MD Anderson

Disease control strategies in the epithelial ovarian, fallopian tube, and primary peritoneal cancer maintenance settings now include the PARP inhibitor olaparib (Lynparza) in combination with bevacizumab (Avastin).

On May 8, 2020, the FDA approved olaparib in combination with bevacizumab as a first-line maintenance option for adults who are in a complete response (CR) or partial response (PR) to first-line platinum-based chemotherapy and whose disease is homologous recombination deficient (HRD), defined by either a deleterious or suspected deleterious 

The approval was based on efficacy data from the phase 3 PAOLA-1 trial (NCT02477644), in which the dual drug approach significantly improved progression-free survival compared with bevacizumab monotherapy in patients with HRD-positive tumors (37.2 vs 17.7 months; HR, 0.33; 95% CI, 0.25-0.45).

®, Shannon N. Westin, MD, MPH, director of early drug development and phase 1 trials in the Department of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center in Houston, discussed the rationale for administering the maintenance therapy in this setting and the broader potential of regimens combining PARP with other therapies.

: How great was the need for a maintenance therapy for this population?

: [For patients with] stage III or IV ovarian cancer, there’s an 80% chance of their cancer going into no evidence of disease, but unfortunately, about 70% to 80% of patients’ disease will recur, and when it recurs, it is much harder to cure. So we have been trying to expand the use of maintenance strategies to really take advantage of that early response rate and gain additional survival time for patients.

What was significant about the efficacy data that led to the approval?

What was really noteworthy was the [efficacy data’s] correlation to the presence of biomarkers. The patients who got the biggest benefit [from the therapy] were those with some type of 

 mutation. [We also saw similar] and impressive activity in the group who had HRD tumors. We saw hazard ratios of 0.31 in the patients with 

There was the expectation that bevacizumab and olaparib could potentially have a greater impact in homologous recombination–proficient patients; however, that was not the case. There was equivalent activity in the 2 arms: the bevacizumab alone arm and the arm that added the olaparib to the bevacizumab. These were interesting and surprising findings.

Are there any toxicities of note when administering this regimen?

I think the most important thing is that the majority of patients were able to stay on the regimen, but sometimes it did require dose adjustments and the addition of other medications for control. The most common grade 3 and 4 adverse events are hypertension and bone marrow issues such as anemia, lymphopenia, and neutropenia. These are [toxicities] that we know we can manage; you just need to be aware of them and vigilant in identifying them.

With the addition of bevacizumab to olaparib, there is no question that you are going to see hypertension. This is expected, so you need to make sure that you have your patients checking their blood pressure at home and are ready to [administer] an antihypertensive [if necessary].

How does this doublet therapy fit into the current treatment paradigm?

I think that for me and for many, the first question is going to be “What are you going to start the patient on?” Because [to use] this regimen, you need to be deciding [whether or not you will use it] basically at the onset of treatment, whereas [with] some of the other agents that are indicated in the maintenance setting, you can wait, do whatever you want in the beginning, and then start your maintenance.

There are some clinicians [who] use bevacizumab for all patients, and there are others [who] use a more nuanced strategy where they would typically reserve bevacizumab and chemotherapy for patients with stage IV disease [for example]. It will come down to what the clinician determines [regarding the] need for the use of bevacizumab; then they can add olaparib at the maintenance [stage].

[Importantly,] this is not a maintenance strategy that needs to continue forever. The PARP inhibition is given for 24 months, and the bevacizumab is [administered] for 15 months, so there is an end point in sight.

What are the next steps for this regimen?

Several ongoing trials are looking at [PARP inhibition combined with] other agents. Over the last year, we have seen approvals for PARP inhibitors alone, as well as this most recent approval with olaparib and bevacizumab, and a number of different studies are either completed or near completion or are actively accruing that combine PARP inhibitors with immuno-oncology and antiangiogenic agents like bevacizumab.

A trial that has already accrued [IMagyn050; NCT03038100] is combining bevacizumab with an immuno-oncology agent and may take PARP inhibition out of the picture for a certain population. I am hopeful that as these trials start reporting out, we will get a better sense of how to select which treatment for what patient.

FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. FDA. Updated May 11, 2020. Accessed June 15, 2020. bit.ly/2N22lcF

Articles

Shannon N. Westin, MD, MPH, discusses the rationale for administering
the maintenance therapy in this setting and the broader potential of regimens
combining PARP with other therapies.

Olaparib Plus Bevacizumab Combination Expands Options in HRD+ Cancer

Preetesh Jain, MD, PhD, clinical fellow in medical oncology at The University of Texas MD Anderson Cancer Center, discusses research efforts examining resistance patterns with venetoclax (Venclexta) in mantle cell lymphoma (MCL).

The findings from a small prospective study indicated that venetoclax-based therapy was highly effective in patients with high-risk MCL and acquired resistance to the agent was predominantly associated with non–BCL-2 mutations. These findings need further validation in a larger cohort of prospectively collected samples, says Jain. Similar types of analyses in other ongoing trials with venetoclax and ibrutinib (Imbruvica) in the frontline setting are also being conducted to understand the pattern of resistance to the agent in less heavily pretreated patients.

To do this, pretreatment samples will need to be collected and studied. In the phase 1 study, the pretreatment samples had been previously treated with other agents, such as ibrutinib or chemotherapy, making the pretreatment clonal evolution data not indicative of what an untreated sample would look like.

Even in patients with poor-risk MCL, the response rate with venetoclax was very impressive. These findings are very provocative, according to Jain, even though it was a retrospective study that had enrolled a small number of patients with limited samples available for whole-exome sequencing. These are preliminary findings, which will potentially lead to studying this particular pattern of resistance in a larger number of samples, concludes Jain.

Videos

Preetesh Jain, MD, PhD, discusses research efforts examining resistance patterns with venetoclax in mantle cell lymphoma.

Dr. Jain on Future Research Efforts Examining Venetoclax Resistance Patterns in MCL

Findings from an exploratory analysis of the phase 1/2 ZUMA-1 trial demonstrated clinical efficacy in patients with relapsed/refractory large B-cell lymphoma (LBCL) who were retreated with the CAR T-cell therapy axicabtagene ciloleucel (axi-cel; Yescarta).

The results showed that patients who achieved a CR with the first infusion of axi-cel had a higher likelihood of attaining a CR during retreatment.

With the first infusion, 7 of the 14 patients who were retreated achieved a CR, 6 achieved a partial response (PR), and 1 had stable disease prior to progression. The median duration of response (DOR) was 3.3 months (range, 1.8-10.9).

Upon retreatment, 57% achieved a response, consisting of 5 CRs and 3 PRs. Additionally, the median DOR to retreatment was 9.4 months, and 2 patients remained in response for 18.2 months and 11.2 months after retreatment.

“While axi-cel has demonstrated durable responses in a subset of patients, approximately half of all responders relapse,” study author, Javier Munoz, MD, MS, FACP, of Banner MD Anderson Cancer Center, said in a virtual presentation during the meeting. “Little is known about the efficacy of retreatment with CAR T-cell therapy.”

In October 2017, the FDA approved the CD19-directed CAR T-cell therapy as a treatment for adults with relapsed/refractory non-Hodgkin lymphoma, based on earlier data from the ZUMA-1 trial.

The trial was divided into 4 cohorts. In cohorts 1 to 3, patients could not have derived a response to their last chemotherapy or had relapsed within 12 months of autologous stem cell transplant (ASCT). Patients enrolled in cohort 4 had to have relapsed/refractory LBCL and received 2 or more prior lines of therapy.

In the trial, eligible patients with refractory LBCL underwent screening followed by leukapheresis and conditioning chemotherapy with 500 mg/m

On day 0, patients were hospitalized and received 2 x 10

 CAR+ cells/kg. Patients stayed in the hospital for 1 week before returning to have their tumors assessed on day 28.

If patients had no evidence of CD19 loss by local review or no dose-limiting toxicities during first treatment, patients underwent another round of conditioning chemotherapy and were retreated with an identical dose of axi-cel.

