FcR target is a very active and preliminary reasonable target for that group of patients.

Belantamab mafodotin has been an important addition to the treatment arsenal. Could you expand on some of the nuances associated with this agent?

This has really been a next-generation agent. When administering this drug to heavily pretreated patients, about one-third of patients will experience nice responses. Those who respond seem to have long-term responses, which makes the agent unique. Moreover, what makes this option very convenient is that it is given in an every 3-week dosing infusion, which averages to about every 6 weeks. However, the drug does have unique toxicity, which is keratopathy. As such, this therapy requires an extra step in that an ophthalmologist needs to examine the eyes prior to each dose of treatment. This was done during the clinical trials.

Notably, if you do that and notice grade 2 or higher keratopathy and hold the dose [for 3 weeks], the toxicity can be reversible in the majority of patients. In addition, the responses to therapy are not lost due to the delay. As such, I believe this is a great addition to the multiple myeloma [treatment arsenal]. Ongoing clinical trials are now trying to determine what the safety profile and efficacy looks like when other agents are added to this agent.

BCMA-directed CAR T-cell therapy is another important focus of research. What is some of the work that is being done right now with this approach in myeloma?



Many BCMA-directed CAR T-cell agents are currently being explored in clinical trials and were presented during the 2020 ASH Annual Meeting & Exposition. From my initial review of phase 2 data that are beginning to mature, the story about the efficacy and toxicity between these products seems to be similar. There are nuances but, in general, the patients who are being treated are heavily pretreated. In relapsed, refractory, triple-class refractory, and 5-drug exposed patients, BCMA-directed CAR T cells have been shown to have an 80% to 100% response rate. The responses that we're seeing in these very heavily treated patients are remarkable.

The toxicities were what you would expect with a CAR T-cell treatment, such as cytokine release syndrome [CRS], which was experienced by most patients. This was typically low grade but about 20% of patients had a high-grade case. Over the years, we have become very comfortable with the treatment of CRS and the vast majority of patients recover with minimal treatment required and low toxicities, as long as they're monitored closely. Moreover, a lower incidence, but a real incidence of neurotoxicity [is also observed]. Again, high-grade neurotoxicity is very infrequent, and the vast majority of patients were able to recover. Cytopenias are also noted; this is usually from the lymphodepleting chemotherapy that the patients received prior to CAR T-cell therapy.

The response rates are remarkable; however, the durability of response remains an issue with these products. The great news is that there are patients who are still responding to CAR T cells after 2-3 years. However, when conglomerating these studies, the average patient responds for about 1 year.

about 1 year or so with a single infusion. More importantly, when compared with non-Hodgkin lymphoma and acute lymphocytic leukemia data, there does not seem to be a plateau in the curve. There seems to be a continued progression in myeloma BCMA-directed CAR T cells.

Most of the work that we're doing now is focused on determining how we can improve on this even further. A few questions remain. Should we do this procedure earlier in the course of the disease rather than waiting for a patient's disease to become very resistant? Should we do it earlier so that we have healthier and more potent T cells? Should we combine the CAR T cells with other therapies that will enhance their persistence?

Edward A. Stadtmauer, MD, highlights the emergence of several BCMA-directed therapies, such as monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies, and how outcomes for patients with multiple myeloma have improved significantly. 

 Stadtmauer Spotlights the Explosion of BCMA-Directed Therapies in Multiple Myeloma 

The management of patients with colorectal liver metastases is complicated and requires careful assessment from a multidisciplinary tumor board—especially in light of recent advances made with chemotherapy, according to Michael J. Cavnar, MD. Now, efforts are being made to confirm the benefit of using hepatic artery infusion pumps to further improve outcomes.

“With the increasing efficacy of chemotherapy, more patients who once would have strictly received palliative therapy can now undergo surgery,” said Cavnar. “I also believe that we’re going to have level-one evidence illustrating the benefits of hepatic artery infusion pumps in the not-so-distant future. I have seen patients start off with high disease burden and, over time, become disease free. Of course, this isn’t the case for everyone; some may progress on this or experience complications. However, I truly believe aggressive treatments such as this one are going to move the dial in metastatic colon cancer.”

