Clinical research in oncology is at a crossroads and in a crisis. Although oncology clinical trial research was always challenging, the pandemic presented unique challenges where patients, physicians, and staff were often physically separated and had to develop unique solutions to enroll and remain on trials. Emerging from a 2-year pandemic, the work-fromhome revolution has led to the migration of staff to the pharmaceutical industry or contract research organizations (CROs).

Now, the effect on clinical trial development, regulatory management, and accrual is being felt. A number of creative solutions to retain staff have emerged, including fl exible work hours and locations but organizations running the trials simply cannot keep up with the differential compensation and work flexibility afforded by industry partners.

Furthermore, there is an additional, embedded cost to the academic and NCI-designated cancer centers’ clinical research operations. Consider the 6 to 12 months it takes to identify, hire, and train these individuals in the nuances and responsibilities of well-conducted clinical research trials. This not only increases budgetary diffi culties at the cancer centers and clinical research offices, but eventually slows recruitment and is counterproductive to what the industry and CROs hope to accomplish.

A number of oncology research organizations such as the American Society of Clinical Oncology, American Association for Cancer Research, and the Society of Immunotherapy for Cancer are actively developing task forces to address the staffi ng and accrual crisis. It should be noted that staff are not the only ones lost from cancer centers: Our experienced oncologists, the trialists themselves, may see industry as a more attractive environment for contributing to the impact in the fi eld of oncology.

Ultimately this will have a long-term dampening effect on progress, so it is gratifying that our oncology organizations and societies are recognizing that we are all on the same team—the patient’s team—in the hopes of developing and speeding progress in cancer clinical trials and oncology research to develop new therapies. Solutions are needed and only through mutual understanding of the issues that have existed for some years, and were accelerated by the pandemic and post-pandemic job shifts, will we address these issues with viable solutions.

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Emerging from a 2-year pandemic, the work-from-home revolution has led to the migration of staff to the pharmaceutical industry or contract research organizations.

Pandemic Spurs Clinical Trial Organizers to Seek New Career Path

The combination of neratinib (Nerlynx) and trastuzumab (Herceptin), with or without fulvestrant (Faslodex), demonstrated beneficial clinical activity in patients with heavily pretreated hormone receptor (HR)-positive, HER2-negative, HER2-mutant metastatic breast cancer (MBC). Komal Jhaveri, MD, FACP, presented these data along with the effectiveness of HER2-directed antibody-drug conjugates (ADCs) in patients with HER2-mutant breast cancer at the 21st Annual International Congress on the Future of Breast Cancer® East hosted by Physicians’ Education Resource, LLC (PER®) in New York, New York.

Results from the SUMMIT basket study (NCT01953926) revealed encouraging results with the triplet regimen in patients with HR-positive/ HER2-negative MBC compared with other variations and monotherapies of the 3 drugs.

The study also assessed the use of neratinib and trastuzumab alone among patients with triplenegative breast cancer (TNBC).

Patients with HR-positive MBC with prior CDK4/6 inhibition who received the triplet (n = 51) had an objective response rate (ORR) of 35.3% (n = 18), whereas patients who received fulvestrant plus trastuzumab or fulvestrant alone had no responses before crossing over to receive the triplet. Of the 18 responses with the triplet combination, 17 patients had partial response (PRs) and 1 patient had a complete responses (CR). Best overall responses, whether confi rmed or unconfirmed, to treatment with the triplet occurred in 25 patients (49.0%). The triplet regimen also had a median duration of response (DOR) of 14.3 months (95% CI, 6.4–not estimable [NE]) and a clinical benefit rate of 47.1%. The median progression-free survival (PFS) for patients receiving neratinib, trastuzumab, and fulvestrant was 8.2 months (95% CI, 4.7-12.7) compared with 3.9 months (95% CI, 1.9-4.1) with fulvestrant plus trastuzumab before crossover and with 4.1 months (95% CI, 1.6-4.1) . with fulvestrant monotherapy before crossover.

The phase 2 SUMMIT trial had a Simon 2-stage design. The primary end point was ORR in patients with HR-positive tumors and ORR at fi rst assessment for patients with TNBC. The secondary end point was confirmed ORR per investigator review.

The most common any-grade adverse events (AEs) among patients with HR-positive disease who received the triplet were diarrhea (90.2%), nausea (72.5%), vomiting (52.9%), and fatigue (43.1%). The most common grade 3 AEs in this group were diarrhea (51.0%), vomiting (7.8%), decreased appetite (7.8%), and fatigue (5.9%). Two grade 4 AEs were also reported: coma (n = 1) and muscle weakness (n = 1).

The neratinib/trastuzumab doublet also showed beneficial results among patients with TNBC (n = 18). The ORR was 33.3% (n = 6), with 1 CR (5.6%) and 5 PRs (27.8%). The best overall response rate was 38.9%. The median DOR was NE and the clinical benefit rate was 38.9%. The median PFS was 6.2 months (95% CI, 2.1-8.2). The median duration of treatment was 4.4 months (range, 0.3-15.4).

The most common any-grade AEs in patients with TNBC who received the doublet regimen were diarrhea (88.9%), nausea (50.0%), vomiting (50.0%), and constipation (38.9%). The most common grade 3/4 AEs were diarrhea (16.7%) and fatigue (16.7%). Thirteen patients (72.2%) discontinued treatment because of disease progression.