The 14 patients retreated with axi-cel had a median age of 59. Though, 5 patients were 65 years or older. Additionally, the majority of patients (79%) were male.

Over half of patients (57%) retreated with axi-cel had an ECOG performance score of 1 and 86% had stage III/IV LBCL. According to the Lymphoma International Prognostic Index (IPI), 64% of patients had a score of 3/4.

Although 0 patients had undergone prior ASCT, 71% had received 3 or more prior therapies. Of these patients, 71% had a diagnosis of diffuse large B-cell lymphoma, 14% had primary mediastinal B-cell lymphoma, and 14% had transformed follicular lymphoma.

Product characteristics of the axi-cel source material were similar between the first and second infusions. One patient had axi-cel manufactured from new apheresis material, 9 had axi-cel manufactured from frozen peripheral blood mononuclear cell from the first apheresis in a second round of manufacturing, and 4 patients received axi-cel from a second bag of initial manufacturing.

In the first infusion, the peak CAR T-cell expansion was 60.8 cells/µL blood. Peak expansion among retreated patients was 4.3 cells/µL blood. Additionally, lower median CAR T-cell expansion was associated with lower median tumor burden.

Additionally, retreatment with axi-cel was associated with significantly lower peak levels of interferon-γ (Wilcoxon test 

 = .0081) and interleukin (IL)-15 (Wilcoxon test 

 = .0012) compared with first treatment. Although peak IL-6 levels were not found to be statistically significant, they were numerically lower with retreatment versus first treatment (Wilcoxon test 

Regarding safety, comparable rates of cytokine release syndrome (CRS) were noted in first treatment and retreatment with axi-cel. In first treatment with axi-cel, 93% of patients experienced some degree of CRS versus 86% in retreatment. No grade 3/4 CRS was reported with axi-cel in either first or second treatment.

Notably, fewer incidences of grade 3/4 neurological events occurred during retreatment compared with first treatment, at 11 events versus 8 events, respectively.

“Based on this limited sample size, retreatment with axi-cel may have clinical efficacy in some patients with LBCL, especially patients who achieved CR with first treatment,” said Munoz. “Durability of response remains to be determined as several patients received consolidative allogeneic transplant. We look forward to additional studies to confirm and expand upon these results.”

Locke FL, Bartlett NL, Jacobson CA, et al. Retreatment of patients with refractory large B cell lymphoma with axicabtagene ciloleucel (axi-cel) in ZUMA-1. Presented at: 2020 European Hematology Association Annual Congress; June 11-21, 2020; Virtual. Abstract EP1259.

Findings from an exploratory analysis of the phase 1/2 ZUMA-1 trial demonstrated clinical efficacy in patients with relapsed/refractory large B-cell lymphoma who were retreated with the CAR T-cell therapy axicabtagene ciloleucel.

Axi-Cel Retreatment Demonstrates Clinical Efficacy in Large B-Cell Lymphoma

Scott Kopetz, MD, PhD, FACP, an associate professor in the Department of Gastrointestinal Medical Oncology, of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the safety data reported from the phase 3 BEACON CRC trial in 

-mutant metastatic colorectal cancer (mCRC).

Patients who enrolled on BEACON CRC were randomized to receive either encorafenib (Braftovi) plus cetuximab (Erbitux) and binimetinib (Mektovi), encorafenib plus cetuximab, or the investigator’s choice of irinotecan plus cetuximab or FOLFIRI (folinic acid, fluorouracil, and irinotecan hydrochloride) plus cetuximab in patients with 

Overall, the safety data reported during the 

 demonstrated that the regimens were well tolerated and consistent with the safety profiles previously reported, says Kopetz. Overall, the treatment discontinuation rate was low. However, numerically, a slightly higher rate of discontinuation was observed in the arm that included binimetinib; this was consistent with the control arm, adds Kopetz. Rates of notable, severe treatment-related AEs were very low, while the rate of patient compliance to the regimens was high, concludes Kopetz.

Scott Kopetz, MD, PhD, FACP, discusses the safety data reported from the phase 3 BEACON CRC trial in BRAF V600E-mutant metastatic colorectal cancer.

