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Findings from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) sent shockwaves through all in attendance at the 2023 ESMO Congress––for the first time, the tried-and-true frontline standard of care, platinum-based chemotherapy, had proven less effective in improving survival than its investigational challenger. Based on the results, investigators concluded that the combination of enfortumab vedotin-ejfv (Padcev) and pembrolizumab (Keytruda; EVP) may become the preferred frontline standard of care for patients with locally advanced or metastatic urothelial cancer regardless of cisplatin eligibility.

The data were presented by Thomas B. Powles, MBBS, MRCP, MD, director of the Barts Cancer Centre at St Bartholomew’s Hospital in London.

EV-302 Trial Transforms the Frontline Treatment Landscape

The open-label, EV-302 trial enrolled 886 patients with previously untreated locally advanced or metastatic urothelial cancer eligible for cisplatin- or carboplatin-containing chemotherapy, enfortumab vedotin, and pembrolizumab. Patients were also required to be naïve to PD-(L)1 inhibitors, have a glomerular filtration rate of at least 30 mL/min, and an ECOG performance status of 2 or less.

The median age in both arms was 69 years and about three-fourths of patients were male. Most patients in the trial were White, making up 69.7% and 65.3% of patients in the EVP and control arms, respectively. About 97% of patients in both arms had an ECOG performance status of 0 or 1.

In the EVP arm, the primary tumor location was upper tract for 30.5% of patients and lower tract for 69.0%. The rates were 23.4% and 76.4%, respectively, in the chemotherapy arm. Fifty-four percent of patients in each arm were cisplatin eligible and approximately 72% had visceral metastases. Regarding PD-L1 status, 58% of patients in each arm had high expression (combined positive score [CPS] ≥10), with the remaining 42% having low expression (CPS <10).

Patients were randomly assigned to standard of care chemotherapy consisting of gemcitabine plus cisplatin or carboplatin for a maximum of 6 cycles (n = 444) or 1.25 mg/kg of intravenous (IV) enfortumab vedotin on days 1 and 8 and 200 mg of IV pembrolizumab on day 1 of every 3-week cycle (n = 442). The maximum number of pembrolizumab cycles allowed was 35 and there was no maximum number of cycles for enfortumab vedotin. The co-primary end points were OS and PFS per blinded independent central review (BICR).

At a median follow-up of 17.2 months, the median overall survival (OS) was 31.5 months (95% CI, 25.4-not reached [NR]) in the EVP arm compared with 16.1 months (95% CI, 13.9-18.3) in the chemotherapy arm (HR, 0.47; 95% CI, 0.38-0.58; 

 < .00001), reducing the risk of death by 53%.

The OS benefit was observed regardless of whether patients in the control arm received cisplatin or carboplatin, and was not impacted by PD-L1 status or existence of visceral metastases.

Moreover, the combination led to a significant improvement in progression-free survival (PFS) vs chemotherapy, with a median PFS of 12.5 months (95% CI, 10.4-16.6) vs 6.3 months (95% CI, 6.2-6.5), respectively, translating to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95%, 0.38-0.54; 

 < .00001). The PFS benefit was sustained across all prespecified subgroups, such as those defined by cisplatin eligibility, PD-L1 status, and visceral metastases.

Additional results showed that the confirmed objective response rate (ORR) was 67.7% (95% CI, 63.1%-72.1%) in the EVP arm compared with 44.4% (95% CI, 39.7%-49.2%) in the chemotherapy arm (

 <.00001). The ORR in the EVP group consisted of a complete response (CR) rate of 29.1% and a partial response (PR) rate of 38.7%. The stable disease (SD) rate was 18.8% and the progressive disease (PD) rate was 8.7%. In the chemotherapy arm, the ORR consisted of a CR rate of 12.5% and a PR rate of 32%. The SD rate was 33.8% and the PD rate 13.6%. The median duration of response was NR (95% CI, 20.2-NR) with the combination vs 7.0 months (95% CI, 6.2-10.2) with chemotherapy.

The median number of cycles received was 12 (range, 1-46) for EVP and 6 (range, 1-6) for chemotherapy. Overall, 67% of patients in the EVP arm and 45.7% of patients in the chemotherapy arm remained on study at the time of the analysis. In the EVP arm, 34.6% of patients discontinued treatment due to progressive disease compared with 16.4% of patients in the chemotherapy arm. Adverse effect (AE)–related discontinuations occurred in 21.9% and 14.0% of patients in the 2 arms, respectively. Regarding subsequent immunotherapy in the chemotherapy arm, 59% received a PD-1/L1 inhibitor and 30% of patients received maintenance avelumab.

In terms of safety, 56% of patients receiving EVP and 70% of patients who received chemotherapy experienced grade 3 or greater treatment-related AEs (TRAEs). Serious TRAEs occurred in 27.7% vs 19.6% of patients in the combination and chemotherapy arms, respectively.

EV-103 Data Deliver an Accelerated Approval

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy.

 The approval was based on data from the earlier EV-103/KEYNOTE-869 trial (NCT03288545). The multi-cohort study evaluated enfortumab vedotin plus pembrolizumab in dose escalation and in cohort A, and patients in cohort K were randomly assigned to receive the combination or enfortumab vedotin alone. Patients had not received prior systemic therapy for locally advanced or metastatic disease and were ineligible for cisplatin-containing chemotherapy.

Efficacy was determined by objective response rate (ORR) and duration of response (DOR) according to blinded independent central review using RECIST v1.1 criteria. The confirmed ORR in the 121 patients who received the combination was 68% (95% CI, 59%-76%), including 12% with complete responses. The median DOR for the dose-escalation cohort and cohort A was 22 months (range, 1+ to 46+) and for cohort K was NR (range, 1 to 24+).

, Powles discussed the magnitude of benefit seen with the combination, both in efficacy and safety, and forecasts the potential role of the combination, both in terms of clinical practice and future benchmarks for clinical research.

: Please provide the rationale for evaluating enfortumab vedotin plus pembrolizumab in locally advanced or metastatic urothelial cancer.