Jhaveri, an associate attending in the Breast Medicine and Early Drug Development Service, section head of the Endocrine Therapy Research Program, and clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, explained the value of ADCs in HER2-mutant tumors. “What we’re beginning to learn with these novel [ADCs], which have a higher drug-to-antibody ratio of cleavable linker and novel payloads, is that they exhibit bystander effect. [This] is not only causing apoptosis of the cancer cell, but it [is] also [causing] killing of the neighboring cancer cells.”

The DESTINY-Breast04 (NCT03734029) trial is a phase 3 multicenter, randomized, open-label, active-controlled trial study of trastuzumab deruxtecan (T-DXd; Enhertu) vs treatment of physician’s choice in patients with unresectable or metastatic disease and low HER2 expression (IHC1+ or IHC2+/ISH–).

 Investigators randomly assigned patients to receive T-DXd 5.4 mg/kg once every 3 weeks (n = 373) or physician’s choice of either capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane; n = 184). The primary end point was PFS in the HR-positive population, and the secondary end points were PFS in all patients, overall survival (OS), ORR, and DOR.

The median PFS for the primary end point was 10.1 months with T-DXd vs 5.4 months with physician’s choice (HR, 0.51; 95% CI, 0.40-0.65; 

 < .001). The median PFS across the whole patient population was 9.9 months with T-DXd vs 5.1 months with physician’s choice (HR, 0.50; 95% CI, 0.40-0.63; 

 < .001). The median OS for patients with HR-positive tumors was 23.9 months with T-DXd vs 17.5 months with physician’s choice of therapy (HR, 0.64; 95% CI, 0.48-0.86; 

 = .003). The median OS among all patients was 23.4 months with T-DXd vs 16.8 months with physician’s choice (HR, 0.64; 95% CI, 0.49- 0.84; 

 = .001). Patients with HR-negative and HER2-low tumors had a median PFS of 8.5 months with T-DXd vs 2.9 months (HR, 0.46; 95% CI, 0.24-0.89), and the median OS for this patient group was 18.2 months with T-DXd vs 8.3 months with physician’s choice (HR, 0.48; 95% CI, 0.24-0.95).

Any grade AEs in patients treated with T-DXd were most commonly nausea (73%), fatigue (48%), and alopecia (38%). The most common grade 3 AEs were neutropenia (14%), anemia (8%), and fatigue (8%). Jhaveri called special attention to drug-related interstitial lung disease (ILD)/pneumonitis and anygrade ILD/pneumonitis. This event occurred in 45 patients (12.1%), with 13 patients having grade 1, 24 as grade 2, 5 as grade 3, none as grade 4, and 3 as grade 5 events.

Activity with T-DXd was also reported in patients with HER2-low and HER2- negative MBC in the phase 2 DAISY trial (NCT04132960).

 Patients were stratified by HER2 status into 3 cohorts: HER2 overexpressing (cohort 1), HER2 low (cohort 2), and HER2 nonexpressing (cohort 3). The best ORR was 71% in cohort 1, 38% in cohort 2, and 30% in cohort 3. The median DOR was 9.7 months in cohort 1, 7.6 months in cohort 2, and 6.8 months in cohort 3. The median PFS was 11.1 months in cohort 1, 6.7 months in cohort 2, and 4.2 months in cohort 3. However, there was no HER2 immunohistochemistry scoring system optimized to distinguish a score of HER2 0 from HER2 1+. These results f rom the DAISY trial a re promising but require validation. 

1. Jhaveri K. What’s new for HER2-mutant and HER2-low metastatic breast cancers. Presented at: 21st Annual International Congress on the Future of Breast Cancer® East; July 15-16, 2022; New York, NY.

2. Oaknin A, Friedman CF, Roman LD, et al. Neratinib in patients with HER2-mutant, metastatic cervical cancer: fi ndings from the phase 2 SUMMIT basket trial. 

. 2020;159(1):150-156. doi:10.1016/j.ygyno.2020.07.025

3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. 

. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

4. Hurvitz SA, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with HER2+ metastatic breast cancer: subgroup analyses from the randomized phase 3 study DESTINY-Breast03. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Session GS3-01.

Results from the SUMMIT basket study revealed encouraging results with a neratinib triplet regimen in patients with HR-positive/ HER2-negative metastatic breast cancer compared with other variations and monotherapies of the 3 drugs.

Clinical Activity Is Found With Triplet Combination and ADCs in HER2-Mutant MBC

Neoadjuvant degarelix (Firmagon) , a hormone therapy, led to a higher likelihood of achieving minimal residual disease (MRD) negativity when used in combination with apalutamide (Erleada) compared with degarelix alone in patients with high-risk prostate cancer after radical prostatectomy, according to findings from the phase 2 ARNEO trial (NCT03080116).

MRD levels below 0.25 mL, the primary end point of the trial, was achieved in 38% of patients in the apalutamide combination arm (n = 45) compared with 9% in the degarelix monotherapy arm (n = 44; risk ratio, 4.2; 

 = .002). The residual cancer burden was a median of 0.48 mL with the doublet and 1.7 mL with the single agent (

“Patients [with high-risk prostate cancer] treated with degarelix plus apalutamide achieved a signifi cantly better tumor response compared [with] the patients treated with degarelix plus matching placebo,” said Steven Joniau, MD, PhD, a consulting urologist and assistant professor in the Department of Urology at University Hospitals Leuven in Belgium, when presenting fi ndings from the ARNEO trial during the European Association of Urology Congress 2022.