Dr. Kopetz on Safety Data From BEACON CRC Trial in BRAF V600E-Mutant mCRC

Ryan W. Huey, MD, an assistant professor within the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, discusses challenges faced with immunotherapy in hepatocellular carcinoma (HCC).

The field of HCC has learned that patient selection is going to be very important moving forward, says Huey, not just in terms of the groups of patients that are being targeted. It is also worth remembering that not all disease is created equal, says Huey. There may be more of a signal with immunotherapy in the early stages of disease, potentially evenresectable disease, whereas patients whose disease has progressed further and have deteriorated liver functionmay not have as much susceptibility to these agents.

The answer to this question is still open, says Huey. The answer might be that immunotherapy by itself is not sufficient and investigators need to find a better way to harness that. An additional challenge faced in the HCC space, is a lack of tissue. As such, the opportunity to find predictive biomarkers is less than it would be in other tumor types, explains Huey. While some biomarkers in other diseases leave oncologists wanting for a bit more, they can help provide a signal for the rationale for immunotherapy, which is something that is not available in HCC, concludes Huey.

Ryan W. Huey, MD, discusses challenges faced with immunotherapy in hepatocellular carcinoma.

Dr. Huey on Challenges Faced With Immunotherapy in HCC

Michael Wang, MD, a professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, discusses the safety and efficacy of KTE-X19 in relapsed/refractory mantle cell lymphoma (MCL).

Results from the phase 2 ZUMA-2 trial indicated that the KTE-X19 pharmacodynamic profiles are generally comparable between patients with low-risk and high-risk MCL, says Wang. Patients were classified as being low risk if they had less than 50% Ki-67 with no 

 mutation, while high-risk patient had a Ki-67 over 50% along with a 

Additionally, results showed that the pharmacodynamic profile of KTE-X19 was efficacious, including early minimal residual disease–negative status. However, investigators also found that the cytokines result in more grade 3 and 4 neurotoxicity events. In other words, Wang explains, cytokines increased with the use of CAR T-cell therapy together with the T-cell expansion, which caused not only high efficacy but increased toxicity. Specifically, an increase in neurological toxicities was observed, in addition to cytokine release syndrome.The resultspresented at 

 focused on the neurological toxicities, concludes Wang.

Michael Wang, MD, discusses the safety and efficacy of KTE-X19 in relapsed/refractory mantle cell lymphoma.

Dr. Wang on the Safety and Efficacy of KTE-X19 in R/R MCL

mutations have historically been difficult to target, said Naveen Pemmaraju, MD. However, preliminary data with the investigational small molecule eprenetapopt (APR-246) have shown promising activity in patients with 

-mutant myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

breakthrough therapy designation to the combination of the eprenetapopt and azacitidine

 for the treatment of patients with MDS with a susceptible 

 mutation. Prior to the 2020 designation, APR-246 received both orphan drug and fast-track designations from the FDA in MDS.

The breakthrough therapy designation is based on findings from a small phase 1b clinical trial, in which the combination of eprenetapoptand azacitidine led to a 100% objective response rate (ORR) among 5 patients with hypomethylating agent (HMA)–naïve, 

-mutant MDS and oligoblastic AML. Moreover, 4 patients achieved a complete response (CR) with complete cytogenetic response and 1 patient achieved a bone marrow CR with partial cytogenetic response.

 positivity at baseline according to immunohistochemistry.

No serious treatment-related adverse effects or dose-limited toxicities were noted with the combination, though grade 4 neutropenia and thrombocytopenia were reported.

At the 2020 European Hematology Association Congress, data from a phase 2 trial led by the Groupe Francophone des Myelodysplasies also showed high response rates with the combination in previously untreated patients with 

-mutant MDS and AML. In response-evaluable patients, the ORR was 77%, including a 49% CR rate. In the subset of patients with MDS, the ORR was 75%, including a 57% CR rate. The response rate in intention-to-treat population (including patients with at least 30% blast AML) was 58%, including a 38% CR/CR with incomplete hematologic recovery (CRi) rate.