: Enfortumab vedotin is an antibody-drug conjugate [ADC] that targets Nectin-4 and has MMAE as the payload. Pembrolizumab is a PD-1 inhibitor. Both agents are widely used in urothelial cancer, particularly in platinum-refractory disease in the second- or third-line setting. In urothelial cancer, chemotherapy, either gemcitabine and cisplatin or gemcitabine and carboplatin has been the standard of care for a generation. There’s been a desire to try and supersede that with non-chemotherapy or platinum chemotherapy regimens.

The rationale was to combine these two active drugs together, enfortumab vedotin very good at getting control of disease and [pembrolizumab], which is associated with durable responses. By combining those two drugs together, we had hoped to show high response rates. [Previously], we did a phase 2 trial, and in that study, we showed that the combination was associated with a 68% response rate, about 12-month PFS about 2-year OS, and that looked higher in indirect comparisons than chemotherapy. For that reason, we embarked on a large, randomized phase 3 study comparing enfortumab vedotin and pembrolizumab with standard chemotherapy in previously untreated patients with metastatic urothelial cancer.

How was the trial designed and what were the eligibility criteria?

The EV-302 study focused on patients with first-line urothelial cancer. They had to have not had systemic therapy for advanced disease, they had to have measurable cancer, they had to have adequate organ function including adequate kidney function, and they had to be eligible for gemcitabine/cisplatin or gemcitabine/carboplatin, standard chemotherapy, and they couldn’t have contraindications to enfortumab vedotin or pembrolizumab. The trial was a one-to-one randomization, open-label trial, with PFS and OS, as primary endpoint. [Patients received] 6 cycles of chemotherapy, and pembrolizumab was given with enfortumab vedotin until progression. The trial had a statistical analysis plan that was followed, and we're presenting the interim analysis, the final analysis [for] PFS, and an interim analysis, which turned out to be the final analysis also for OS, because that [turned out to be] positive.

How do you see the results shaping the treatment armamentarium?

Approximately 850 patients were randomized to 1:1 in this trial. The population was characteristic of urothelial cancer. About 70% of patients had visceral metastasis, about 55% received cisplatin-based therapy. Most patients had performance status of 0 or 1, and the population was nicely balanced between the two arms. The median follow-up of the trial was 17 months. The results showed a dramatic increase in PFS. In fact, there was a hazard ratio of 0.45, a 55% reduction in the risk of progression compared with chemotherapy, which is somewhat unprecedented. But more importantly, we also showed an over 50% reduction in the risk of death with a hazard ratio of 0.47, and we’ve not previously managed to beat first-line chemotherapy in any trial in unselected first-line urothelial cancer. This is a big step in that direction. It’s important to recognize that there was a high response rate, 68%, a CR rate of 29%, which is impressive, and the durability of response has not yet been reached. This is a very comprehensive efficacy suite of end points, all of which have been hit.

The second component is the AE profile, and grade 3 or 4 AEs occurred with chemotherapy in 70% and with enfortumab vedotin and pembrolizumab in 56% of patients. AEs of special interest with enfortumab vedotin include skin toxicity, peripheral neuropathy, and hyperglycemia, all of which appeared manageable and in line with data we’ve seen in previous trials. Treatment-related deaths, there were only four in both arms, and those were not related to skin, peripheral neuropathy, or hyperglycemia in the enfortumab vedotin arm. It’s fair to say that these results are striking and transformative for urothelial cancer patients. An over 50% reduction in the risk of death is important. We’ve never seen anything like that before in urothelial cancer.

The control arm was platinum-based chemotherapy, six cycles, and 31% of those patients received maintenance avelumab [Bavencio] as well, which became the standard of care during the conduct of the trial. Real-world data suggest that under 50% of patients get maintenance avelumab. That is at least in part a contemporary control arm, and indeed, you can see the control arm performed well in the OS component in the trial. It’s also important to recognize the benefits were seen irrespective of platinum-based chemotherapy, PD-L1 status, and sites and metastasis. In summary, the trial is very positive. The combination is tolerable and in line with expectations. The drug works across all subgroups of patients, the control arm performed as expected. These data will be important for doctors and patients moving forward.

How do these data affect the clinical landscape and future research avenues for patients with this disease?

The future of urothelial cancer is very bright. These data will change the way we treat patients but also prompt a series of new trials. In fact, some of those trials are ongoing. We're looking at enfortumab vedotin and pembrolizumab, and enfortumab vedotin, durvalumab [Imfinzi], and tremelimumab-actl [Imjudo] in the neoadjuvant space. We have a spectrum of enfortumab vedotin and enfortumab vedotin plus immune checkpoint inhibition, particularly pembrolizumab and durvalumab/tremelimumab trials moving forward in this muscle-invasive space. I also think these data are the first combination of immune checkpoint inhibition and ADC therapy, and it’s my feeling that we need to explore this combination because it’s been so active in urothelial cancer in other cancers that have high expression of Nectin-4. It’s a very exciting time.

Powles TB, Perez Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: open-label, randomized phase III study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC). 

. 2023;34(suppl 2):S1340. doi:10.1016/j.annonc.2023.10.106

FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. News release. FDA. April 3, 2023. Accessed October 22, 2023. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic

Articles

Findings from the EV-302 trial presented at the 2023 ESMO Congress revealed that the combination of enfortumab vedotin and pembrolizumab may become the preferred frontline standard of care for patients with locally advanced or metastatic urothelial cancer regardless of cisplatin eligibility.

EV-302 Regimen Bests Chemo in Advanced Urothelial Cancer

The implementation and subsequent optimization of a health information technology module within the electronic health record (EHR) has allowed clinicians across a diverse health care system to identify barriers to improve discrete capture of cancer staging and design solutions to address them, according to findings from a quality improvement pilot study published in 

. Study authors noted that the approach is scalable and could be applied to other initiatives in the realm of health information technology.

At baseline, a period spanning March 2018 to December 2019, 6628 patients with cancer across 11 centers had an eligible first visit encounter; 31% of patients had their cancer staging discretely captured via the EHR-integrated module and 19% were staged discretely in what investigators had determined to be a timely manner. After identifying key barriers that were thought to be driving the lack of discrete staging capture and implementing solutions, the improved module resulted in a discrete capture rate of 58% and a timely discrete capture rate of 35%, representing respective increases of 87% and 84%, among 4346 patients with cancer across 55 outpatient clinics who had a first visit encounter between the July 2021 go-live date and the September 2022 data cutoff.

