The CAR T-cell therapy BNT211, with or without an mRNA vaccine, produced efficacious and tolerable safety results, according to data from a phase 1 trial (NCT04503278) presented at at the 2022 AACR Annual Meeting.

The trial of BNT211, consisting of a Claudin-6 (CLDN6)-targeting CAR T-cell product plus the CAR T-cell cell-amplifying RNA vaccine (CARVac), had an overall response rate (ORR) of 43% and an acceptable safety profile in 14 patients with relapsed/refractory testicular cancer, ovarian cancer, or other solid tumors.

“We found robust engraftment of CAR T cells in all patients, which translated into a very encouraging clinical benefit with an ORR of 43% and a disease control rate of 86%. CARVac really supports the T-cell engraftment and also mediates expansion,” John Haanen, MD, PhD, director of the Center for Cellular Therapy at the Netherlands Cancer Institute and professor of translational immunotherapy of cancer at Leiden University, said during his presentation.

CAR T-cell therapy has demonstrated limited success in patients with solid tumors. CLDN6 was identified as a tumor-specific antigen expressed in solid tumors but silenced in adult healthy tissue during organogenesis, leading to the development of a second-generation CAR T-cell product with high affinity and specificity for CLDN6. In addition, CARVac encoded with CLDN6 has previously been demonstrated to promote expression and persistence of CLDN6 CAR T cells.

In part 1 of the study, patients received 1 course of lymphodepletion (LD) followed by dose escalation of CAR T cells to assess dose-limiting toxicities (DLTs) and determine a recommended phase 2 dose. In the second part, patients received a dose escalation of CAR T cells and CARVac starting on day 4. There were 2 dose levels in each part. Doses were increased every 3 weeks and CARVac was administered every 6 weeks.

As of March 10, 2022, 3 cohorts with a total of 16 patients were treated, and 1 more cohort is ongoing. The patient population included 8 patients with testicular cancer, 4 with ovarian cancer, and 4 with other solid tumor types.

Robust CAR T-cell engraftment was seen in all patients across dose levels and in both parts. At an assessment 6 weeks following infusion, 14 of 16 patients were evaluable. There were 6 partial responses (PR), 5 with stable disease (SD) with shrinkage of target lesions, and 1 with SD alone. At 12 weeks, patients with a PR showed a deepening of response including 1 complete response (CR), though investigators observed disease progression in 5 patients who had previously had SD or PR.

“These early responses unfortunately don’t appear to be as durable as we would have hoped because only 1 patient in the analysis set had a response past 18 weeks and that was the CR,” Vincent K. Lam, MD, assistant professor of oncology and director of the Esophageal Cancer Research Program at Johns Hopkins University, said during the conference presentation. “We do note, though, that there’s another patient with ongoing PR at about 6 weeks and we await further follow-up.”

The patient with CR had failed 6 previous lines of treatment for testicular cancer. His remission included a lowered level of alpha-fetoprotein that has lasted for 6 months. This patient’s CAR T cells persisted for 150 days and had a dominant phenotype of effector memory cells re-expressing CD45RA, while other patients had a phenotype of effector memory cells negative for CCR7 and CD45RA.

Two cases of DLTs were observed, 1 in each arm. In the monotherapy arm, prolonged cytopenia was observed after LD in a patient with testicular cancer who had recently received high-dose chemotherapy and autologous stem cell transplant, leading to the creation of a cohort who would receive reduced or no LD. Hemophagocytic lymphohistiocytosis occurred in a patient with ovarian cancer in the CARVac arm before CARVac was started. Both toxicities were managed successfully.

Grade 3 or higher adverse events were mainly caused by LD or were asymptomatic enzyme elevations. Manageable grade 1 or 2 cytokine release syndrome occurred in 8 patients, 7 of whom were in the CARVac arm and 70% of whom were treated with the higher dose level. These patients showed an increase in interleukin-6 and elevated lipase but were confirmed to not have pancreatitis.

According to Lam, “CARVac appears safe in combination with CLDN6 CAR T, but CAR T persistence does not appear to be consistently enhanced yet.” He suggested that more optimal timing, dose, and duration of CARVac could maximize its effectiveness in mediating CAR T cell persistence. 

Though these data are preliminary, and the study population is small, it suggests a future role for CAR T cells in solid tumors including testicular and ovarian cancer as well as CLDN6’s potential as a targetable biomarker.

“The infusion of CLDN6 CAR T, alone or in combination with CARVac, is safe and holds promise for patients with CLDN6-positive cancers,” Haanen stated in a press release.

 “CLDN6 was never targeted before with cellular therapy, but in our study, this approach is already showing efficacy that may be better than the data from other CAR T trials in solid tumors.”

Haanen JB, Mackensen A, Koenecke C, et al. CT002 - BNT211: A Phase I trial to evaluate safety and efficacy of CLDN6 CAR-T cells and CARVac-mediated in vivo expansion in patients with CLDN6-positive advanced solid tumors. Presented at: American Association for Cancer Research Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT002.

Reinhard K, Rengstl B, Oehm P, et al. An RNA vaccine drives expansion and efficacy of claudin-CAR-T cells against solid tumors. 