Downstaging was more common following treatment with apalutamide and degarelix than with degarelix and placebo. In the combination arm, downstaging to pT2 occurred in 51% of patients compared with 27% in the monotherapy arm (P = .03), and downstaging to pT3a occurred in 27% and 39%, respectively.

The probability of biochemical recurrence was significantly reduced in patients who achieved pathologic complete response to treatment and had MRD negativity compared with those who had MRD positivity. “Deep pathological response was correlated with less or almost no risk of biochemical progression,” Joniau said.

Historically, clinical trials have not shown a survival benefit for neoadjuvant treatment prior to radical prostatectomy despite demonstration of pathological response, but Joniau noted that these studies explored the use of first-generation antiandrogens in men with low- and intermediate-risk prostate cancer. However, one retrospective analysis did show a survival benefit for neoadjuvant hormonal therapy in patients with high-risk prostate cancer. The analysis showed that the risk of prostate cancer–related death was decreased by 50% with neoadjuvant treatment (P = .0014), but it was suggested that it could have been due in part to the use of radiotherapy after surgery.

The ARNEO study enrolled patients with high-risk nonmetastatic prostate cancer who had a prostate-specifi c antigen (PSA) level higher than 20 ng/mL, a Gleason score between 8 and 10, and/or 2 to 3 intermediate risk factors. Statistical analysis required at least 84 patients to be enrolled. Patients were randomly assigned to receive either neoadjuvant degarelix and apalutamide or degarelix and placebo for 3 months prior to surgery. Blinded prostate-specifi c membrane antigen (PSMA) PET/MRI scans were conducted before and after treatment. The primary end point was MRD rate, and secondary end points included PSA kinetics, toxicity, quality of life, and biomarkers for pathological response.

At baseline in the combination arm, the median PSA level was 12.6 ng/mL, and most patients had cT3a disease (40%) and an International Society of Urological Pathology (ISUP) grade of 5 (43%). Comparatively in the degarelix monotherapy arm, the median PSA level was 11.2 ng/mL, and most patients had cT3a disease (46%) and ISUP grade 4 disease (39%).

 < .0001) and PSMA maximum standard uptake value (

 < .0001) after neoadjuvant therapy were correlated with cancer volume at fi nal pathology and pathological response. PTEN loss was considered a negative predictor for MRD, as patients with PTEN loss at baseline were less likely to achieve MRD (11% vs 43% with PTEN; 

 = .002). Joniau concluded that this study was a solid foundation for ongoing and planned phase 3 trials in this setting. 

1. Devos G, Tosco L, Baldewijns M, et al. ARNEO: a randomized phase II trial of neoadjuvant degarelix with or without apalutamide prior to radical prostatectomy for high-risk prostate cancer. Presented at: European Association of Urology Congress 2022; July 1-4, 2022; Amsterdam, Netherlands.

2. Tosco L, Laenen A, Briganti A, et al. The survival impact of neoadjuvant hormonal therapy before radical prostatectomy for treatment of high-risk prostate cancer. Prostate Cancer Prostatic Dis. 2017;20(4):407-412. doi:10.1038/pcan.2017.29

Positive findings were reported from the phase 2 ARNEO trial during the European Association of Urology Congress 2022.

Neoadjuvant Combination Improves MRD Rates in High-Risk Prostate Cancer

Toripalimab (Tuoyi), a PD-1 inhibitor, with chemotherapy showed promising efficacy data as neoadjuvant treatment for patients with upper tract urothelial carcinoma (UTUC). These preliminary data were presented at the 37th Annual European Association of Urology Congress in Amsterdam, Netherlands, by Xingang Bi, MD, PhD of the Department of Urology at the Cancer Institute and Hospital, Chinese Academy of Medical Sciences in Beijing, China.

Among 11 patients who enrolled, 8 completed treatment and were preliminarily analyzed. Three of the 8 patients (37.5%) had a pathological complete response (pCR). The downstaging rate was 75% (6/8), and the disease control rate was 100%. All patients were alive and tumor free at the median follow-up of 5.8 months.

In this phase 2 multicenter study (NCT04099589), investigators planned to enroll 34 patients to receive toripalimab plus a gemcitabine/cisplatin chemotherapy regimen. Toripalimab was administered in 240 mg doses on day 1, and gemcitabine and cisplatin were administered in 1000 mg/m

on day 1, respectively. Each treatment cycle lasted 21 days. Neoadjuvant therapy was followed by radical nephroureterectomy and pelvic lymphadenectomy.

The primary end point of the study is pCR, and the secondary end points include downstaging rate, objective response rate, 3-year disease-free survival, 3-year overall survival, and safety. Patients were eligible to enroll in the study if their ureteroscopic biopsy confirmed a diagnosis of UTUC, their tumor tissue was PD-L1 positive, they had no previous chemotherapy or immunotherapy, they had no tumors in the bladder, they were between the ages of 18 and 75, and they had an ECOG performance score of 0 or 1.