“The documentation of cancer staging within a standardized module embedded in the EHR is a distinct form of staging documentation that has its own potential benefits and challenges compared with providing this information solely within a physician’s note,” Neelima Vidula, MD, and Jeffrey Peppercorn, MD, wrote in an editorial in 

, which accompanied the study. “If used correctly and routinely, staging modules may facilitate quality improvement, outcomes analysis, recruitment to trials, targeted supportive care screening and interventions, and accurate billing, as collection of staging information from a physician’s note can be labor intensive.”

In 2018, a discrete data module for cancer staging was made available in the EHR of the Northwestern University health care system, however the adoption rate was poor across the 11-hospital health care system and the impact on staging data capture was minimal. Although clinicians were reminded to use the module to stage patients, staging documentation was often nonexistent or included as free text in the form of note documentation outside of the module. Without the imbedded staging documentation in the EHR, the health care system faced challenges in driving downstream programs to improve the delivery of care. Thus, investigators set out to identify barriers to utilization of the module, identify health information technology solutions to expand discrete capture of cancer staging data, and increase capture across the oncology divisions of the health care system.

To conduct their study, investigators used Six Sigma quality improvement methodology (define, measure, analyze, improve, control [DMAIC]) to define the problems with discrete staging capture, perform data-driven analyses to better understand these problems, prioritize key root causes of the issues, implement solutions, and sustain the improvements that were observed. Additionally, a failure modes and effects analysis (FMEA) was utilized to determine and prioritize high-risk process points that caused problems with discrete staging documentation.

The study recruited a multidisciplinary team to take on the quality improvement project of improving the staging module and implementing the staging module. The group was split into 2 pilot teams: team 1 included gastrointestinal (GI) cancer clinicians from multiple regional sites and team 2 was made up of genitourinary disease specialists and additional GI clinicians. Both teams contained mid- and advanced-level clinicians and included medical oncologists, surgical oncologists, and surgery specialists.

Pilot team 1 was tasked with developing the user requirements needed for optimized health information technology solutions, then using these to develop prototype interventions and modifications. During pilot testing, clinicians used real patient encounter workflows and real-time feedback to develop the enhancements to the module. Interventions were rolled out in 2 separate 4-week testing cycles, each of which ended with data review and qualitative user evaluation. Members of both teams were surveyed to determine which interventions would be deployed as the system standard, and the module went live across 55 outpatient clinics.

The patient population included those with a solid organ tumor diagnosis at an outpatient encounter who either had treatment administered within 30 days or had a minimum of 2 established visits within 30 days. The 11-site health care system consisted of 1 academic medical center, 1 tertiary community hospital, and 9 community hospitals.

The primary outcome of the study was discrete capture, defined as the number of patients with cancer staging—clinical or pathologic—discretely captured, irrespective of the amount of time that elapsed. Timely discrete capture, defined as discrete capture that occurred within 30 days of the first encounter or date of treatment, represented a secondary outcome.

After applying the DMAIC and FMEA processes the 3 key barriers responsible for the lack of discrete cancer stage capture were determined to be workflow inefficiency, limited clinician accountability, and incongruence between the technical design and clinical ideals. To break down each barrier, investigators decided the best path was to continue to move forward with the EHR-integrated module and optimize the process. Thirty-six user-centered design enhancements were proposed, a majority of which (70%) were deemed to be within the study authors’ control and were implemented (

For example, to address issues with workflow, investigators created a comprehensive tool within the EHR to provide quick access to commonly reviewed laboratory results, including tumor markers, pathology reports, and imaging to reduce information seeking. To address accountability, they added reminders to alert the user when there was a deficiency in terms of staging data and if the capture was not complete within 24 hours, routing another reminder at 72 hours.

In total, study authors implemented 7 enhancements to address the accountability barrier, 11 to address technical design flaws, and 6 to address workflow barriers. They also identified additional limitations in workflow (n = 2) and technical design (n = 9) and proposed enhancements for them but were not able to implement them.

Additional findings from the study revealed that, overall, the mean time from first cancer encounter to discrete staging entry was reduced from 186 days to 22 days (88%) from baseline to the data cutoff. The academic medical center showed the greatest increase in discrete staging capture from baseline to data cutoff, at 15% and 45%, respectively (a 200% increase). “It is possible that the improvement of Walesa et al in rates of completion of staging modules was due in part to rigorous evaluation of inefficiencies, stakeholder feedback, and serial adaptation of the process to address clinician concerns and barriers in their pilot design,” the editorial authors noted.

The study authors highlighted that their research had multiple limitations, including that the customization of health information technology is often discouraged and can cause organizational burden. Additionally, they noted clinician distrust of the module, behavioral factors influencing staging capture, and the inability to evaluate patient clinical outcomes based on the data in the collected in the study.

 benefits of cancer staging modules are clear, but how to best realize this potential is an ongoing challenge,” the editorial authors wrote in conclusion. “Capitalizing on artificial intelligence technology to pull the information required to complete staging modules from notes, pathology reports, and other sources, without substantial time from any clinician, but allowing for editing and updating by clinicians, may help increase efficiency. If the responsibility of staging modules falls on the clinician, it is important to incorporate the clinician’s voice and feedback to ensure this task is designed and understood to be compatible with the goals of high-quality patient care and not seen as a distraction from those efforts.”

Walesa MB, Denny A, Patel A, et al. Enhancement and implementation of a health information technology module to improve the discrete capture of cancer staging in a diverse regional health system. 

. 2023;19(10):e957-e966. doi:10.1200/OP.23.00104

—the benefits and challenges of completing standardized staging modules. 

. 2023;19(10):835-838. doi:10.1200/OP.23.00500

The implementation and subsequent optimization of a health information technology module within the electronic health record has allowed clinicians across a diverse health care system to identify barriers to improve discrete capture of cancer staging and design solutions to address them. 