. 2020;367(6476):446-453. doi:10.1126/science.aay5967

New CAR T-cell Therapy for Solid Tumors Was Safe and Showed Early Efficacy. American Association for Cancer Research. Published April 10, 2022. Accessed April 11, 2022. https://bit.ly/3KrcZFY

Articles

The CAR T-cell therapy BNT211, with or without an mRNA vaccine, produced efficacious and tolerable safety results.

CAR T-Cell Therapy Demonstrates Efficacy With or Without mRNA Vaccine in Solid Tumors

Atezolizumab (Tecentriq) with or without radiotherapy did not demonstrate efficacy in patients with advanced squamous cell carcinoma of the penis, according to results from the phase 2 PERICLES trial (NCT03686332) presented at the 2022 American Society of Medical Oncology Genitourinary Cancers Symposium.

The data showed patients with stage IV disease did not achieve the desired primary end point of 1-year progression-free survival (PFS). At a median follow-up of 22 months, only 12.5% of patients had a PFS of 1 year or more (95% CI, 5.0-31.3).

The PERICLES trial investigated whether immunotherapy would be effective against advanced squamous cell carcinoma of the penis based on preclinical data suggesting patients had high rates of intratumoral CD8 T cells and 40% to 60% PD-L1 positivity. Patients in 1 of the 2 arms of the study were also to receive radiotherapy to control locoregional lymph node disease.

“Advanced penile cancer has a very poor prognosis, especially for those patients with stage IV disease, and these patients have limited options…for treatment,” lead study author Hielke Martijn de Vries, MD, of Netherlands Cancer Institute, said during the presentation.

According to de Vries, his institution ran 2 previous studies in this setting. A trial of neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil was judged to have high toxicity and early relapses, with 23% of patients discontinuing treatment.

 A trial of chemoradiation resulted in less toxicity and better PFS than the chemotherapy, but this study was not restricted to advanced-stage disease.

 Neither trial included patients with distant metastases.

In the PERICLES trial, patients in both arms received 1200 mg of atezolizumab every 3 weeks, while the radiotherapy arm also received 33 fractions of 1.5 Gy (locoregional affected lymph nodes) and 1.8 Gy (macroscopic tumor and margin) irradiation.1 There were 12 patients in the atezolizumab arm and 20 patients in the atezolizumab plus radiotherapy arm.

All patients had stage IV disease with an inoperable primary tumor and a World Health Organization performance status of 0 or 1. Patients were allowed to have received any previous treatment besides immunotherapy; only 25% had no prior treatment. The percentage of patients with distant metastases was 59%.

In addition to the primary end point of PFS of 35% or greater at 1 year (to exclude 15%), there was a secondary end point of 2-year overall survival rate in both arms combined.

The median PFS was 2.5 months with no significant difference between the treatment arms.1 Patients with PD-L1 positivity, as well as those who were positive for human papilloma virus (HPV), showed slightly higher PFS. “It’s interesting here to notice that the 2 patients in arm B who responded well to treatment were both PD-L1 positive and high-risk HPV-positive,” de Vries said in his presentation.

The median overall survival (OS) was 12 months (95% CI, 5.5-19.7) and the 1-year OS rate was 43.4% (95 CI, 28.4-66.1), though further follow-up is needed, according to de Vries.

Response to treatment was evaluated according to RECIST1.1 with 12-weekly scans of the abdomen and thorax. While some durable responses and complete responses (CRs) were observed, including 2 patients with pulmonary metastases achieved CRs, overall response rates were low. Out of 30 evaluable patients in both arms, there were 7 (23%) partial responses (PRs) and 3 (10%) CR. In the radiotherapy arm (n = 18), there were 6 PRs and 2 CRs, while there was only 1 PR and 1 CR in the arm that received atezolizumab (n = 12).

In terms of toxicity, 20 patients (63%) across both arms experienced any grade of immunotherapy-related adverse events (AEs) while 3 (9.4%) experienced grade 3 or 4 AEs. In the radiotherapy arm, 18 patients (90%) experienced radiotherapy-related AEs, with 13 (65.0%) being grade 3 or 4.

Despite some evidence of antitumor activity from atezolizumab, the trial did not meet its goals. The combination with radiotherapy did not improve outcomes of immunotherapy, though de Vries noted that a more optimal radiotherapy schedule might increase efficacy. De Vries suggested that further investigation could assess not only the biomarkers associated with improved response but those linked to resistance to the treatment.

“We also saw in this trial an incomplete immunological activity and early resistance to atezolizumab… and we’re currently looking at pre- and on-treatment biopsies to see if there are other biomarkers for response and which combination therapies would be best to overcome this resistance,” de Vries said. “So while there is still a lot of work to be done, we’re quite enthusiastic about immunotherapy for the treatment of advanced penile cancer.”

De Vries HM, De Feitjer J, Bekers E, et al. Clinical results of PERICLES: A phase II trial investigating atezolizumab +/- radiotherapy for advanced squamous cell carcinoma of the penis. 