The median age of the 8 patients was 64.5 years, and 62.5% (5/8) were men. Five of the 8 patients had ureteral cancer, 3 had renal pelvic cancer, and all 8 patients were considered high risk. All but 1 patient received 4 cycles of neoadjuvant therapy, and the remaining patient received 3 cycles. All patient tumors were unifocal. The median maximum tumor diameter was 2.5 cm (range, 1.5-5.1). Every patient had obstructed hydronephrosis. Multiparameter MRI confirmed clinical T staging, which found 7 patients were T3 and 1 patient was T2.

Seven patients had high-grade and 1 patient had low-grade urothelial carcinoma, according to the ureterorenoscopic biopsy. The median time from the end of neoadjuvant therapy to the start of radical nephroureterectomy was 7.3 weeks (range, 3.0-10.1).

Three patients (37.5%) had grade 3 chemotherapy-related adverse events (AEs) in the form of myelosuppression. No patients presented with grade 4 or grade 5 chemotherapy-related AEs. However, 2 patients had immune-related AEs in the form of grade 2 hypothyroidism and grade 2 adrenal insufficiency. No patients reported surgery-related complications, and the readmission rate was 0%.

The combination of toripalimab and chemotherapy displayed promising efficacy results. Safety was manageable, but immune-related AEs may occur and may result in prolonged treatment period.

1. Bi X, Shou J, Zhou A, et al. Neoadjuvant combined chemotherapy and immunotherapy for upper tract urothelial carcinoma: preliminary results of a phase II study. Presented at: 37th Annual European Association of Urology Congress; July 1-4, 2022; Amsterdam, Netherlands. Abstract A0301.

The combination of toripalimab and chemotherapy displayed promising efficacy results in a phase 2 study.

Toripalimab and Chemotherapy Combination Reveals Promising Efficacy for UTUC

Adjuvant pembrolizumab (Keytruda) continued to show an improvement in disease-free survival (DFS) benefit over placebo after 30 months of follow-up in patients with renal cell carcinoma (RCC), according to updated results from the phase 3 KEYNOTE-564 trial. The DFS benefit was continued across prespecifi ed subgroups.

A similar benefit was observed in an exploratory analysis of distant metastasis-free survival (DMFS) and was demonstrated across recurrence risk subgroups.

“Adjuvant pembrolizumab continues to demonstrate these impressive results with disease-free survival, particularly across subgroups of patients,” Thomas Powles, MD, MBBS, MRCP, said when presenting longer-term findings from the trial at the European Association of Urology Congress 2022.

 Powles is a professor of genitourinary oncology, director of Barts Cancer Centre at St. Bartholomew’s Hospital, and lead for solid tumour research at Cancer Research UK Barts Centre in London, England.

KEYNOTE-564 (NCT03142334) is a double-blind multicenter trial of pembrolizumab vs placebo after surgery in patients with RCC. The study enrolled 994 patients with clear cell RCC who had intermediate-high or high-risk disease or M1 no evidence of disease status after surgery as well as no prior systemic treatment and an ECOG performance status of 0 or 1. Patients were randomly assigned to receive either pembrolizumab 200 mg every 3 weeks for approximately 1 year (n = 496) or matching placebo (n = 498).

The primary end point was DFS by investigator assessment and secondary end points were overall survival (OS) and safety. Exploratory end points included DMFS and second progression-free survival (PFS2).

Baseline characteristics were well balanced between the 2 arms. Overall, the majority of patients were male (71%), had M0 intermediate high disease (86.5%), no sarcomatoid features (55.9%), positive PD-L1 expression by combined positive score (75.3%), T3 disease stage (88.6%), and lymph node–negative disease (93.8%).

The DFS end point was met as of the first protocol-specified interim analysis.

 At 24 months, the estimated DFS rate was 77.3% with adjuvant pembrolizumab compared with 68.1% with placebo (HR, 0.68; 95% CI, 0.53-0.87; 2-sided 

After a median of 30.1 months of follow-up (range, 20.8-47.5), the 24-month DFS rates were 78.3% in the pembrolizumab arm and 67.3% in the placebo arm. The median DFS was still not reached in either arm (HR, 0.63; 95% CI, 0.50-0.80; nominal 

Across subgroups, DFS favored the pembrolizumab arm for all key subgroups. Significant benefit for the use of pembrolizumab was seen in patients with M1 no evidence of disease (HR, 0.28; 95% CI, 0.12-0.66), T1 disease stage (HR, 0.19; 95% CI, 0.04- 0.89), and those who underwent partial nephrectomy (HR, 0.22; 95% CI, 0.05-1.04). However, all of these were in smaller groups of patients.

DMFS was higher in the placebo arm than in the pembrolizumab arm; the majority of recurrence events were distant metastasis, approximately 87%.

At 24 months, the rate of DMFS was 80.1% in the pembrolizumab arm and 69.9% in the placebo arm and the median was not reached in either arm (HR, 0.63; 95% CI, 0.49-0.82).

Among patients with M0 disease, the DMFS rate was 20.8% in the pembrolizumab arm compared with 29.0% in the placebo arm, and for patients with M1 no evidence of disease, the rates were 20.7% and 55.2%, respectively. A total of 7 patients in the pembrolizumab arm and 10 in the placebo arm died without distant recurrence.