Development of EHR-Integrated Cancer Staging Module Identifies Barriers, Increases Discrete Capture

The first-line standard-of-care treatment for patients with metastatic HER2-positive breast cancer, consisting of a taxane and trastuzumab (Herceptin) plus pertuzumab (Perjeta) followed by maintenance therapy, has proven to be an efficacious option for patients, however, combating resistance mechanisms and treating brain metastases in this patient population remain areas of unmet need.

“One of the greatest challenges [in caring] for patients with metastatic HER2-positive breast cancer is the prevention and treatment of brain metastases because up to 50% of our patients will develop brain metastases,” Kay T. Yeung, MD, PhD, said in an interview with OncLive

With a primary end point of progression-free survival (PFS), the phase 3 HER2CLIMB-05 trial (NCT05132582) is examining the efficacy of the addition of tucatinib (Tukysa) to trastuzumab and pertuzumab as maintenance therapy for patients with advanced HER2-positive breast cancer who have received 4 to 8 cycles of induction therapy with trastuzumab, pertuzumab, and a taxane.

The trial is enrolling patients with asymptomatic brain metastases that are untreated and do not need immediate treatment, those with asymptomatic metastases that were previously treated, and those without brain metastases.

“In other settings tucatinib has been shown to delay resistance to trastuzumab-based therapy,” Halle C.F. Moore, MD, an associate professor in the Department of Medicine at Case Western Reserve University School of Medicine and member of the Population and Cancer Prevention Program at Case Comprehensive Cancer Center in Cleveland, Ohio, noted in an interview with OncLive.

“The tyrosine kinase inhibitor [TKI] tucatinib does represent a different mechanism of action in terms of targeting the HER2 pathway,” Yeung, an associate professor of medicine at UC San Diego Health in California, added. “We are hoping that tucatinib can not only address the unmet need in brain metastases, but also potentially extend that duration of response without incurring too much impact on quality of life [QOL].”

Tucatinib, which inhibits phosphorylation of HER2/3 resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation,

 has shown promise for patients with brain metastases as the small molecule inhibitor of HER2 can cross the blood-brain barrier.

Additionally, the agent is highly selective for HER2, with a greater than 1000-fold specificity for HER2 compared with EGFR.

Previously, data from the pivotal phase 2 HER2CLIMB (NCT02614794) study showed that, regardless of whether patients with HER2-positive breast cancer had active or stable brain metastases, treatment with tucatinib in addition to trastuzumab and capecitabine resulted in a 61.4% reduction in the risk of central nervous system (CNS)-PFS vs placebo plus trastuzumab and capecitabine (HR, 0.39; 95% CI, 0.27-0.56; P < .001).

“When patients develop brain metastases their QOL suffers,” Nicholas P. McAndrew, MD, MSCE, an assistant professor in the Division of Hematology/Oncology at UCLA David Geffen School of Medicine in Los Angeles and Santa Monica, California, said in an interview with OncLive. “If this drug combination does reduce the rate, or at least significantly delay the likelihood, of developing brain metastases, that would be an important unmet need.”

Findings from HER2CLIMB led to the April 2020 FDA approval of tucatinib in combination with trastuzumab and capecitabine for those with or without brain metastases and unresectable or metastatic HER2-positive disease, providing an efficacious option for those with brain metastases but only in the second line or beyond.

“The goal is to see whether we can bring tucatinib into an earlier line, in this maintenance line, before brain metastases even develop or before brain metastases progress,” Yeung said.

In HER2CLIMB, 48% of patients had brain metastases, which closely aligns with the rate of brain metastases in the real-world population of patients with HER2-positive metastatic breast cancer. An analysis of patients with brain metastases (n = 291) demonstrated that adding tucatinib to trastuzumab and capecitabine reduced the risk of intracranial progression and death; patients in the tucatinib arm (n = 198) achieved a median CNS-PFS of 9.9 months (95% CI, 8-13.9) compared with 4.2 months (95% CI, 3.6-5.7) for those who received placebo plus trastuzumab and capecitabine (n = 93).

“The original HER2CLIMB study is enlightening in the sense that we see that patients with active brain metastases, or even treated stable brain metastases, can experience an overall survival [OS] benefit,” Yeung noted. Additionally, patients in the tucatinib arm experienced a 68% reduction in the risk of progression in the brain or death vs the placebo arm (HR, 0.32; 95% CI, 0.22-0.48; P < .0001). The estimated 1-year OS rate was 70.1% (95% CI, 62.1%-76.7%) vs 46.7% (95% CI, 33.9%- 58.4%), respectively.

“HER2CLIMB-05 is interesting because it offers a nonchemotherapy triplet combination, and hopefully will also delay the time to progression which would then delay the time to needing additional chemotherapy,” Moore explained.

In patients evaluable for the OS analysis in HER2CLIMB, the median OS for those treated with tucatinib plus trastuzumab and capecitabine (n = 410) was 21.9 months (95% CI, 18.3-31.0) vs 17.4 months (95% CI, 13.6-19.9) for those who received placebo plus trastuzumab and capecitabine (n = 202; HR, 0.66; 95% CI, 0.50- 0.87; P = .0048). The median PFS was 7.8 months (95% CI, 7.5-9.6) for patients in the investigational arm (n = 320) compared with 5.6 months (95% CI, 4.2-7.1) for patients in the control arm (n = 160; HR, 0.54; 95% CI, 0.42-0.71; P < .00001).

“[With] HER2CLIMB-05 [we’re] trying to see if we can improve upon the maintenance phase of the first-line treatment of metastatic HER2-positive breast cancer,” McAndrew explained. “The current SOC is to give approximately 6 cycles of a taxane combined with trastuzumab and pertuzumab.

Then, if the patient’s still responding well and tolerating the regimen, we typically drop the taxane and continue with trastuzumab and pertuzumab. Patients do very well with this first-line regimen; however, progression is still essentially universal in this population, unfortunately.”

Treatment with HER2-targeted TKIs may result in high incidences of adverse effects (AEs) such as diarrhea and skin toxicity due to the off-target effects the drugs have on the EGFR receptor. However, tucatinib is highly selective for the HER2 receptors and has demonstrated minimal inhibition of other HER2 receptors, including EGFR.

“In the past HER2CLIMB study a lot of the AEs can potentially be [attributed to] capecitabine,” Yeung said. “With tucatinib and trastuzumab I would look at [data from the phase 2] MOUNTAINEER study [NCT03043313] in terms of the safety profile.”