 2022;40(suppl 6):3. doi:10.1200/JCO.2022.40.6_suppl.003

Djajadiningrat RS, Bergman AM, van Werkhoven E, Vegt E, Horenblas S. Neoadjuvant taxane-based combination chemotherapy in patients with advanced penile cancer. 

2015;13(1):44-49. doi:10.1016/j.clgc.2014.06.005

Ottenhof S, Doodeman B, Vrijenhoek GL, Djajadiningrat RS, Horenblas S, Pos FJ. Chemoradiation in the treatment of loco-regionally advanced penile cancer. 

 2019;18(1):e655. doi:10.1016/S1569-9056(19)30484-1

Atezolizumab with or without radiotherapy did not demonstrate efficacy in patients with advanced squamous cell carcinoma of the penis.

Atezolizumab Fails to Meet PFS End Point in Advanced Penile Squamous Cell Carcinoma

Biomarkers such as mismatch repair deficiency (dMMR), microsatellite instability (MSI), 

 mutations possess the potential to inform treatment decisions in patients with endometrial cancer, but several questions still need to be addressed, according to Casey M. Cosgrove, MD.

For example, Cosgrove added that dMMR or MSI status and increased tumor mutational burden are more clearly defined for use in clinical practice, but it is still unclear whether a patient with a tumor that harbors a

“[We] must continue to integrate the right biomarkers that we have information for into clinical practice,” Cosgrove said. “Certainly, it is easy to order a lot of testing, but if we do not have a clear game plan with what we are going to do with that testing, then we [could] harm our patients. [We need to practice some] caution when we are discussing biomarkers and new technologies with any cancer types.”

® during the 2022 SGO Winter Meeting, Cosgrove, an assistant professor in the Department of Gynecologic Oncology at The Ohio State University College of Medicine, discussed the current state of biomarkers in the realm of endometrial cancer and how they may be optimally leveraged for prognostic and predictive purposes.

OncLive®: What is the interest in biomarkers for endometrial cancers?

 We know that with many different types of cancers, we’re starting to look at a more specialized approach as to how we can better take care of our patients, and endometrial cancer certainly has many opportunities where we can identify molecular markers or things that we can’t see under the microscope to help guide the best way to treat these patients.

We can use biomarkers to treat patients, to guide which trial metric to use, [or] which type of treatment we want to use. But we can also use biomarkers to tell us which patients should be treated, or maybe even which patients should not be treated. It’s an incredibly exciting area of research for endometrial cancer because it allows us to home in on their individual types of cancers and treat them with the most individualized approach.

What is the current landscape of endometrial cancer?

One of the things that needs to be highlighted about endometrial cancer is it's one of the few cancers that is getting worse. We have more patients dying of endometrial cancer now than we did last year, and that's a travesty. Endometrial cancer is aligning itself to overtake ovarian cancer to become the deadliest gynecologic cancer in the United States in the near future. We need our researchers and clinicians to be aligned with what patients that are having poor outcomes are seeing.

What biomarkers are most relevant to endometrial cancer and what role do they play?

With biomarkers in endometrial cancer, there are 2 fundamental questions. The first question is, ‘Who should we be treating?’ Several studies have looked at the best ways that we can predict whether patients' cancers will come back or not.

Classically, we have been guided by [disease] stages or the histology, as well as several other features. However, now, we are starting to appreciate that we can use molecular signatures to tell us whether these cancers are at higher or lower risk for recurrence.

There have been reports from our group, as well as others, that have looked at different markers that have predicted higher-risk cancers; this can include 

 or genomic alterations, and several other mutations that we have noted. If we identify patients who have some of those higher-risk features, they may derive benefit from receiving extra treatment. Another marker, [referred to as] 

, is needed to help the DNA repair itself; this allows for the immune system, without any additional treatment, to fight cancer cells better. We see that those patients [with 

A question that we have also been asking is, ‘Can we 

 treat these patients, even if they traditionally would have had higher-risk features?’ [Specifically regarding] biomarkers, [we want [to see whether] we [can] work smarter, and not necessarily harder. Can we target therapies that are based off molecular signatures?

Perhaps the one that we have the most research and the most experience with is deficiencies in MMR proteins or MSI within endometrial cancers; these markers predict response for immunotherapies. As such, when we look at an endometrial cancer that has 1 of these markers, perhaps we should jump right to immunotherapy as opposed to going through our classical chemotherapy algorithms. We also know that MMR and MSI status can also be an important prognostic biomarker because these patients seem to also have poor outcomes.

As such, taken collectively, a patient that has a dMMR tumor or MSI-high tumor may benefit from receiving more aggressive treatment and a [potentially] smarter [approach] with immunotherapy as opposed to traditional chemotherapy.

What are the most significant potential areas for improving care?

Several ongoing clinical trials are trying to refine the way that we take care of a patient with endometrial cancer. What I hope that we can see through all these trials is that we have some easily applied clinical markers that are going to directly impact our decision making. The ProMisE [Proactive Molecular Risk Classifier for Endometrial Cancer system] from the University of British Columbia, which establishes endometrial cancer into 4 different molecular groups, has the most traction right now throughout the gynecologic oncology community.