A phase 3 clinical trial (NCT03745716), which is evaluating the combination for the frontline treatment of this patient population, completed accrual in June 2020. Results from the trial are expected in the second half of 2020.

 is extremely important as it is mutated in up to 50% of all human cancers,” said Pemmaraju. “That makes it one of the most common mutations in both solid and liquid tumors. We are seeing responses with this combination in this population that is considered high risk.

Pemmaraju, an associate professor in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed what the early data with eprenetapoptin combination with azacitidine could mean for the future in MDS and AML.

 a challenging target in MDS? What are your thoughts on the combination of eprenetapopt

In 2020, one of the key concepts in MDS and AML has become targeting the 

 axis in cancer cells. In addition to being ubiquitous, 

has historically been extremely difficult—if not impossible—to directly target. Other molecules have tried to indirectly target the 

 axis. Furthermore, across hematologic malignancies, most patients who are 

-mutated invariably have a poor prognosis. This is across chronic and acute diseases.

 is a well sought-after target [that highlights] an urgent unmet medical need [as it is a] poor prognostic feature.

Currently, there are several molecules [that are being tested] as single agents or in combination that are [showing real promise] in targeting 

 mutations. One of those agents is eprenetapopt.

Eprenetapopt, as a single agent or in combination with the hypomethylating agent azacitidine, is showing early, but promising clinical data in patients with 

Of course, as with any novel combination of new drugs or old drugs, we have to [be observant] of toxicity. We also need to see what is happening to the 

 variant allele burden and mutation pattern over time. It will also be of paramount importance to see what the long-term remission duration and overall survival of this novel combination is.

 has been the holy grail of cancer, particularly in [hematologic] cancers. It is encouraging to see eprenetapopt, as well as other molecules like anti-CD47 molecules, that have some hint of activity in targeting 

Sallman DA, DeZern A, Sweet K, et al. Phase Ib/II combination study of APR-246 and azacitidine (AZA) in patients with 

 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). 

. 2018;78(suppl 13):CT068. doi:10.1158/1538-7445.AM2018-CT068

Cluzeau T, Sebert M, Rahme R, et al. APR-246 combined with azacitidine in TP53 mutated myelodysplastic syndromes (MDS) and acute myeloid leukemia. A phase 2 study by the groupe francophone des myelodysplasies (GFM). Presented at: 2020 European Hematology Association Virtual Congress; June 11-21, 2020; Virtual. Abstract S181.

Naveen Pemmaraju, MD, discusses what the early data with eprenetapopt in combination with azacitidine could mean for the future in MDS and AML. 

Eprenetapopt/Azacitidine Shows Promise, Advances to Phase 3 Trial in TP53-Mutant MDS/AML

The combination of the first-in-class humanized monoclonal antibody cirmtuzumab and the BTK inhibitor ibrutinib (Imbruvica) was found to be an active, well-tolerated regimen for patients with relapsed/refractory mantle cell lymphoma (MCL) and treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from a phase 1b/2 study (NCT03088878).

The trial enrolled patients with relapsed/refractory MCL, or relapsed/refractory or treatment-naïve CLL or small lymphocytic lymphoma (SLL) who had measurable disease and had either limited or no prior treatment with BTK inhibitors. The trial is comprised of 3 parts: a phase 1 dose-escalation phase with cirmtuzumab (part 1), an expansion cohort (part 2), and phase 2 randomization of the cirmtuzumab/ibrutinib combination versus ibrutinib alone (part 3).

As of January 29, 2020, 12 patients with relapsed/refractory MCL were enrolled onto part 1 of the trial. All patients had stage III/IV disease at diagnosis and 25% had bulky tumor at the time of study entry. Fifty-eight percent of these patients had Mantle Cell Lymphoma International Prognostic Index risk scores of intermediate or high, and 83% had received ≥2 prior regimens. Additionally, a total of 34 patients with CLL were enrolled onto either part 1 of the trial (n = 18) or the part 2 expansion phase (n = 16).

 by lead author Hun Ju Lee, MD, showed a high tumor response rate with the combination in those with MCL, with an objective response rate (ORR) of 83% and a complete response (CR) rate of 58%. The initial median progression-free survival with the regimen was 17.5 months. Those who had received 1 to 10 months of prior ibrutinib also responded well to the combination; 2 patients achieved CRs and 2 achieved partial responses (PRs).