Although it was conducted in patients with gastrointestinal cancer rather than breast cancer, findings from MOUNTAINEER, which examined tucatinib plus trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wildtype unresectable or metastatic colorectal cancer, demonstrated a favorable safety profile. When investigators evaluated treatment-emergent AEs in the safety population treated with the combination (n = 86), no deaths were attributed to AEs and 5 patients discontinued treatment due to AEs.

Further, 22.1% of patients experienced serious AEs and 38.4% experienced grade 3 or higher AEs encompassing hypertension (7.0%), diarrhea (3.5%), and fatigue (2.3%) among others.

McAndrew added that “as a class of drugs, TKIs, especially HER2-targeted TKIs, can cause diarrhea. Pertuzumab can cause diarrhea [as well]—it causes it by a different mechanism of action––and we’re interested to see to what degree differences in diarrhea between the 2 groups [are observed].” 

McAndrew also explained that liver function test abnormalities can be seen with tucatinib. Yeung noted that “there is a chance for liver injury, which typically is elevation of liver enzymes; sometimes when it’s bad, it can cause hyperbilirubinemia, but fortunately that is not common, and it could be monitored and tracked. Also, with any medications, tucatinib is not an exception, there can be allergic reactions which I have seen [with the drug].”

An analysis of the HER2CLIMB trial data showed that health-related QOL (HRQOL) was preserved for patients treated with tucatinib in combination with trastuzumab and capecitabine. For those with brain metastases, HRQOL was maintained for longer in patients who received tucatinib than in those who did not.

“We know that the combination of trastuzumab and pertuzumab can increase the risk for cardiac toxicity, and that does not appear to be further increased with the addition of tucatinib,” Moore explained.

The randomized, double-blind HER2CLIMB-05 study will enroll patients with locally advanced or metastatic HER2-positive breast cancer that is unresectable who have received 4 to 8 cycles of prestudy induction therapy with trastuzumab, pertuzumab, and taxane as first-line therapy; patients must not have experienced disease progression following the completion of induction therapy. Additionally, both patients with hormone receptor–positive and those with hormone receptor– negative disease will be enrolled and status must be known.

The primary end point is PFS by investigator assessment per RECIST 1.1 criteria. Secondary end points include OS, time to deterioration of HRQOL, CNS-PFS, and AEs, among others. 

Patients will receive tucatinib 300 mg orally twice daily or placebo orally twice daily in addition to intravenous (IV) trastuzumab 6 mg/kg or 600 mg via subcutaneous injection every 21 days and IV pertuzumab 420 mg every 21 days. A combination trastuzumab/pertuzumab product may also be administered in place of the individual agents and is comprised of pertuzumab 600 mg, trastuzumab 600 mg, and 20,000 units hyaluronidase given via subcutaneous injection every 21 days.

Patients must be able to undergo a contrast-enhanced brain MRI to be enrolled in the study. Those who received prior HER2-targeting or EGFRtargeting TKI therapy will not be included. CNS exclusion based on screening of brain MRIs and clinical assessments will occur for those with symptomatic brain metastasis after CNS-directed local therapy; progression of brain metastases since starting first-line trastuzumab, pertuzumab, and taxane treatment; untreated brain lesions in anatomic sites that may pose risk; and known or suspected leptomeningeal disease. 

“We will have to see whether tucatinib is helpful in the first-line setting,” Yeung said. “My hope is that we will see some positive signal. At the end of the day, it’s how we can understand the approaches of managing and limiting the occurrences of brain metastases in patients with HER2-positive breast cancer [that is key]. We should pay close attention to any agents that can pass the blood-brain barrier and see if we can bring them into studies.”

Tucatinib, which inhibits phosphorylation of HER2/3 resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation, has shown promise for patients with brain metastases as the small molecule inhibitor of HER2 can cross the blood-brain barrier.

Addition of Tucatinib to Breast Cancer Maintenance Therapy Aims to Fill Unmet Need for Patients With Brain Metastases

Exogenous testosterone has long been attributed to the development and progression of prostate cancer. In fact, androgen deprivation therapy (ADT) is the mainstay treatment for patients with advanced and metastatic prostate cancer. Nevertheless, the aging male population is at increased risk for both hypogonadism and prostate cancer. Therefore, some hypogonadal men with prostate cancer may be deprived of the benefits of testosterone replacement therapy (TRT) with significant effects on their quality of life, especially since many of these patients will be managed with active surveillance rather than treatment.

Abraham Morgentaler, MD, FACS, and Abdulmaged M. Traish, PhD, described the androgen saturation model where prostate growth is highly affected by androgens in the setting of very low concentrations but becomes less sensitive to higher or oscillating androgens levels. They described that androgens operate through activation of the androgen receptors, whose maximal binding capacity is reached at androgen concentration below normal physiological levels.

 Findings from multiple studies showed that TRT did not confer worse oncologic outcomes after prostate cancer treatment.

 Interestingly, another study showed that TRT after prostatectomy might reduce or delay time to biochemical recurrence.

There are limited data concerning the effect of TRT among patients with treatment-naive prostate cancer on surveillance. We hypothesized that testosterone replacement does not have a negative impact on the oncologic outcomes of these patients.

We performed a retrospective review of our institutional active surveillance prostate cancer database. Hypogonadal men with prostate cancer who received TRT during surveillance were identified. To limit the effect of confounders, we performed propensity score matching to identify a control group of patients who underwent surveillance without TRT (in terms of age, body mass index, Charlson Comorbidity Index, race, prostate volume, Gleason grade, number of positive cores, percent core involvement, clinical T stage, prostate specific antigen [PSA], PSA density [PSAd], PSA doubling time [PSADT], National Comprehensive Cancer Network [NCCN] risk status, family history of prostate cancer, and follow-up duration).

Patients with NCCN very low, low, and favorable intermediate-risk disease were offered active surveillance and followed in accordance with NCCN Guidelines with PSA testing no more often than every 6 months unless clinically indicated and annual digital rectal examination no more often than every 12 months unless clinically indicated.

 Follow-up MRI and/or prostate biopsy were performed as clinically indicated. Prostate biopsies were graded based on the International Society of Urological Pathology consensus.