 [positivity], and grouping endometrial cancers into 1 of 4 groups.

Depending on which group [patients] fall into, then the next question will be, ‘What is the best treatment for those individuals?’ This has been evaluated through several trials. There is a lot of excitement [in this area] and we hope to get some answers over the next couple of years. The endometrial cancer [setting] has a lot of opportunity for growth in patient care, and we, as clinicians, are going to have to start integrating a lot of this information quickly as it becomes available.

With the improvements in technology, we are going to be getting more information for each cancer type in the future than we have ever had before. Assimilating that information into the clinical setting [may represent] a major barrier for patients and clinicians alike. [That being said], hopefully, we will have some standardized protocols that [can help] us to [select] the [best] way to care for each individual patient.

What studies are further exploring biomarkers in the endometrial setting? Which ones are you most excited about?

The RAINBO [trials] are very exciting because not only are [the investigators] using the molecular classifications to determine the risk for recurrence and the aggressiveness of treatment, but they are also integrating novel treatment strategies for the different molecular groups. As suh, I might identify that a patient is at higher risk, and I know what [treatments are] available, but I can [consider adding] more targeted therapies because of that molecular class, and I can treat them more aggressively and with a smarter therapy.

One of the things that is most notable is the vast amount of ongoing research that we have in the area right now; this also highlights the vast number of [unanswered] questions right now. One potential concern is that physicians may start integrating little pieces of this information into their clinical practice, without having a full tool belt available for what they need to be doing [with respect to] what are the right tests [to use] and the right treatments that might be available.

How do the National Comprehensive Cancer Network (NCCN) guidelines align with this new biomarker research?

Within the past 1 or 2 years, the NCCN guidelines have started incorporating the algorithms for molecular classification with endometrial cancer.

 Traditionally, we have broken endometrial cancers into type 1 and type 2, with type 1 being a less aggressive type of [disease], and type 2 being more aggressive. In 2013, the Cancer Genome Atlas [TCGA] broke endometrial cancer [down further,] into 4 important groups with differing risk of recurrence and differing molecular features.

 Recent research has tried to integrate those in the clinical setting because TCGA uses technologies that we cannot apply to the bedside. By utilizing newer technologies, we are able to start integrating some of their findings into clinical care.

The NCCN has started to appreciate that, and [currently uses] the algorithm for breaking endometrial cancers into 1 of 4 molecular groups, as opposed to the 2 groups that we had traditionally [used]. We also see a greater emphasis on what we can do with that information in the NCCN guidelines. For instance, 1 of the most important molecular groups is the MSI or dMMR group. Not only is this an important prognostic biomarker, but it is also a predictive biomarker for the use of immunotherapy—that has been highlighted in the more recent editions of the NCCN guidelines, where they say if [a patient] recurs [and has] MSI-high disease or dMMR, then immunotherapy is very appropriate.

The other thing that the NCCN guidelines highlight is that even in the absence of having a biomarker, patients can receive immunotherapy with the combination of lenvatinib [Lenvima] and pembrolizumab [Keytruda]. As such, sometimes having a negative biomarker can be just as informative for guiding treatment.

What is your take-home message to your colleagues working in this space?

One of the most important concepts to understand is that we do not have all the answers quite yet; we are still working on it. As we get more information, [we may identify other biomarkers] to look for. It is hard to cherry pick 1 or 2 things that [we] can utilize [for all patients]. The question is whether we need to have a whole grouping of testing to make the right decision for our patients.

Right now, we are [in] a situation where there are clearly defined biomarkers that can be utilized in a clinical setting, like dMMR or MSI status and increased tumor mutational burden, but we still have unclear knowledge whether a patient with a tumor with, [for instance], a 

 mutation, can safely forego treatment. If you hear that these tumors have no recurrences, [we want to know] why we are treating them with chemotherapy and radiation, which have high toxicities. However, at the same time, we have not clearly proven that withholding treatment [in these patients] is not compromising outcomes.

[It is also important to note] our reliance on classic pathologic findings, histology, and stage, and [reflect on] how we integrate that into our patient care algorithms. Once we start getting more molecular data, how do we integrate the old and new data? What do we do if we have conflicting information? This could cause problems in the future if we do not adequately study these questions.

Kommoss S, McConechy MK, Kommoss F, et al. Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series. 

 2018;29(5):1180-1188. doi:10.1093/annonc/mdy058

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Uterine Cancers, version 1.2022. Accessed January 24, 2022. 

Levine D, Cancer Genome Atlas Research Network. Integrated genomic characterization of endometrial carcinoma [published correction appears in 

. 2013;497(7447):67-73. doi:10.1038/nature12113

Casey M. Cosgrove, MD, discussed the current state of biomarkers in the realm of endometrial cancer and how they may be optimally leveraged for prognostic and predictive purposes. 

Leveraging Biomarkers in Endometrial Cancer Requires Careful Integration, More Research

Sintilimab (Tyvyt) plus standard-of-care chemotherapy failed to demonstrate a significant improvement in overall survival (OS) and progression-free survival (PFS) vs standard-of-care chemotherapy alone but did result in an improved objective response rate (ORR) in patients with metastatic or recurrent pancreatic adenocarcinoma (PDAC), according to findings from the phase 3 CISPD3 trial that were presented during the 2022 Gastrointestinal Cancers Symposium.