By risk status, the 24-month DMFS rate in the intermediate-high risk group was 82.7% with pembrolizumab compared with 74.0% with placebo (HR, 0.67; 95% CI, 0.50-0.90). In the high-risk group, DMFS was 50.8% with pembrolizumab and 36.6% with placebo at 24 months (HR, 0.66; 95% CI, 0.36-1.23). For patients with M1 no evidence of disease, the 24-month DMFS rates were 81.4% and 47.4% with pembrolizumab and placebo, respectively (HR, 0.28; 95% CI, 0.11-0.73). The median DMFS was not reached with pembrolizumab in any recurrence risk subgroup (TABLE

Powles commented that going against expectations, the majority of benefit was not seen in the M1 subgroup, though a signifi cant difference also was seen in this group. As of the second interim analysis, only 33% of the 200 deaths required for the final OS analysis had occurred at the time of data cutoff, so the median was not yet reached in either arm. At 24 months, the OS rate was 96.2% in the pembrolizumab arm compared with 93.8% in the placebo arm (HR, 0.52; 95% CI, 0.31-0.86; 

“We’re looking at overall survival but we’re not yet calling it significant despite the numbers looking very impressive. From our perspective, we’d like to see a mature survival signal and 30 months is not yet mature. [However,] 0.52 is a provocative number. It’s half the number of events in 1 arm vs the other and clearly if this trend continues, it’s going to be statistically signifi cant in the future, but who knows what the future holds,” Powles said.

Median PFS2 also was not reached in either treatment arm with a 24-month rate of 92.7% with adjuvant pembrolizumab and 88.6% with placebo (HR, 0.57; 95% CI, 0.39- 0.85). “It does seem that early intervention with immune therapy does appear to be having an effect on the biology of the disease,” Powles said.

No new safety signals were reported with the updated findings, and there was no notable increase observed in any-grade or grade 3/4 treatment-related adverse events (TRAEs).

The most common any-grade TRAEs in the pembrolizumab arm were fatigue (20.3%), pruritus (18.6%), and hypothyroidism (17.4%). Comparatively, in the placebo arm, the most common TRAEs were fatigue (14.3%), pruritus (11.5%), and diarrhea (10.3%). More common grade 3/4 AEs in the pembrolizumab arm included diarrhea, fatigue, and rash. The median time to fi rst onset in the pembrolizumab arm was shortest with hypothyroidism (3.1 weeks; range, 2.1-60.9) and longest with myalgia (12.8 weeks; range, 0.1-46.4).

1. Powles T, Tomczak P, Park SH, et al. Pembrolizumab (pembro) as adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): Updated results from the 30-month follow-up of KEYNOTE-564. Presented at: EAU Congress 2022; July 1-4, 2022; Amsterdam, Netherlands. 

2. Choueiri TK, Tomczak P, Park SH, et al; KEYNOTE-564 Investigators. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391

Adjuvant pembrolizumab continues to demonstrate these impressive results with disease-free survival in renal cell carcinoma, according to Thomas Powles, MD, MBBS, MRCP.

Pembrolizumab Delays Disease and Distant Metastasis in RCC

A decade ago, a diagnosis of chronic lymphocytic leukemia (CLL) came with very few therapeutic options. “Chemoimmunotherapy was the standard of care,” Nicole Lamanna, MD, associate clinical professor of medicine in the Hematologic Malignancies Section of the Hematology/Oncology Division at Columbia University Herbert Irving Comprehensive Cancer Center in New York, New York, said in an interview with Targeted Therapies in Oncology™.

The only question was whether the patient was young and fit enough to be a candidate for stem cell transplant. Most patients were not, said Anthony Mato, MD, MSCE, director of the CLL Program at Memorial Sloan Kettering Cancer Center in New York, New York. “And they ended up dying of refractory disease or transformation of disease,” Mato said during an interview with

However, a lot can change in a decade. In the case of CLL, the change began in February 2014, with the FDA’s accelerated approval of ibrutinib (Imbruvica) to treat CLL in patients who had received at least 1 prior therapy.

 “That drastically changed things,” Lamanna said.

Ibrutinib was the first Bruton tyrosine kinase (BTK) inhibitor to be granted FDA approval for CLL in November 2013.

 Later, in the RESONATE trial (NCT01578707), the therapy had a 6-month progression-free survival (PFS) rate of 88% and a 12-month overall survival (OS) rate of 90% in previously treated patients with CLL. In this trial, the control group received ofatumumab (Arzerra), and at 12 months, the OS rate was 81% and the PFS was 8.1 months.

In an accompanying editorial in the New England Journal of Medicine, Robin Foà, MD, professor of hematology and head of the Division of Hematology at the Sapienza University of Rome in Italy, asserted that oncologists were “witnessing a new mechanism-driven era” associated with “the development of compounds capable of targeting the B-cell receptor signaling pathway” in the treatment of CLL.

 That assertion has stood the test of time.

The 8 years since that publication have seen a steady pipeline of new targeted therapies for CLL. The result is that clinicians and patients now have a vastly different range of therapeutic options to choose from. However, with those options have come new questions about how best to choose, sequence, and combine those agents to achieve the best long-term results. Experts such as Lamanna and Mato say the answers to those questions will only come with signifi cantly more research.