® during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Cancers, Cavnar, an assistant professor of surgery at the University of Kentucky Markey Cancer Center, highlighted the role of surgery in colon cancer, the role of tumor sidedness in informing surgical decisions, and research efforts that are being done to evaluate the utility of hepatic artery infusion pumps.

®: What are some of the key components of surgical care in CRC that everyone should be aware of?

 I'm a surgical oncologist, so the treatments I provide generally focus on surgery. However, for this disease process, we need to look at much more than surgery. When treating patients with colon cancer, we must collaborate with colleagues across many specialties, particularly those in medical oncology.

It’s also important to be aware of the historical aspects of liver metastases, which are largely surgical. Notably, several advances have also been made with chemotherapy, which is used around the time of surgery for after resection of liver metastases. We also [consider] palliative chemotherapy, which is given to [those with] unresectable disease.

In addition, [another topic of interest has to do with] the hepatic artery infusion pump, which is one of my areas of specialty. At the University of Kentucky, we have a clinical trial that has been ongoing for about 6 months now; this is an effort that I am actively working on.

Tumor sidedness is another key component to consider when selecting the appropriate treatment approach for patients with this disease. What are some of the factors that you use to inform surgical decisions?

The right side of the colon is the easiest to remove surgically. As such, if someone has a right-sided cancer, unless it's very bulky or advanced, we typically perform the surgery laparoscopically. A hospital stay for that type of operation could be several days, and recovery is typically quick. Left-sided disease, depending on where it is, can be more complicated. If the tumor is in the upper part of the left colon, we call this a descending or sigmoid colon. Those [cases], surgically, are fairly straightforward and usually don't involve a diverting ileostomy. As you get down into rectal cancer, which technically would fall under a left-sided disease, the surgical management is much more complicated and often involves neoadjuvant radiation. The anastomosis is much higher risk and is frequently protected with a diverting ileostomy, which later requires another surgery to reverse.

If a patient just has a primary tumor, the surgical aspects are the dominant factor because up-front surgery for primary colon cancer is the standard of care. If the patient has synchronous metastatic disease, meaning they have metastatic disease that is diagnosed at the same time as their primary tumor, then the left- versus right-sidedness helps guide the selection of chemotherapy; that is an evolving practice.

A typical first-line chemotherapy regimen for either a left- or right-sided colon cancer would be something like FOLFOX/bevacizumab [Avastin], which both should respond to. If you get into a situation where a patient could not receive bevacizumab, maybe due to some cardiovascular issues, then we consider adding other biologics. If [we are dealing with] a 

 mutant left-sided tumor, then that patient would not receive an EGFR inhibitor.

What is your approach for treating liver metastases in practice? How has this evolved in recent years?

The standard of care largely depends on the burden of the disease. A patient with confined liver metastases and only 1 or 2 small lesions can be managed with a minimally invasive procedure. In my practice, smaller lesions are typically done with a laparoscopic or robotic approach, which consists of small incisions and a 1-2 day hospital stay. Almost all patients with metastatic colon cancer receive some type of perioperative chemotherapy. Although there are some variations to this, giving 6 months of chemotherapy both before and after surgery is fairly standard. As the number and the complexity of the metastases increases, things become more complicated.

Notably, there is this concept of a future liver remnant, which I believe is a major advancement in liver surgery. We used to be under the impression that, in order to do surgery on the liver, we had to do a major hepatectomy—either a left hepatectomy, which involves removing about 40% of the liver, or a right hepatectomy, which involves removing about 60% of the liver. These are major operations and about 5 years ago, they carried over a 5-year mortality rate. As the understanding of liver surgery and the biology of colon cancer has evolved, it's now understood that [the goal is focused] not so much about getting a wide margin, but about taking out the metastasis and leaving as much healthy liver as possible. Historically, major hepatectomies accounted for most surgeries performed; however, now they are the minority.

What data have been reported regarding the utility of hepatic artery infusion pumps?

Hepatic artery infusion pumps have been around since the 1970s. They basically capitalize on the fact that liver metastases obtain their blood supply from the artery that feeds the liver. Ultimately, the liver has a dual inflow of blood; about one-third is from the hepatic artery

and about two-thirds is from the portal vein. For whatever reason, colorectal liver metastases only obtain blood flow from the artery, which has been demonstrated for many years.