The standard of care for PDAC is the chemotherapy combination FOLFIRINOX (folinic acid, fluorouracil, irinotecan hydrochloride, and oxaliplatin) or modified-FOLFIRINOX (mFFX [folinic acid, irinotecan, oxaliplatin followed by fluorouracil]). Researchers in this study investigated whether sintilimab, a human immunoglobin G4 monoclonal antibody that binds to PD-1 and has shown efficacy in other cancer types, could improve outcomes for patients with PDAC in the first or second line.

“Pancreatic cancers are resistant to PD-1 [and] to PD-L1 used as monotherapy, so the chemotherapy may expand the efficacy of immunotherapy,” said Tingbo Liang, chairman of The First Affiliated Hospital at Zhejiang University School of Medicine, in his presentation.

The single-center, open-label phase 3 CISPD3 trial randomized patients 1:1 to receive either 200 mg of sintilimab every 3 weeks plus mFFX (irinotecan 85 mg/m

) every 2 weeks versus mFFX alone. Of the study population of 110 total patients, only 3 patients on the sintilimab arm and 5 on the mFFX-alone arm had previous chemotherapy.

Patients were treated until disease progression, unacceptable toxicity, or other reasons for discontinuation. The primary end point was OS, while secondary end points included ORR, PFS, and disease control rate (DCR).

Twenty-one patients receiving sintilimab had a partial response (PR) and 1 had a complete response (CR), while 11 had a PR and none had a CR when receiving mFFX alone. In the sintilimab arm, 11 patients were not evaluable compared with 9 in the mFFX arm. The ORR for sintilimab was 50.0% compared with 23.9% with mFFX alone (

 = .05). The duration of response was 7.85 months for sintilimab compared with 4.63 months for mFFX, but this was not statistically significant (

 > .05). The DCR was 84.0% and 71.7% for sintilimab and mFFX, respectively (

However, the median OS was similar between the 2 arms for the intention-to-treat population: 10.9 months for sintilimab and 10.8 months for mFFX alone with a hazard ratio (HR) of 1.09 (95% CI, 0.70-1.690; 

 > .05). The median PFS was 5.9 months for sintilimab and 5.73 months for mFFX with a HR of 0.93 (95% CI, 0.62-1.41), showing no improvement in survival outcomes based on these data.

In terms of safety, grade 3 or higher treatment-emergent adverse events (TEAEs) occurred in 45 patients (84.9%) in the sintilimab arm compared with 40 (74.1%) in the mFFX-alone arm. The most common grade 3 or higher AE was neutropenia, which was reported in 31 patients (58.5%) given sintilimab and 24 patients (44.4%) given mFFX alone. Other AEs included thrombocytopenia, anemia, vomiting, and increased aminotransferase. Immune-related AEs of grade 3 or higher occurred in 3 patients in the sintilimab arm (5.7%) and pulmonary AEs occurred in 3 patients (5.7%) as well.

“From the study we conclude that from addition of the sinitilimab to the mFFX, we improved the ORR significantly for metastatic pancreatic cancer, but no superior OS and PFS were observed. The toxicity was manageable and acceptable until growth. These data suggest that a combination with PD-1 antibody may expand the benefit of the chemotherapy protocol,” said Liang.

Fu Q, Chen Y, Huang D, Guo C, et al. Randomized phase III study of sintilimab in combination with modified folfrinox versus folfrinox alone in patients with metastatic and recurrent pancreatic cancer in China: The CISPD3 trial. Presented at: 2022 ASCO Gastrointestinal Cancers Symposium. January 20-22, 2022. Abstract 560. 

Sintilimab plus standard-of-care chemotherapy failed to demonstrate a significant improvement in overall survival and progression-free survival vs standard-of-care chemotherapy alone but did result in an improved objective response rate in patients with metastatic or recurrent pancreatic adenocarcinoma, according to findings from the phase 3 CISPD3 trial.

Sintilimab Plus Standard Chemotherapy Misses OS End Point in Metastatic Pancreatic Cancer

Acalabrutinib (Calquence) demonstrated an advantage in quality-adjusted survival compared with other standard treatments for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), according to findings from a post-hoc risk-benefit analysis that were presented during the 2021 ASH Annual Meeting and Exposition.

Acalabrutinib, a next-generation Bruton tyrosine kinase (BTK) inhibitor, showed progression-free survival (PFS) benefit in phase 3 trials versus previous approved treatments for CLL as well as tolerable toxicity.

 Investigators applied Quality-adjusted Time Without Symptoms and Toxicity (Q-TWiST) analysis, a quality-adjusted life-year (QALY) method that assesses the risks and benefits of treatment based on drug efficacy and toxicity profile, to the results of these studies. The findings demonstrated that acalabrutinib offers significant quality-adjusted survival gains compared with immunotherapy or a PI3K inhibitor, as well as clear benefit over ibrutinib (Imbruvica), a first-generation BTK inhibitor.