A Wave of Approvals Ibrutinib, which was approved as a first-line therapy in 2016, was the first targeted therapy approved for CLL,

 but it was not the last. That same year, the FDA approved idelalisib (Zydelig), an inhibitor of the delta isoform of PI3K, in combination with rituximab (Rituxan) for use in patients with relapsed CLL.

 In 2018, duvelisib (Copiktra) gained FDA approval.

Meanwhile in 2016, the agency approved venetoclax (Venclexta), initially for patients with 17p deletions whose cancers had progressed after previous treatment with at least 1 other therapy. The drug targets BCL2, which is a protein that promotes tumor cell survival.7 That approval was later expanded to include patients without 17p deletions.

 In 2019, the drug was approved as a first-line CLL therapy in combination with the anti-CD20 monoclonal antibody, obinutuzumab (Gazyva).

Even as PI3K and BCL2 inhibitors were beginning to hit the market, drug developers were working on second-generation BTK inhibitors, including acalabrutinib (Calquence), which was approved for CLL treatment in 2019,

and zanubrutinib (Brukinsa), which Lamanna said is likely to gain FDA approval later this year.

The days of chemoimmunotherapy as the major treatment for CLL are over, Lamanna said. “Chemoimmunotherapy is not used very often, if at all,” she said. “Now [oncologists choose] between a BTK inhibitor or venetoclax [plus] obinutuzumab in [the] front line.”

Although BTK inhibition has proven to be a major development in the treatment of CLL, this class of drugs carries a signifi cant risk of adverse events (AEs) and treatment resistance. Newer BTK inhibitors are more selective and have improved the safety profi les for patients with comorbidities.

For instance, results from the phase 3 ELEVATE-RR trial (NCT02477696) published in 2021 showed acalabrutinib had a lower risk of cardiovascular AEs compared with ibrutinib.

 Interim results from the ALPINE study (NCT03734016) showed zanubrutinib had a signifi cantly better overall response rate (ORR) compared with ibrutinib (78.3% vs 62.5%;

 = .0006) and led to lower rates of atrial fi brillation or flutter.

Lamanna noted that historically, patients with significant cardiovascular issues would be considered poor candidates for BTK inhibitors, but that is not necessarily the case anymore. “For somebody who had bad hypertension, bad cardiac issues, and was on anticoagulation, we would avoid ibrutinib and go to venetoclax,” she said. “Now with the second generation, you can challenge that a little. It [depends] on how severe their cardiac issues are.” Lamanna also said the decision can in part depend on the physician’s comfort level with the different therapeutic options.

Mato said comorbidities and fi tness are important to consider when deciding on a treatment regimen. The molecular genetic profile of the malignancy is somewhat less important than it used to be, he said, as BTK inhibitors and venetoclax are “equally useful” options for patients who are standard or high risk. Another factor to consider is patient preference, according to Mato. “The limiting factor of the BTK inhibitors is that they’re continuous therapies,” he said. “People tend to want to stop at some point.”

Noncovalent BTK Inhibitors in the Pipeline 

The evolution of BTK inhibition is continuing with noncovalent BTK inhibitors, such as pirtobrutinib and nemtabrutinib. Unlike earlier BTK inhibitors, they do not bind covalently to C481 of the BTK protein, making them a meaningful option, even for patients with acquired resistance to earliergeneration agents.

In phase 1/2 data published in 2021, investigators, including Lamanna and Mato, found that pirtobrutinib produced strong ORR results, even in patients who had previously been treated with BTK inhibitors. ORRs of 67%, 52%, and 71% were found in patients with previous resistance to covalent BTK inhibitors, previous intolerance to BTK inhibitors, and BTK C481 mutations, respectively.

 Those data suggest pirtobrutinib may be another treatment option for patients with BTK C481 mutations who have become resistant to ibrutinib.

Trials are also under way for other noncovalent BTK inhibitors, including nemtabrutinib. In results presented the European Hematology Association 2022 Congress, investigators found the therapy had an acceptable safety profi le and an ORR of 57.9% in heavily pretreated patients.

 Another drug, fenebrutinib, was the subject of a recently completed phase 1 study (NCT01991184).

 Twenty-four patients were enrolled in this study and 8 patients had an ORR. Best responses included 3 patients with partial response with lymphocytosis, 4 with a partial response, and 1 with a complete response (TABLE

Meanwhile, Sunesis Pharmaceuticals, Inc, terminated a phase 1b trial of vecabrutinib, yet another noncovalent BTK inhibitor. In that case, investigators found the drug was well tolerated but did not appear to have sufficient evidence of antitumor activity.

For Lamanna, the big picture is that these third-generation BTK inhibitors have the potential to further expand the treatment landscape, thereby increasing the range of therapeutic strategies for patients and their physicians. “The point is we’ll have [more drugs] in our armamentarium,” she said. “Of course, our goal would be to cure CLL, but if we can’t cure CLL, you’re always thinking, ‘How do I keep these patients going? How do I go from one drug to another drug and really make it a chronic disease?’”