In the 1970s, they started infusing chemotherapy directly into the liver. The dose that you would need to put into [a patient’s] veins to achieve that level would be incredibly toxic to the body. Instead, we can achieve a dramatic response by [infusing] a small amount [of chemotherapy] at a high concentration directly into theliver. Although this sounds great conceptually, we need to prove this. To this end, so much work has been conducted at Memorial Sloan Kettering Cancer Center; this is where I did all of my training and learned about the artery pump; it’s truly one of the biggest programs in the country and in the world.

Could you expand on some of these efforts?

Many clinical trials have been conducted over the years, with the early trials focused on how this [approach] could be [used] safely. [Investigators] generally started with patients who had high disease burden, along with those who had unresectable disease. These patients were initially given hepatic artery chemotherapy through the pump. However, early on, it was learned that although this controlled liver disease, patients could still develop lung metastases. They learned that you could safely give regular chemotherapy, along with pump chemotherapy; as such, this became the standard. They then played around with different regimens, determining which would be the best to give.

The biggest bulk of data are focused on adjuvant pumps; this means that patients who undergo complete resection of liver metastases have a pump implantation at the same time of their surgery, so they leave their operating room with a pump. Then, a few weeks after surgery, they start chemotherapy into the liver remnant.

This process has been studied in a randomized trial, which was first [published] in 1999 in the 

; there was follow-up [information that was released] later on. [The approach was found to] unequivocally lower recurrence within the liver. The randomized study compared patients who had resection and just received adjuvant fluorouracil [5-FU] versus that plus a hepatic artery pump. The study showed that, initially, the OS was significantly longer in patients who received the pump. At the 10-year follow-up, that statistical difference drifted a little bit. If you look at the graph, the curves are still different, but the 

value is 0.1, which led many to believe that the pump did not work.

What is being done to settle the debate of whether the pump should be utilized in practice?

A trial examining today’s modern chemotherapy, with or without the pump, has not been done.

This is a very difficult study to set up because those who believe in the pump, like myself, believe in it strongly, while others really do not. That being said, I'm actually involved in a multinational consortium on the hepatic artery pump, which just started. We recently had a Zoom call with about 50 different surgeons from all over the world; it was impressive to see these people all together. We're in the early stages of developing [such a] clinical trial, [and] we believe we could prove [the effectiveness of] this [approach].

In the meantime, the group at Memorial Sloan Kettering Cancer Center has come out with really powerful support of this [approach in the form of] retrospective data. They had a paper published in 2016 in the 

 that included about 2000 patients who had liver resection in result of CRC liver metastases.

All patients received modern chemotherapy, typically FOLFOX. They looked at the patients who received pumps and compared them with those who did not. They used propensity matching, which basically compares apples to apples and oranges to oranges, and the survival difference was dramatic. A 10-year survival of approximately 40% was reported [with the pump], which is essentially a cure, versus about 23% [in those without it]—almost a doubling of survival. We, in this consortium, mark that date as the time when the game started to change again.

Michael J. Cavnar, MD, highlights the role of surgery in colon cancer, the role of tumor sidedness in informing surgical decisions, and research efforts that are being done to evaluate the utility of hepatic artery infusion pumps. 

Aggressive Treatment Approaches May Move Dial in Metastatic Colon Cancer 

Despite the benefit achieved with standard-of-care radiation therapy plus androgen deprivation therapy (ADT) with a luteinising hormone-releasing hormone analogue, 15% of patients with very high-risk, localized prostate cancer still go on to develop incurable distant metastases within 5 years underscoring a need to augment this approach, according to Ray McDermott, MB, BCh, BAO, PhD, MBA, FRCPI.

The ongoing phase 3 DASL-HiCaP trial (NCT04136353), presented during the 

, may address this challenge, as investigators are evaluating the efficacy of adding darolutamide (Nubeqa) to ADT and radiation treatment either as a primary definitive therapy or adjuvant therapy in this patient population.

“Patients with high-risk prostate cancer are those whose prostate-specific antigen [PSA] levels have gone up after undergoing a radical prostatectomy,” said McDermott. “We must find ways to leverage treatment options for these patients [in order to] prevent disease recurrence. I encourage patients to look for centers where this study is open to see whether they’re eligible to participate.”