The Q-TWiST analysis focused on a pair of phase 3 studies, the ASCEND trial (NCT02970318) and ELEVATE-RR trial (NCT02477696). The ASCEND trial compared acalabrutinib with either bendamustine (Bendeka) plus rituximab (Rituxan) or idelalisib (Zydelig) plus rituximab in patients with R/R CLL. The ELEVATE-RR trial compared acalabrutinib with ibrutinib in patients with R/R CLL with high-risk genomics.

For this analysis, investigators looked at patients from the trials in 3 states: duration with toxicity before disease progression, duration without progression or toxicity, and duration from disease progression to death or end of follow-up. Toxicity was defined based on grade 3 and 4 adverse events (AEs), and when comparing acalabrutinib to ibrutinib, it was also measured by grade 2 to 4 AEs and the occurrence of AEs of any grade that occurred frequently.

“We also applied definitions of grade 2 to 4 AEs and any-grade AEs occurring in 10% or more patients because a significant clinical burden is associated with persistent low-grade adverse events in BTK inhibitor treatment,” John F. Seymour, AM, from the Peter MacCallum Centre and the Royal Melbourne Hospital in Melbourne, Australia, said in his presentation.

Investigators created Kaplan-Meier survival curves for time from toxicity to disease progression, PFS, and overall survival. The Q-TWiST analysis was based on the total of the weighted restricted mean durations of each of the 3 states.

When comparing acalabrutinib with bendamustine/rituximab or idelalisib/rituximab, patients spent an average 3.58 more months without progression or toxicity with acalabrutinib (95% CI, 2.42-4.74) and 2.51 fewer months between disease progression and death (95% CI, −3.50 to −1.60) and 0.73 fewer months with toxicity but before disease progression. The Q-TWiST with acalabrutinib was 17.48 months compared with 15.52 months with immunotherapy or PI3K inhibitors, a difference of 1.96 months (95% CI, 1.13-2.81).

In the acalabrutinib versus ibrutinib comparison, patients who received acalabrutinib had an average 0.37 months more between disease progression and death or relapse (95% CI, −1.82 to 2.60; 

 = .749). When analyzing toxicity by counting all AEs that affected at least 10% of patients, their Q-TWiST was 33.02 months with acalabrutinib versus 30.46 months with ibrutinib, an increase of 2.56 months (95% CI, 0.19-4.83). When considering grade 2, 3, and 4 AEs, the Q-TWiST difference was 2.58 months (95% CI, 0.22-4.89). When only considering grade 3 and 4 AEs, the difference was 1.28 months, which was not statistically significant (95% CI, −1.34 to 3.80).

A sensitivity analysis based on utility measures from the study did not find statistically significant improvement in Q-TWiST for acalabrutinib in either study population regardless of toxicity definition; however, the investigators noted in their presentation that the 2 studies were not designed to collect EuroQol-5 Dimension quality of life data from patients after treatment discontinuation.

“Overall, acalabrutinib demonstrated a favorable benefit-risk profile compared with idelalisib or B/R [bendamustine plus rituximab] in ASCEND or ibrutinib in ELEVATE-RR among patients with relapsed/refractory CLL,” Seymour concluded.

Seymour JF, Gaitonde P, Emeribe U, Cai L, Mato AR. A quality-adjusted survival (Q-TWiST) analysis to assess benefit-risk of acalabrutinib versus idelalisib/bendamustine plus rituximab or ibrutinib among relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 3722.

Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia

. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. 

 2021;39(31):3441-3452. doi:10.1200/JCO.21.01210

Acalabrutinib demonstrated an advantage in quality-adjusted survival compared with other treatments for relapsed/refractory chronic lymphocytic leukemia.

Acalabrutinib Shows Superior PFS, Safety Over Other Treatments in Relapsed/Refractory CLL

The combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) led to a lower rate of minimal residual disease (MRD) compared with fludarabine, cyclophosphamide, and rituximab (Rituxan; [FCR]) in patients with treatment-naïve chronic lymphocytic leukemia (CLL), according to preliminary findings from the phase 2 ERADIC trial (NCT04010968) that were presented at the 2021 ASH Annual Meeting and Exposition.

The randomized phase 2 ERADIC trial, a French Innovative Leukemia Organization (FILO) trial presented by co-principal investigator Anne-Sophie Michallet, MD, of the department of hematology at the Centre Léon Bérard, compared ibrutinib plus venetoclax with the standard FCR regimen in medically fit, previously untreated patients with intermediate-risk CLL. These patients had either unmutated 

, 11q deletion, or complex karyotype in the absence of 

The investigators’ goal was to evaluate whether ibrutinib in combination with venetoclax, a BCL2 inhibitor, could lead to a lower MRD. However, at the 9-month interim follow-up, FCR showed a greater rate of reduced MRD in patients than ibrutinib/venetoclax. This result may not be indicative of the full trial length of 27 months.