Combining Targeted Therapies The new CLL therapies have also created the opportunity for new fixed-duration combination regimens, including those studied in the GLOW and CAPTIVATE trials. In December 2021, results from the phase 3 GLOW trial (NCT03462719) showed that combining ibrutinib with venetoclax led to fewer fi rst-year relapses in treatment-naïve patients who were elderly or unfit, compared with chlorambucil (Leukeran) plus obinutuzumab. At 30 months, patients in the ibrutinib plus venetoclax cohort had a PFS rate of 80.5% compared with 35.8% for patients receiving chlorambucil plus obinutuzumab. The trial did not include patients with 17p deletions or known TP53 mutations.

Findings from the CAPTIVATE trial (NCT02910583) of ibrutinib plus venetoclax have also been promising.

 This trial produced an ORR of 96% in treatment-naïve patients who were 70 years or younger at a 3-year follow-up. That study was notable in part because the response data were consistent, even for patients who were highrisk and including those with 17p deletions, 

 mutations, unmutated IGHV, and/or complex karyotypes.

Beyond evaluating the efficacy of the treatment combination, this study is also important because it could help investigators better understand the role minimal residual disease (MRD) can play in tracking patient responses to therapy. Lamanna noted that CAPTIVATE is designed so that after a prerandomization phase, patients who are MRD positive will continue treatment with ibrutinib either alone or combined with venetoclax. Those who have confi rmed undetectable MRD will continue with ibrutinib or be switched to placebo. The results could help oncologists better understand whether and how MRD can be used to guide therapy.

“Patients and specialists want to use MRD to guide exposure,” Mato said. “There has not been a lot of use of MRD, but I think people are ready to go in that direction. I really do.” He also added that, so far, no CLL therapies have been approved based on trials with an MRD end point; however, an MRD assay has been approved.

Another combination therapy, venetoclax plus rituximab, was the subject of the MURANO trial (NCT02005471), which found superior OS and PFS at 5 years compared with bendamustine (Treanda) plus rituximab. The estimated 5-year OS was 82.1% for the venetoclax regimen vs 62.2% for the bendamustine regimen.

In addition, a phase 1 trial (NCT03328273) evaluating the second-generation BTK inhibitor acalabrutinib plus the ataxia telangiectasia and RAD3-related inhibitor ceralasertib (also known as AZD6738) is currently ongoing.

Investigators are also examining how best to sequence therapies and what strategy to take when a patient experiences relapse or needs to discontinue a medication. Lamanna said patients who start with a BTK inhibitor can be easily retreated with venetoclax and rituximab or venetoclax plus a monoclonal antibody. “There’s no doubt that we have very good data that [show] the venetoclax-based regimens can salvage patients who either have intolerance to a BTK [inhibitor] or who have progressed,” she said. In such cases, patients can take fixed-duration venetoclax-based regimens, and if all goes well, they may be able to completely go off therapy for months or even years.

A 2020 study showed that, in cases where patients discontinued venetoclax, BTK inhibitors were the most effective choice for their next therapy, provided the patient was either BTK inhibitor naïve or had previously responded to a BTK inhibitor.

 Yet another study found that patients with venetoclax-based regimens can benefit from retreatment with venetoclax following remission, particularly if they achieved a complete response from their initial therapy.

Lamanna said the optimal treatment remains to be determined for patients who receive a doublet or triplet combination and eventually relapse. “Hopefully some of these studies will help tell us,” she said. The trials could also answer questions about whether fixed-duration therapies are appropriate for all patients, including patients who are high-risk, according to Lamanna.

Another potential option for patients is cellular therapies, such as lisocabtagene maraleucel (Breyanzi), which was approved in 2021 in combination with ibrutinib to treat relapsed or refractory large B-cell lymphoma. Lisocabtagene-maraleucel is an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell therapy.

Lamanna noted that the idea of using CAR T cells to treat CLL has been around for more than a decade, but the AEs associated with the therapy required a signifi cant learning curve. However, she noted that significant progress has been made in terms of curbing AEs. “That’s the good news,” she said. The bad news is that CAR T has yet to achieve wide adoption within the CLL oncology community because of the steady stream of other therapies that have become available, Lamanna explained.

“It’s still being relegated a little bit to specialty places [that] could do CAR T,” Lamanna said. She believes CAR T-cell therapy will eventually be approved for CLL, but in a crowded field of therapies, she does not expect it to become a prominent component of CLL care.

Mato said he believes cellular therapies will have a role in the future of CLL therapy. “It’s a question about what line [of therapy],” he said. “Current patients are referred after they’re out of options. Sometimes that probably limits the success of the cellular therapy, because not only do you need to be able to harvest T cells, but you [also] need to have functional T cells.” Mato also said it will be important to have studies that examine the ideal candidates and sequence to offer CAR T-cell therapy.

The need for more research is a major theme in Mato’s assessment of the current CLL treatment picture. Although he is excited about the new therapies, he also thinks drug developers need to do a better job of carrying out relevant trials that will help oncologists better understand which of the new therapies work best in which situations. “The limitations are that they’re never compared [with] one another,” he said.

Most of the studies still compare the newer therapies with older, less-relevant regimens. Mato said a more helpful approach would be to test these new targeted therapies against other targeted therapies. “What we really need to move the fi eld forward are headto-head comparisons of relevant classes of drugs, and we need studies that allow us to understand sequencing,” he said.