In the double-blind, placebo-controlled phase 3 trial, a total of 1100 patients will be stratified based on whether they are receiving adjuvant docetaxel, have pelvic nodal involvement, or they have undergone a radical prostatectomy. Participants will be randomized 1:1 to receive either 600 mg of darolutamide or placebo twice daily for the duration of 96 weeks. They will also receive a luteinising hormone releasing hormone analogue for 96 weeks and radiation therapy on weeks 8-24 following randomization.

Despite delays caused by the coronavirus disease 2019 (

) pandemic, investigators plan to open the trial at 100 sites across the United States, Canada, Ireland, the United Kingdom, Australia, and New Zealand.

 McDermott, a clinical professor of medical oncology at the University College Dublin, discussed the key objective of the DASL-HiCaP trial in patients with very high-risk prostate cancer and the benefits of darolutamide compared with other novel antiandrogens that are available.

: What was the rationale for the DASL-HiCaP trial in patients with very high-risk prostate cancer?

: Two populations of patients [will be] included in this study. First, there are the patients who are being treated definitively with radiation and ADT for very high-risk prostate cancer. The second population of patients are those who have already had a radical prostatectomy and whose PSA levels have not dropped to 0; these patients are planned [to receive] salvage radiotherapy with hormones.

In both of those cases, with the current standard of care, a significant proportion [of patients] will still develop metastatic disease over the next 5 years. The [rationale] for this research is to evaluate the addition of darolutamide, which is a novel androgen receptor blocker, to see whether we can reduce the incidence of patients developing metastases over time.

Notably, the study does not allow patients with metastatic disease to enroll, but those who have nodal involvement in their pelvis are permitted; that’s 1 of the stratification factors. Another factor is whether patients used adjuvant docetaxel; in some centers, this agent is used in this setting, as well. The other stratification factor is whether patients have undergone a radical prostatectomy. 

The study was originally designed in Australia, but will be conducted in the United States, Canada, Europe, and New Zealand. A total of 1100 patients will be randomized 1:1 to receive darolutamide for 96 weeks or placebo.

How might this research help to address the unmet needs still faced in these patients with very high-risk prostate cancer?

[In these] high-risk patients, specifically those whose PSA levels increased after undergoing a radical prostatectomy, we know that despite our best efforts and the use of ADT, many will still develop PSA recurrence. When patients recur, a large percentage will then develop metastases; this may lead to the prostate cancer ultimately taking the patient’s life. The ultimate goal of this study is to reduce the number of PSA relapses.

What are some of the benefits associated with darolutamide over other available antiandrogens?

One of the advantages with darolutamide compared with some of the other novel antiandrogen agents out there is that it doesn't cross the blood–brain barrier. One of the main adverse effects we observe with other antiandrogens is that they can increase the risk of falls; they can also affect cognition and memory. However, this does not seem to be the case with darolutamide. Patients are going to be on this medication for close to 2 years, which is a very important point. We don’t want to excessively interfere with our patients’ quality of life.

When might results from the trial be expected? Has the pandemic impacted accrual?

The study has only recently opened. Accrual began in March 2020, and as of August 2020, 30 patients had been enrolled to the trial. We will continue to accrue patients over the next few years, and we will report our findings in the future after accrual is completed.

We want to open this trial to different centers across the world, although the COVID-19 pandemic has delayed this. There will be an accrual period over the next 2 years and then a follow-up period.

One of the good things about prostate cancer is that if the disease is going to recur, it may happen later rather than straightaway. Therefore, the follow-up for this trial will probably take a number of years before the primary end point is determined.

Is there any other research in this space that you’re excited about and wanted to highlight?

The survival advantage with PARP inhibitors demonstrated in the PROfound study was very exciting. Although this is a smaller patient population, this trial emphasized the importance of testing patients to see whether they harbor any of these actionable mutations. [With these options], patients are living longer and are avoiding more toxic treatments like chemotherapy.

Niazi T, Williams S, Davis ID, et al. DASL-HiCaP: darolutamide augments standard therapy for localised very high-risk cancer of the prostate (ANZUP1801). A randomised phase III double-blind, placebo-controlled trial of adding darolutamide to androgen deprivation therapy and definitive or salvage radiation. 