Participants in the study were randomized 1:1 between receiving 6 cycles of FCR versus ibrutinib 420 mg and 400 mg venetoclax each daily, with 60 patients in each arm. Patients in the ibrutinib/venetoclax arm received ibrutinib monotherapy as a lead-in for the first 3 months. Treatment was either continued or discontinued after the results of bone marrow (BM) MRD assessment using flow cytometry at 9 months from the start of treatment. If BM MRD was below 0.01%, patients would continue treatment for 6 more months, for a total of 15 months. If BM MRD was above 0.01%, treatment would continue for 18 months instead, for a total of 27 months.

The trial’s primary end point in both arms was the percentage of patients at 27 months with BM MRD of 0.01%, while secondary end points included progression-free survival, overall survival, complete response (CR) rate at 27 months, and safety of both arms.

According to Michallet, at the ninth month of treatment, patients received evaluations including CT scans, bone marrow biopsies, and both peripheral blood (PB) MRD and BM MRD assessment. The interim results she presented had a median follow up of 11 months (95% CI, 2.9-19.8).

Of the 120 patients, 103 had reached 9 months of treatment at the data cut-off. There were 56 evaluable patients in the FCR arm. One of the 4 who were not evaluable experienced early disease progression. In this arm, 90% of patients received the full 6 cycles of FCR.

There were 47 evaluable patients in the ibrutinib/venetoclax arm. Ibrutinib was discontinued for 4 patients permanently and 3 patients stopped but were able to resume at a lower dose, while 4 patients discontinued taking venetoclax permanently due to digestive toxicities and grade 4 neutropenia.

Of the evaluable patients, 71% in the FCR arm and 42% of patients in the ibrutinib/venetoclax arm achieved BM MRD of below 0.01% at 9 months. In the FCR arm, 75.5% had PB MRD of below 0.01% compared with 48% in the ibrutinib/venetoclax arm.

This was also consistent for more detailed analysis of the sensitivity level of the MRD. “When we look at the sensitivity of the MRD responses, the result is also very clear, with a higher rate and higher depth of minimum residual disease undetectable in the blood and the marrow for the FCR compared to the IV [ibrutinib/venetoclax],” Michallet stated in her presentation.

In the FCR arm, 50% had a CR and 48% had a partial response (PR), while in the ibrutinib/venetoclax arm, 64% had a CR and 32% had a PR.

There was a wide range of serious adverse events (SAEs) in both arms; 31 patients were evaluated for SAEs in the FCR arm and 25 patients in the ibrutinib/venetoclax arm. SAEs included tumor lysis syndrome, infections, neutropenia, and digestive issues. Notably, investigators observed more frequent hematological and infectious toxicities in the FCR arm. However, they observed 8 cardiovascular disorders in the ibrutinib/venetoclax arm, including 3 cases of atrial fibrillation and 2 sudden deaths. According to Michallet, the patients who died had no known cardiovascular issues in the past and had no predictive factors for cardiovascular risk.

While the ibrutinib/venetoclax arm showed significantly lower BM MRD, this could change as the trial period continues. “The BM MRD rate should improve after longer exposure to the IV combination, and the analysis of the primary end point at 27 months will be decisive in determining the best therapeutic strategy,” Michallet concluded.

Michallet AS, Quinquenel A, Letestu R, et al. Preliminary results of the Filo phase 2 trial for untreated fit patients with intermediate risk chronic lymphocytic leukemia comparing ibrutinib plus venetoclax (IV) versus FCR. Presented at: 2021 American Society of Hematology Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA. Abstract 641

The combination of ibrutinib and venetoclax led to a lower rate of minimal residual disease compared with fludarabine, cyclophosphamide, and rituximab in patients with treatment-naïve chronic lymphocytic leukemia, according to preliminary findings from the phase 2 ERADIC trial.

Ibrutinib Plus Venetoclax Induces Lower MRD Rate Vs FCR in Previously Untreated CLL

Significant outcome differences were observed in premenopausal vs postmenopausal patients with hormone receptor (HR)–positive, HER2-negative breast cancer who had 1 to 3 positive lymph nodes and received adjuvant chemotherapy as well as endocrine therapy, according to the updated results of SWOG S1007 RxPONDER trial (NCT01272037), presented at the 2021 San Antonio Breast Cancer Symposium.

 Results from the study were also published in the 

The investigators found a statistically significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in premenopausal women who received adjuvant chemotherapy, while no improvement was observed in postmenopausal patients. Kevin Kalinsky, MD, MS, director of Emory University Winship Cancer Institute’s Glenn Family Breast Center, also reported on post hoc analyses of subgroups among premenopausal patients and observed benefit for chemotherapy in premenopausal patients in terms of disease recurrence-free interval (DRFI), a more informative measure than DRFS.

“As opposed to DFRS, DRFI excludes death from non–breast cancer or unknown cause, and only includes distant recurrence or death from breast cancer,” Kalinsky said in his presentation. “This is a clinically important outcome given its relevance to long-term breast cancer–related survival.”