Part of the reason such studies are rare is that drug developers are reticent to do competitions among “winners,” because the results might mean their product goes from being a go-to therapy to being a therapy that is less sought after, Mato explained. Thus, it is hard to fi nd industry support for the kinds of large-scale, head-to-head studies that are necessary. “If you’re not going to have that support, then the ability to fund a meaningful randomized clinical trial is really hard to come up with,” he said

On a smaller scale, Lamanna said there is also a need for clinicians to expand the knowledge of these new therapies by being strategic about how they use them. She cautioned that clinicians should not be too quick to change from one therapy to the next when patients experience AEs. Although patient status and toxicities may warrant a change in therapy, she said not every AE requires stopping the drug. “Sometimes a little diarrhea [or] nausea—you can work through them,” she said, noting that careful patient counseling ahead of time and thoughtful management of AEs during treatment can allow patients to continue on a therapy in many cases.

Doctors and patients who can stick with a regimen despite relatively minor AEs will ultimately have more options later in the treatment journey, which could then lead to better long-term outcomes. “It takes more time and effort, but it’s worth it, because these drugs are going to be the mainstay of our treatment for CLL for quite some time,” she said.

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5. U.S. Food and Drug Administration approves Gilead’s Zydelig (idelalisib) for relapsed chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma. News release. Gilead; July 23, 2014. Accessed August 4, 2022. https://bit.ly/3zYfDAf

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7. FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality. News release. FDA; April 11, 2016. Accessed August 4, 2022. https://bit.ly/3zUXVxA

8. FDA approves new treatment option for previously treated chronic lymphocytic leukemia. News release. Genentech; June 8, 2018. Accessed August 4, 2022. https://bit.ly/2l0fuVD

9. AbbVie announces US FDA approval of Venclexta (venetoclax) as a chemotherapy-free combination regimen for previously untreated chronic lymphocytic leukemia patients. News release. AbbVie; May 15, 2019. Accessed August 4, 2022. https://bit.ly/2OGvJJp

10. Project Orbis: FDA approves acalabrutinib for CLL and SLL. News release. FDA; November 21, 2019. Accessed August 4, 2022. https://bit.ly/3BCs6ee

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15. Woyach J, Flinn IW, Awan FT, et al. Nemtabrutinib (MK-1026), a non-covalent inhibitor of wild-type and C481S mutated Bruton tyrosine kinase for B-cell malignancies: efficacy and safety of the phase 2 dose-expansion BELLWAVE-001 study. Presented at: European Hematology Association 2022 Congress; June 9-12, 2022; Vienna, Austria. Abstract P682. https://bit.ly/3HDw2fC

16. Byrd JC, Smith S, Wagner-Johnston N, et al. First-in-human phase 1 study of the BTK inhibitor GDC-0853 in relapsed or refractory B-cell NHL and CLL. 

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17. Allan JN, Patel K, Mato AR, et al. Ongoing results of a phase 1b/2 dose-escalation and cohort-expansion study of the selective, noncovalent, reversible Bruton’s tyrosine kinase inhibitor, vecabrutinib, in B-cell malignancies. 

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18. Kater A, Owen C, Moreno C, et al Fixed-duration ibrutinib and venetoclax (I+V) versus chlorambucil plus obinutuzumab (CLB+O) for first-line (1L) chronic lymphocytic leukemia (CLL): primary analysis of the phase 3 GLOW study. Poster presented at: European Hematology Association 2021 Congress; June 9-17, 2021; virtual.

19. Wierda WG, Barr PM, Siddiqi T, et al. Fixed-duration (FD) ibrutinib (I) + venetoclax (V) for first-line (1L) treatment (tx) of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): three-year follow-up from the FD cohort of the phase 2 CAPTIVATE study. 

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20. Kater AP, Kipps TJ, Eichhorst, B, et al. Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia (R/R CLL) patients (Pts) following fixed-duration venetoclax-rituximab (VenR) therapy (Tx). Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 125. Accessed August 1, 2022. https://bit.ly/3d8OCRu

21. Jurczak W, Elmusharaf N, Fox CP, et al. Phase 1/2 results of ceralasertib (Cerala) as monotherapy or in combination with acalabrutinib (Acala) in high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Presented at: American Association for Cancer Research Annual Meeting 2022; April 8-13, 2022; New Orleans, LA. Abstract CT532. Accessed April 8, 2022. https://bit.ly/3JvBzpz

22. Mato AR, Roeker LE, Jacobs R, et al. Assessment of the efficacy of therapies following venetoclax discontinuation in CLL reveals BTK inhibition as an effective strategy. Clin Cancer Res. 2020;26(14):3589-3596. doi:10.1158/1078-0432.CCR-19-3815

23. Thompson MC, Allan JN, Sail K, et al. Venetoclax re-treatment of chronic lymphocytic leukemia (CLL) patients after a previous venetoclax-based regimen. Presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 3136. Accessed August 1, 2022. https://bit.ly/3OZwzKT

24. U.S. FDA approves Bristol Myers Squibb’s CAR T cell therapy Breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy. News release. Bristol Myers Squibb; June 24, 2022. Accessed August 12, 2022. https://bit.ly/3C0lEOa

Doctors and patients who can stick with a regimen despite relatively minor adverse event will ultimately have more options later in the treatment journey, which could then lead to better long-term outcomes in chronic lymphocytic leukemia.

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