. 2020;31(suppl 4):S548-S549. doi:10.1016/j.annonc.2020.08.2088

Ray McDermott, MB, BCh, BAO, PhD, MBA, FRCPI, discusses the benefit achieved with standard-of-care radiation therapy plus androgen deprivation therapy with a luteinising hormone-releasing hormone analogue. 

Addition of Darolutamide May Augment Standard Treatment for Localized, Very High-Risk Prostate Cancer

Molecular testing is a critical component of the treatment selection process in lung cancer, as a host of effective drugs have since been developed to target alterations such as 

, according to Yujie Zhao, MD, PhD, who added that the integration of RNA-based sequencing into these strategies could potentially provide further benefit to patients

“It’s paramount for patients to undergo molecular testing; this allows us to discover actionable alterations. We also encourage the use of liquid biopsies,” Zhao emphasized. “[Sometimes we are faced with the] issue of tissue availability; sometimes this can be due to limitations of local expertise. If that is the case, I would encourage [that you] consider sending patients to a tertiary center. There, interventional radiologists, or even thoracic surgeons, could help them obtain tissue for testing. I would also encourage the incorporation of RNA-based sequencing into your approach, as well.”

® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Zhao, an internist oncologist at Mayo Clinic, highlighted progress made with actionable alterations in lung cancer, the importance of molecular testing, and efforts needed to overcome resistance mechanisms to available targeted agents.

®: Several agents have been developed to target

alterations in this disease. Of course, there was crizotinib (Xalkori), and agents like alectinib (Alecensa) and brigatinib (Alunbrig) have since joined the treatment arsenal. How do these agents compare?

 Alectinib has been compared head-to-head with crizotinib and this research showed superiority [with alectinib] in terms of progression-free survival and overall survival. Moreover, alectinib was found to have better central nervous system penetration and intracranial activity, which is a huge advantage.

Similar to alectinib, brigatinib has also demonstrated superior efficacy and excellent intracranial activity; this agent was [also found to] outperform crizotinib. The response rate was high with this drug and the responses appeared to be durable.

Lorlatinib (Lorbrena) has also emerged as an option for use following progression on crizotinib. What is the hope for moving this agent into earlier lines of treatment?

This agent shows great activity in later-line settings and has very promising activity in the first-line setting, [as was seen in the phase 3 CROWN trial]. However, the agent has not been FDA approved [for use] in the frontline setting yet.

fusions, the field has seen a lot of activity over the past year with drugs that have shown impressive activity. Could you discuss selpercatinib (Retevmo) and the data that have been reported from the first-in-human LIBRETTO-001 trial?

LIBRETTO-001 is a phase 1/2 study that evaluated the role of selpercatinib in patients with 

-altered lung and thyroid cancers. This study had multiple arms. In non–small cell lung cancer, the agent was found to work very well. The response rate was around 85% in the treatment-naïve patients and 64% in those who received prior platinum-based chemotherapy. These response rates were excellent.

Pralsetinib (Gavreto) also obtained regulatory approval in September 2020 based on data from the ARROW trial.

What is the efficacy of this agent, particularly in those with brain metastases?

Pralsetinib has demonstrated great activity. The overall response rate in patients [previously treated with platinum chemotherapy] was 55%; [it was 66% in treatment-naïve patients]. Three patients, out of 9, had an intracranial complete response to treatment. Although the number of patients was small, the response rates reported were impressive.

With all of these additional actionable targets, what is your approach for molecular testing?

Molecular testing is very important. When it comes to fusions such as 

, the treatments available are very effective and well tolerated. The responses [elicited with these agents] are also very durable. It's important that we do not miss any patients who could potentially be candidates for these therapies.

Broad panel DNA-based next-generation sequencing (NGS) is commonly used in this space; however, there are some limitations with this approach. In research published by [investigators from the] Memorial Sloan Kettering Cancer Center, 232 patients did not have any actionable alterations, per DNA-based NGS results. However, when RNA sequencing was performed, it was discovered that 33 patients did have actionable fusions. Among these patients, some had 

 exon 14 skipping mutations, 10 patients had 

 fusions or rearrangements, and a few more had 

 gene fusions. With this said, I would encourage my colleagues to consider both DNA-based NGS and also RNA-based sequencing. This may be more costly and take more time [for the results] to turnaround, but it will provide great value to our patients.