The randomized phase 3 RxPONDER trial enrolled approximately 5000 patients with HR-positive, HER2-negative breast cancer with 1 to 3 positive lymph nodes, no distant metastasis, and a 21-gene Oncotype DX Recurrence Score (RS) lower than 25. Those with a higher RS were treated off study and recommended to receive both endocrine therapy and chemotherapy, according to Kalinsky. Patients with a score of 25 or below were randomized to receive either chemotherapy followed by endocrine therapy or endocrine therapy alone. Among the 4983 patients evaluated in the updated results were 1654 premenopausal women and 3329 postmenopausal women.1

Patients in the endocrine therapy group received adjuvant endocrine therapy consisting of tamoxifen citrate, 1 of the aromatase inhibitors anastrozole (Arimidex), letrozole (Femara), or exemestane (Aromasin), or both tamoxifen citrate and an aromatase inhibitor. Patients in the chemotherapy group received an endocrine therapy in addition to systemic chemotherapy.

The primary end point of the study was IDFS and a secondary end point was DRFS. The 

 showed differences in IDFS and DRFS between premenopausal and postmenopausal patients who received chemotherapy. At a median follow-up of 6.1 years, the updated results contained 553 IDFS events. The results showed that in patients who were premenopausal, there was a 5-year absolute benefit of 4.9% for IDFS with chemotherapy (adjusted HR, 0.64; 95% CI, 0.47-0.87; 2-sided 

 = .004). There was a 5-year absolute benefit of 2.5% for DRFS with chemotherapy (adjusted HR, 0.66; 95% CI, 0.45-0.97; 2-sided 

“In an updated analysis, we report with longer follow-up that postmenopausal women with recurrence scores of 0 to 25 continue to not benefit from adjuvant chemotherapy,” said Kalinsky. In postmenopausal women, the 5-year IDFS rate was 91.2% in those treated with chemotherapy plus endocrine therapy compared with 91.9% in those treated with endocrine therapy alone (adjusted HR, 1.06; 95% CI, 0.87-1.30; 2-sided 

= .55). The 5-year DRFS rate was 94.3% with added chemotherapy vs 94.8% without (adjusted HR, 1.12; 95% CI, 0.88-1.44; 2-sided 

“However, premenopausal women with recurrence scores 0 to 25 do, with a 44% to 46% decrease in IDFS, DRFS, and DRFI events,” Kalinsky added.

For premenopausal patients, those who received chemotherapy demonstrated an improved DRFI of 2.4% (adjusted HR, 0.64; 95% CI, 0.43-0.95; 2-sided 

= .026) over those who only received endocrine therapy. For those with an RS of 0 to 13, the DRFI was 2.3%, while it was 2.8% for those with an RS of 14 to 25. However, postmenopausal patients did not show any DRFI benefit from chemotherapy in addition to endocrine therapy (HR, 1.12; 95% CI, 0.82-1.52; 2-sided 

Post hoc analysis showed that in 206 premenopausal women who had micrometastases of 0.2 to 2 mm in their lymph nodes, a 7.3% absolute benefit in IDFS from chemotherapy was observed with a hazard ratio of 0.44 (95% CI, 0.18-1.08). The absolute benefit in 5-year IDFS for 1403 patients with larger lymph node metastases of over 2 mm was 4.8% (HR, 0.64; 95% CI, 0.46-0.90).

“It does appear that premenopausal women with [only] micrometastases benefit from chemotherapy, though there [was] a limited number of events [n = 22], and there was a wide confidence interval,” Kalinsky noted.

In premenopausal patients who only received endocrine therapy, 50% stopped having periods in the first 6 months, compared with 25% of those who received chemotherapy as well. In the first 24 months, 58.9% of those receiving only endocrine therapy stopped having periods within the first 24 months, while 80.8% of those who also received chemotherapy stopped having periods in the first 24 months. In both arms, patients who stopped having periods also had a higher IDFS rate vs those who continued to have periods, with a hazard ratio of 1.56 (95% CI, 0.85-2.86) in those receiving chemotherapy and endocrine therapy vs a hazard ratio of 1.48 (95% CI, 0.92-2.40) in those receiving only endocrine therapy.

For those only treated with endocrine therapy, a 2-year landmarked analysis of ovarian function suppression (OFS) was meant to determine if it was linked to IDFS. A total 17.2% of premenopausal patients in this group underwent OFS. However, no difference in IDFS was observed based on OFS status (HR, 0.88; 95% CI, 0.47-1.63). The study was not able to establish that the benefit from chemotherapy was related to OFS. OFS rates were low in both treatment arms but were higher in the endocrine therapy–alone arm.

“It remains unclear if ovarian function suppression can replace chemotherapy in premenopausal women with hormone receptor–positive, HER2-negative, node-positive breast cancer,” Kalinsky said. “We conclude that future randomized trials should be considered to address this important clinical question in a genomically-defined population.”

Kalinsky K. Updated results from a phase 3 randomized clinical trial in participants (pts) with 1-3 positive lymph nodes (LN), hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25 randomized to endocrine therapy (ET) +/- chemotherapy (CT): SWOG S1007 (RxPONDER). Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS2-07.

Kalinsky K, Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. Published online December 1, 2021. 

Significant outcome differences were observed in premenopausal vs postmenopausal patients with hormone receptor–positive, HER2-negative breast cancer who had 1 to 3 positive lymph nodes and received adjuvant chemotherapy as well as endocrine therapy.

Jonah Feldman