In patients with CLL/SLL, treatment with the combination led to an overall best response rate of 88% and a clinical benefit rate of 100%. One patient experienced a CR and has since remained in remission for over 8 months and off all CLL treatment. Three other patients achieved PRs with the regimen.

With regard to safety, the most common adverse effects (AEs) potentially related to the combination were fatigue, diarrhea, and contusion. One patient with MCL and 8 patients with CLL reported treatment-related severe AEs. However, the events were thought to be related to ibrutinib or the combination rather than cirmtuzumab alone. Grade 3 or higher AEs included atrial fibrillation (n = 5), pneumonia (n = 3), pericardial hemorrhage, pleural effusion, pyrexia, hyperkalemia, gastrointestinal hemorrhage, and staph infection (n = 1, each).

“In terms of medium follow up, it's very short so I don't want to get too excited. The median follow-up was 8 months and the median PFS is 17 months,” said Lee. “We are very happy with the results we have, and we look forward to building on top of this. There are ways to get rid of MCL but some of the ways that you take have a lot of toxicities involved. It is really exciting that all of my patients did not have any toxicity.”

, Lee, an assistant professor of medicine in the Department of Lymphoma & Myeloma and the Jessica and Jeffrey Brue Endowed Professor of Lymphoma Research at The University of Texas MD Anderson Cancer Center, further discussed the interim results of the study examining cirmtuzumab plus ibrutinib and the next steps with this research in MCL and CLL/SLL.

: Could you provide some background on cirmtuzumab and the rationale to explore it in combination with ibrutinib in this setting?

: As you know, the holy grail of cancer therapy is to find a target on the cancer cell that is not expressed on normal cells. Ideally, with lymphomas we're looking for a target on the lymphoma cell that is different from the proteins expressed on the surface of normal B cells. We would like to treat the lymphoma without harming normal B cells. Preclinical studies have examined ROR1, a family of proteins that are expressed in embryonic protein during early life and [then] disappear. [Investigators have] found [that these proteins] were expressed on the lymphoma cells and leukemia cells. [Investigators thought that] if [ROR1] was expressed on malignant lymphoma and leukemia cells and 

 expressed on normal cells, then it would serve as a great target [for therapy].

Rituximab (Rituxan) was developed in the early 90s and it targets CD20, which is expressed on normal cells. As such, when you give treatments like rituximab, even though the agent is well-tolerated, it does have some collateral damage. Rituximab decreases lymphocyte counts and we do have patients who require intravenous immunoglobulin therapyfollowing prolonged rituximab maintenance [if they have] lowlymphocyte counts.When they observed this finding, investigators questioned whether this is something that can be targetable. However, before we can develop a treatment [we have to understand] what it does.

What they found was that it is 1 of the proliferative survival signals, that are complementary to another system of proteins called immunoglobulin and that is the B-cell receptor. We know that B-cell receptor targeting has been tremendous with the targeting of BTK with ibrutinib and idelalisib (Zydelig). In all these pathways, targeting has generated great treatment options for many of our patients. However, we know that the difficulty with ibrutinib, idelalisib, the PI3K inhibitors, and BTK inhibitors, is that they don't [lead to an] 100% complete remission.

Where is it? How are these B cells surviving? What about the patients who are primary refractory? What about the patients who respond initially and then relapse? Where are these cells coming from and where's the survival? We're almost trying to play chess with these lymphoma cells because we know that they're using biological mechanisms to achieve a survival advantage.