How are you utilizing liquid biopsies in practice?

Liquid biopsies are important because we can have trouble obtaining tissue. Many times, we send out a test, and we are told that the tissue [sample] is insufficient. As such, liquid biopsies, which utilize circulating DNA in the peripheral blood, have been very helpful.

 fusion and we wanted to put her on trial, but we couldn't find her initial biopsy. We ordered a liquid biopsy, which confirmed that she had a 

 fusion and as a result, we were able to enroll this patient to a clinical trial. It’s also important to note that liquid biopsies have a quicker turnaround than tissue biopsies.

What is some of the work that is being done to address resistance to these agents?

We understand that patients will eventually develop resistance to these targeted therapies.

With this said, we must determine which mechanisms need to be overcome and how we can do that.

For all these therapies, [we know of] 2 types of resistance mechanisms. One would be a mechanism that the cancer cell utilizes to bypass the effect of the drug. For example, there can be an activation of additional pathways in the cancer cells. Another mechanism could be a mutation that arose in the target genes, such as 

. Those mutations will enable the kinase to avoid the interaction or interfere with the interaction of the drug with the target.

These are the types of alterations that can lead to drug resistance. A few ongoing trials are evaluating new agents that could potentially overcome this challenge.

Yujie Zhao, MD, PhD, highlights molecular testing and how it's a critical component of the treatment selection process in lung cancer, as a host of effective drugs have since been developed to target alterations such as ALK, ROS1, and RET. 

 Need for Molecular Testing in Lung Cancer Is Underscored as Additional Targets Emerge

Twice-weekly text message reminders did not improve adherence to aromatase inhibitors (AIs) for postmenopausal patients with early-stage breast cancer; therefore, increasing the odds of long-term adherence for this population will require more personalized approaches, explained Julie Gralow, MD.

Non-adherence to AIs is not uncommon and increases the risk of recurrence in patients with breast cancer. In the randomized SWOG S1105 trial, investigators evaluated the effect that text messages had on treatment compliance, aiming to help doctors find the optimal therapy for each patient. Non-adherence was defined by a negative urine AI metabolite assay at 36 months.

A total 724 patients were assessed for non-adherence to AIs every 3 months. At 36 months, the observed adherence rate was 55.5% for those who received text messages and 55.4% for those who did not. Data also showed that there was no difference in time to adherence failure by arm, as the 3-year adherence failure rate was 81.9% in the text message–arm vs 85.6% in the control arm (HR, 0.85; 95% CI, 0.76-1.05;

Moreover, baseline scores from the Brief Pain Inventory, Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES), the Treatment Satisfaction Questionnaire for Medication, and the Brief Medication Questionnaire were strongly associated with non-adherence.

, Gralow, clinical director of Breast Medical Oncology at Seattle Cancer Care Alliance, professor of medical oncology at the University of Washington School of Medicine, and professor of the Clinical Research Division at Fred Hutchinson Cancer Research Center, discussed exciting research in HER2-positive breast cancer. 

: Could you spotlight the importance of the SWOG S1105 study?

: We know that a large number of women who are taking adjuvant endocrine therapy, whether it be AIs or tamoxifen, can't complete the recommended 5 years; other patients can receive 10 years of therapy. It’s widely understood that if patients can take the agent for a longer period of time, that there's added benefit and the toxicities build up.

The SWOG S1105 trial was an interesting study that used text messaging to try to improve adherence in women who are taking adjuvant AIs. This trial showed that twice-weekly text messages, for a total of 3 years, that were not personalized did not improve the adherence to AIs. The adherence of patients to AIs in the text-messaging arm versus the non–text-messaging arm was equal and only at about 60% [for adherence]. A lot of women dropped out for a variety of reasons.

We then went back into the study and we looked at the factors that were collected at baseline that could have predicted those who were going to drop out and those who were unable to tolerate the drug. We decided to focus on that group in terms of future studies and future interventions. 

Notably, we collected a ton of patient-reported outcomes (PROs). At baseline, we asked if they were having endocrine symptoms, joint aches, the pains that come along with AIs. There were brief validated surveys that asked about their thoughts on medications in general.

Julie Gralow, MD, discusses exciting research in HER2-positive breast cancer. 

Erica DiNapoli