Follow-up of patients receiving testosterone entailed repeat testosterone, hematocrit, and liver function tests at 6 to 12 weeks after treatment initiation, then at the time of PSA testing per active surveillance protocol described above.

Conversion to treatment was defined as discontinuation of surveillance with the receipt of radiotherapy, radical prostatectomy, or ADT. Twenty-four patients who received TRT during surveillance were identified and were matched to 72 patients on surveillance who did not receive TRT.

Median duration of TRT was 5 years (IQR, 3-9), and median duration of TRT while on active surveillance was 3 years (range, 1-6). After a median follow-up of 6 years (IQR, 3-9), 22 patients (23%) converted to treatment. Patients who did not receive TRT had a mean increase in PSA of 0.08 ng/ml per month (

 < .01) compared with only 0.01 ng/ml per month (

Five patients in the TRT group converted to treatment compared with 17 in the control group (

 < .20). One patient died because of prostate cancer in the no-TRT group.

Three- and 5-year treatment-free survival rates were 95% and 74%, respectively, in the TRT group compared with 86% and 76%, respectively, in the no TRT group (log-rank P=.87).

 Multivariable Cox regression model showed that only PSA density was associated with conversion to treatment (HR, 1.08; 95% CI, 1.03-1.13; 

Our findings are in line with the androgen saturation model in that we did not identify a difference in conversion to treatment between both groups. However, controversy about safety of TRT in the context of prostate cancer among clinicians providing care to the hypogonadal patient remains. The European Association of Urology Guidelines still considers localized and metastatic prostate cancer an absolute contraindication for testosterone replacement.

 The American Urological Association states there is no strong evidence linking testosterone replacement with increased risk of developing prostate cancer.

Additionally, findings from a meta-analysis performed by Parizi et al showed that TRT does not increase the risk of biochemical recurrence after local therapy with curative intent.5 For active surveillance, evidence remains even more limited. The meta-analysis found a total of 6 studies, but only 1 was a double-armed study with shorter follow-ups compared with our study.

 The other 5 studies in that meta-analysis were limited to case reports.

 The influence of androgens on prostate cancer pathophysiology seems to be so heterogenous that its administration as a treatment alternative has also been explored. Isaacs et al laid out the rationale behind this concept by describing bipolar androgen therapy. The authors described that supraphysiologic levels of testosterone induce cell death in castration-resistant prostate cancer that is well known for displaying an upregulation of androgen receptors.

Although the available evidence, including our retrospective study, does not support the notion that TRT may adversely affect outcomes for hypogonadal men with localized prostate cancer on active surveillance, close follow-up of these patients is recommended. Clinicians should ensure that there is a low threshold for obtaining prostate MRIs and repeat biopsies with discontinuation of TRT with any evidence of disease progression.

The retrospective nature of our analysis and propensity score matching have their inherent limitations. Additionally, the small sample size precludes further analysis of the effect of the individual routes of administration of TRT.

Society. AC. Cancer Statistics Center 2022 [Available from: http://cancerstatisticscenter.cancer.org2022.

Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. 

. 2001;86(2):724-731. doi:10.1210/jcem.86.2.7219

Morgentaler A, Traish AM. Shifting the paradigm of testosterone and prostate cancer: the saturation model and the limits of androgen-dependent growth. 

. 2009;55(2):310-320. doi:10.1016/j.eururo.2008.09.024

Kaplan AL, Trinh QD, Sun M, et al. Testosterone replacement therapy following the diagnosis of prostate cancer: outcomes and utilization trends. 

. 2014;11(4):1063-1070. doi:10.1111/jsm.12429

Parizi MK, Abufaraj M, Fajkovic H, et al. Oncological safety of testosterone replacement therapy in prostate cancer survivors after definitive local therapy: a systematic literature review and meta-analysis. 

. 2019;37(10):637-646. doi:10.1016/j.urolonc.2019.06.007

Boyle P, Koechlin A, Bota M, et al. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate-specific antigen (PSA) level: a meta-analysis. 

. 2016;118(5):731-741. doi:10.1111/bju.13417

Ahlering TE, My Huynh L, Towe M, et al. Testosterone replacement therapy reduces biochemical recurrence after radical prostatectomy. 

. 2020;126(1):91-96. doi:10.1111/bju.15042

Daza J, Ahmad A, Shabir U, et al. Does testosterone replacement therapy increase the risk of conversion to treatment in patients with prostate cancer on active surveillance? 

. 2023;S1078-1439(23):00215-00216. doi:10.1016/j.urolonc.2023.06.002

NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 4.2023. October 27, 2023. bit.ly/3ScFnCz

Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: definition of grading patterns and proposal for a new grading system. 

. 2016;40(2):244-252. doi:10.1097/PAS.0000000000000530

EAU Guidelines 2023. Accessed October 27, 2023. bit.ly/3MeF4Dd

Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and management of testosterone deficiency: AUA Guideline. 

. 2018;200(2):423-432. doi:10.1016/j.juro.2018.03.115

Kim M, Byun SS, Hong SK. Testosterone replacement therapy in men with untreated or treated prostate cancer: do we have enough evidences?. 

. 2021;39(4):705-723. doi:10.5534/wjmh.190158

Kacker R, Hult M, San Francisco IF, et al. Can testosterone therapy be offered to men on active surveillance for prostate cancer? preliminary results. 

. 2016;18(1):16-20. doi:10.4103/1008-682X.160270

Morgentaler A. Two years of testosterone therapy associated with decline in prostate-specific antigen in a man with untreated prostate cancer. 

. 2009;6(2):574-577. doi:10.1111/j.1743-6109.2008.01066.x

Morgentaler A, Lipshultz LI, Bennett R, et al. Testosterone therapy in men with untreated prostate cancer. 

. 2011;185(4):1256-1260. doi:10.1016/j.juro.2010.11.084

Berookhim B, Krishnan R, Nelson C, Mulhall J, editors. Testosterone replacement therapy in men undergoing active surveillance for prostate cancer. JOURNAL OF SEXUAL MEDICINE; 2015: WILEY-BLACKWELL

Ory J, Flannigan R, Lundeen C, et al. Testosterone therapy in patients with treated and untreated prostate cancer: impact on oncologic outcomes. 