[When the BTK is being blocked, these lymphoma cells] reroute the survival signal through another survival channel. We believe one of the mechanisms that this drug works by, is by blocking the ROR1, which is one of the other survival signals. When we gave ibrutinib in preclinical studies, [it was found to] increase the signaling pathway in the ROR1 pathway. If you block the BTK, the cells find an alternative route. The lymphoma and leukemia cells are very smart. They are able to take advantage of alternate sources of growth signals. That's where the idea came in, combined with the results from preclinical studies demonstrating that patients who had high levels of ROR1 had lower survival.

 way that the lymphoma cells escape mechanism. We know that there's mutations in the BTK and so forth and so on. However, this may be one of the contributing factors that help these lymphoma and leukemia cells become resistant to BTK inhibition. Therefore, we feel that blocking this pathway will block both pathways, thus, leading to a deeper response, meaning more CRs.

Could you discuss the design of the trial and the dosing schedules that were investigated?

This was designed as an open-label, phase 1/2 study. We knew that BTK inhibition and the ROR1 works in a complimentary fashion. We already knew the dosing schedule for ibrutinib, but we did multiple-dose escalations to try to find the right recommended dose [for cirmtuzumab] in the phase 2 [portion of the] study. We had 2 mg, 4 mg, 8 mg, 16 mg, 3 kg, and a flat dosing of 300 mg and 600 mg. Ultimately, after the phase 1 study, went with the 600 mg flat dosing, and that was found to be very well tolerated.

This goes right into the safety issue. We're looking for any toxicity. One of the remarkable things about this protein is that many of the antibody-driven therapies have been very well tolerated, and cirmtuzumab has also been very well tolerated. We did not see any grade 3 toxicity for cirmtuzumab.

Do anti-ROR1 antibodies have an established toxicity profile or is it still under investigation?

That is still under investigation, but in combination with the ibrutinib, we did not have any signal in terms of dose-limiting toxicities with the doses that we gave. Here, at The University of Texas MD Anderson Cancer Center, we gave the 2 mg through 18 mg per kilograms and the high and low flat dosing, and it was found to be very tolerated.

The efficacy seen with the combination was very interesting. Two histologies were studied: MCL and CLL. I am leading the MCL side and Michael Choi, MD, of the University of California, San Diego Medical Center, is leading the CLL portion of this study.

The MCL portion showed tremendous, exciting signal on phase 1 and 2 of this study. The ORRs were north of 80%, and the real kicker, knock-your-socks-off data are the CR rates. We were able to get 58% CR rates for many of these very heavily pretreated patients. We had approximately 40% of patients who had undergone autologous stem cell transplantation; we have patients who failed ibrutinib; and we have patients who had received [prior] CAR T-cell therapy and responded. Those findings gets people excited. I was surprised at how good the response was, given that usually toxicity and response go hand in hand. When you get more responses, you usually have very high toxicity. However, we really did not see any grade 3 toxicities.

Tons of CAR T-cells are being developed, but they come with fairly heavy prices. The headlines are big, but I know behind [the scenes], because I take care of these patients. It's not easy; if a patient is 70 years of age, they’re barely getting into the clinic. [When they ask for a CAR T], I get nervous; it is tough. But with this [combination], the majority of my patients [did not even feel that they were on a treatment]. This is very exciting for our patients.

The ORRs were north of 80%, and there was a 58% CR rate. We have 12 patients treated. Part 2 is open and it's accruing very nicely so we're trying to get more patients to enroll. This space is very tight; I'm sure you're aware that MCL is a tough place now because of the success achieved by Michael Wang, MD, of the University of Texas MD Anderson Cancer Center, with ibrutinib and CAR T. We're competing against some big agents, which are very effective. However, it's [a good thing] for our patients, because they have many treatment options that are available.

In terms of CLL, we did see high response rates; however, we did not see the robust CR rates that we saw in MCL; that’s one thing to note. They're up to part 2 and that part of the trial is enrolling much faster than MCL. CLL is the most common lymphoid malignancy in North America so investigators are readily finding patients. We're hoping that the enrollment for the MCL portion can get going and will show robust data.

Is there anything that you would like to add?

There was a rapid attainment of CR rates observed. Many of these patients have had hyper-CVAD, autologous stem cell transplantation, and CAR T-cell therapies, among others. [These were not patients who had only received 1 line of prior] therapy. If you start using ibrutinib earlier in treatment, you get higher levels of CRs and higher levels of PFS. However, these are patients that are heavily pretreated with fairly aggressive histologies and behavior. If you look at the waterfall plot, you can clearly see a rapid drop in the tumor sizes of the patients with MCL.