. 2016;196(4):1082-1089. doi:10.1016/j.juro.2016.04.069

Morgentaler A, Magauran D, Neel D, et al. Recurrence rates following testosterone therapy in a large clinical cohort of men with prostate cancer. 

Morales A. Effect of testosterone administration to men with prostate cancer is unpredictable: a word of caution and suggestions for a registry. 

. 2011;107(9):1369-1373. doi:10.1111/j.1464-410X.2011.10193.x

Isaacs JT, D'Antonio JM, Chen S, et al. Adaptive auto-regulation of androgen receptor provides a paradigm shifting rationale for bipolar androgen therapy (BAT) for castrate resistant human prostate cancer. 

. 2012;72(14):1491-1505. doi:10.1002/pros.22504

Oncology Live®

Investigators hypothesized that testosterone replacement does not have a negative impact on the oncologic outcomes of treatment-naive patients with prostate cancer on surveillance and they performed a retrospective review of an institutional active surveillance prostate cancer database.

TRT in Patients With Prostate Cancer on Active Surveillance: Are We Really Putting Gas on Fire?

Although myeloproliferative neoplasms (MPNs), which are comprised of essential thrombocythemia, polycythemia vera (PV), and myelofibrosis, remain relatively rare— with estimated annual incidence rates of 1.03, 0.84, and 0.47 per 100,000 individuals, respectively—there remains an unmet need for effective treatment options for patients with these diseases who progress on standard of care therapies.

 However, significant progress has been made in terms of understanding this group of disorders and developing treatment strategies to combat them, with Naveen Pemmaraju, MD, saying the medical field has entered a “golden era” of MPN treatment.

 video series titled “Expert Insights Into the Management of MPNs,” Jamile M. Shammo, MD, explained, “MPNs represent a heterogeneous group of hematopoietic stem cell neoplasms that share common features. Myeloid proliferation is certainly something that we see [in MPNs], as well as a propensity for thrombotic events, symptoms that are related either to constitutional symptoms or splenomegaly related. All 3 entities tend to progress to higher myeloid neoplasms; essential thrombocythemia [to] PV that goes to myelofibrosis and then myelofibrosis can evolve into acute leukemia. Of course, the rate of progression varies from one entity to the other, with essential thrombocythemia having the lowest risk [of progression].” 

The development of MPNs is almost always associated with mutations in JAK2, making this family of genes an attractive treatment target. JAK2 mutations are observed in approximately 95% of patients with PV and approximately 50% of both patients with essential thrombocythemia and myelofibrosis. Notably, the emergence of additional treatment targets also has sparked the development of novel agents in recent years.

During the discussion, expert oncologists reviewed updated findings from ongoing and completed clinical trials in the field. They primarily focused on studies evaluating emerging agents in PV and myelofibrosis.

Abdulraheem Yacoub, MD, began the discussion on PV by noting that the JAK1/2 inhibitor ruxolitinib (Jakafi) has been the standard-of-care agent in PV since 2015. Prior to this, PV was historically managed with phlebotomy, hydroxyurea, and/or interferons. Ruxolitinib became the first FDA-approved drug for the treatment of patients with PV in December 2014 when it received an indication from the agency for patients who had an inadequate response to or were intolerant of hydroxyurea.

"The introduction of ruxolitinib to the treatment landscape of patients with myelofibrosis has truly been transformative,” Shammo commented. “We all remember the patients we had in the clinic [in the past] and how we had simply nothing but supportive care to offer. Ruxolitinib was approved based on the results of 2 phase 3 studies. COMFORT-I [NCT00952289] randomly assigned patients [with myelofibrosis] to receive ruxolitinib or placebo and examined [spleen] volume reduction and reduction in total symptom score from baseline at 24 weeks. COMFORT-II [NCT00934544], which ran mostly in Europe, randomly assigned patients to be treated with ruxolitinib or best available therapy [as selected by the investigator]. This study [also evaluated] spleen volume reduction, but at week 48. In either trial, ruxolitinib was statistically significantly more active in attaining the primary end point and for that reason it was approved. Some might say that the evidence is perhaps less compelling than what you would [typically] find in a phase 3 study, but when you have multiple studies showing the same thing, that treatment with ruxolitinib improves [outcomes] compared with placebo or best available therapy, I tend to feel like it’s reasonable enough to believe that actually is the case."

Long-term data from 2 phase 3 trials, RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036), comparing the safety and efficacy of ruxolitinib with best available therapy in different patient populations with PV recently were published in 

. RESPONSE enrolled adult patients with PV who were resistant to or intolerant of hydroxyurea and randomly assigned them 1:1 to receive either ruxolitinib (n = 110) or best available therapy (n = 112; hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide (Agrylin), approved immunomodulators, or observation without pharmacological treatment). RESPONSE-2 enrolled a higher-risk patient population; eligible patients had inadequately controlled PV without splenomegaly and were intolerant of or resistant to hydroxyurea with an ECOG performance status of 2 or less. They were randomly assigned to receive ruxolitinib (n = 74) or best available therapy (n = 75).

Follow-up data from RESPONSE demonstrated that the 5-year overall survival (OS) rate was 91.9% (95% CI, 84.4%-95.9%) in the ruxolitinib group vs 91.0% (95% CI, 82.8%-95.4%) in the best available therapy arm. Most patients (88%) in the best available therapy arm crossed over to receive ruxolitinib, and no patients remained in this arm after week 80. There were 25 primary responders in the ruxolitinib arm, 6 of whom had progressed by the time of the final analysis. The 5-year probability of maintaining a primary composite response was 74% (95% CI, 51%-88%), the probability of maintaining complete hematological remission was 55% (95% CI, 32%-73%), and the probability of maintaining overall clinicohematological responses was 67% (range, 54%-77%).