Many more patients were included in the CLL [portion of the study] and they do have a response, but the majority of these responses were PR, so they were not able to attain CR. Although they do have a response, it is not as dramatic as the MCL population.

If you look at the PFS curves for MCL they look nice. It's a very limited population with very limited follow up, so this will need to be followed up for much longer.

This is going to be leading to a very exciting time for cirmtuzumab and ibrutinib as we enroll for part 2 [of the trial], which is going to be the efficacy signal that we will be seeing moving forward. Additionally, other agents are being developed for the ROR1 targets, but the efficacy that we saw in our study with our limited number of patients is very exciting.

Lee HJ, Choi MY, Siddiqi T, et al. Clinical activity of cirmtuzumab, an anti-ROR1 antibody, in combination with ibrutinib: interim results of a phase Ib/II study in mantle cell lymphoma (MCL) or chronic lymphocytic leukemia (CLL). 

2020;38(suppl 15):8036. doi:10.1200/JCO.2020.38.15_suppl.8036

Hun Ju Lee, MD, discusses the interim results of a study examining cirmtuzumab plus ibrutinib and the next steps with this research in mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma.

Cirmtuzumab Plus Ibrutinib Shows Activity and Tolerability in MCL and CLL

Hun Ju Lee, MD, an associate professor of medicine in the Department of Lymphoma & Myeloma and the Jessica and Jeffrey Brue Endowed Professor of Lymphoma Research at The University of Texas MD Anderson Cancer Center, discusses novel targets in lymphomas and leukemias.

The goal of cancer therapy is to find a target on cancer cells that is not expressed on normal cells, says Lee. For lymphomas specifically, investigators are searching for a target on the lymphoma cell that differs from the proteins expressed on the surface of normal B cells, explains Lee. If this is done successfully, investigators can avoid harming normal tissue.

ROR1, a type I orphan-receptor tyrosine kinase–like surface protein that is expressed early in life and then disappears, says Lee. In preclinical research, it has been discovered that ROR1 proteins were expressed on lymphoma and leukemia cells. Investigators concluded that if these proteins were expressed on malignant lymphoma and leukemia cells and not on normal cells, then ROR1 could serve as a promising target in this space, explains Lee.

Notably, rituximab (Rituxan) targets CD20, a protein expressed on the surface of normal B cells. Because CD20 is expressed on normal cells, the agent does have some collateral damage despite being tolerated very well in patients, adds Lee. It is known that rituximab could decrease lymphocyte counts, especially in patients on prolonged treatment, resulting in the need of intravenous immunoglobulin treatment, concludes Lee.

Hun Ju Lee, MD, discusses novel targets in lymphomas and leukemias.

Dr. Lee on Examining Novel Targets in Lymphomas and Leukemias

Brandon G. Smaglo, MD, FACP, associate professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the future of immunotherapy in gastric cancer.

Future directions in gastric cancer all come back to immunotherapy, says Smaglo. For example, full data from the phase 3 KEYNOTE-026 trial, which examined pembrolizumab as first-line treatment for patients with advanced gastric or gastroesophageal junction adenocarcinoma, are highly anticipated, says Smaglo.

Additionally, now that the field understands the scoring system better there are different ways in which that information can be applied to better utilize immunotherapy, which will be exciting, adds Smaglo. For example, unfortunately, the JAVELIN Gastric 100 data with avelumab (Bavencio) was a negative study. In that trial, investigators evaluated a maintenance approach with immunotherapy. Patients were started on chemotherapy to achieve initial cancer control and then they were switched to receive immunotherapy; that approach did not prove beneficial.

However, notably, that study did not examine the different biomarker data. It will be interesting to see in similar studies if there is a subset of patients with gastric cancer who would benefit from maintenance immunotherapy if a tumor biomarker like PD-L1 is present and potentially indicative of benefit, concludes Smaglo.

Brandon G. Smaglo, MD, FACP, discusses the future of immunotherapy in gastric cancer.