At a median follow-up of 67 months (IQR, 65-70), findings from RESPONSE-2 showed that the 5-year OS rate was 96% (95% CI, 87%-99%) in the ruxolitinib arm compared with 91% (95% CI, 80%-96%) in the best available therapy arm. In the ruxolitinib arm, 22% of patients (95% CI, 13%-33%) achieved durable hematocrit control with an estimated median duration of control not reached (NR) at week 260 (95% CI, 144-NR). Most patients in the best available therapy arm (77%) crossed over to ruxolitinib, no patients continued with best available therapy after week 80 per protocol, and the median duration of hematocrit control was not reported due to the small number of responders at week 80.

In light of findings from RESPONSE and RESPONSE-2, investigators in both studies concluded that ruxolitinib is a safe and effective long-term treatment option for patients with PV for whom hydroxyurea proved ineffective.

“Both studies have ong-term follow-up and have published 5-year data showing very durable responses,” Yacoub said. “There were very few late failures on ruxolitinib and no unexpected adverse effects were observed with longterm follow up. This has built a strong case for ruxolitinib as a standard treatment for patients [with PV] after hydroxyurea failure.”

A more recent breakthrough for patients with PV was the emergence of the interferon ropeginterferon alfa-2b-njft (Besremi). In November 2021, ropeginterferon became the first agent to receive FDA approval for patients with PV regardless of their treatment history.

Ropeginterferon was compared with hydroxyurea in the phase 3 PROUD-PV trial (NCT01949805) and its extension continuation study, CONTI-PV (NCT02218047). Eligible patients were 18 years or older and had earlystage PV with no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment. Patients could opt to enter CONTI-PV after 1 year of initial treatment in PROUD-PV.

Findings from the studies revealed that at a median follow-up of 182.1 weeks (IQR, 166.3- 201.7) patients in PROUD-PV who received ropeginterferon (n = 122) achieved complete hematological response with normal spleen size at a rate of 21% compared with 28% of patients who received hydroxyurea (n = 123). However, in CONTI-PV, 53% of patients in the ropeginterferon arm (n = 95) had a complete hematological response with improved disease burden at 36 months vs 38% of patients in the hydroxyurea arm (n = 74; P = .044). Moreover, at 36 months in CONTI-PV, the complete hematological response rate regardless of spleen criterion was 71% vs 51% in the investigative and comparator arms, respectively (P = .012); at 12 months in PROUD-PV these rates were 43% vs 46%, respectively (P = .63).

Study authors concluded that ropeginterferon was effective in inducing hematological responses. Although noninferiority to hydroxyurea in terms of hematological response and normal spleen size was not observed at 12 months, improved responses vs hydroxyurea were present at 36 months. Thus, the authors wrote that ropeginterferon offers an effective and “safe long-term avenue for treatment with distinct features from hydroxyurea.”

“It’s wonderful to have options because we get patients with PV [who] could not be any more different,” Yacoub said. “They have different goals of care, and at the end of the day, we are treating individual patients, not diseases. For each patient, we have to define what we are trying to achieve. There are patients who are going to live with the disease a lot longer. They have more high-risk presentations and would benefit from the maximum data that we have with the application of the effective agents. There are patients who have relatively low-risk disease, and they’re likely going to live their natural lives with some medical management from our end. We have to individualize our choices.” 

Looking ahead, the phase 3 VERIFY trial (NCT05210790) is underway with the aim of adding rusfertide (PTG-300), a novel and potent hepcidin mimetic, to the PV treatment landscape. Rusfertide previously demonstrated clinical activity in early-phase studies, characterized by good tolerability and consistent and durable hematocrit control, as well as improvements in iron deficiency among patients who required higher than normal amounts of phlebotomies even after standard-of-care therapy.

VERIFY is enrolling patients with PV who have received at least 3 phlebotomies in the previous 6 months or at least 5 in the previous 12 months as a result of inadequate hematocrit control, with or without concurrent cytoreductive therapy. Eligible patients will be randomly assigned 1:1 to receive either placebo plus ongoing therapy or rusfertide plus ongoing therapy. 

Part 1a of the trial is the double-blind, placebo- controlled, add-on phase that will enroll parallel groups and last 32 weeks. During part 1b, patients who complete part 1a will receive rusfertide for 20 weeks. Patients who successfully complete part 1b will enter the long term extension phase, part 2, and will continue to be treated with rusfertide for 104 weeks. The primary end point is the proportion of patients achieving a response in from week 20 to week 32 in part 1A. The study was initiated in January 2022 and has a target enrollment of 250 patients.

Patients with myelofibrosis have more FDA-approved treatment options than those with PV. To date, 3 Janus kinase (JAK) inhibitors have been approved for the treatment of patients with myelofibrosis: ruxolitinib, fedratinib (Inrebic), and pacritinib (Vonjo). 

Similar to PV, ruxolitinib became the first FDA-approved therapy for the treatment of patients with myelofibrosis, gaining an indication for patients with intermediate- and high-risk disease in November 2011. In August 2019, patients with intermediate- 2 or high-risk primary or secondary myelofibrosis gained fedratinib as an FDA-approved option. Finally, the FDA approved pacritinib in March 2022 for the treatment of adult patients with intermediate- or high-risk primary or secondary myelofibrosis with platelet levels below 50,000/μL.

“The current NCCN [National Comprehensive Cancer Network] guidelines are really agnostic of the second-line therapy, which is interesting,” Raajit K. Rampal, MD, PhD, said. “You can start a patient who [at that time] has over 50,000 platelets on ruxolitinib or fedratinib. And if there is a need to change therapy, you could use any of these 3 agents. That’s an important message for our audience to remember, that the second line is not platelet restricted. We have an abundance of options.” 

After summarizing updated data from pivotal trials of the already approved agents, the panelists shifted their focus to new findings from trials evaluating investigational therapies beyond JAK inhibitors in myelofibrosis. Updates from the studies were presented during the 2023 American Society of Clinical Oncology Annual Meeting in June.

Novel Agents Seek to Augment the Armamentarium 

In the phase 2 ACE-536-MF-001 trial (NCT03194542), investigators examined the erythroid maturation agent luspatercept-aamt (Reblozyl) for the management of anemia in patients with myelofibrosis; it occurs in approximately 40% of patients. Investigators noted that luspatercept demonstrated anemia improvement across all cohorts of in the study, regardless of transfusion dependency and use of ruxolitinib. For example, 26.3% (95% CI, 13.4%- 43.1%) of patients who were red blood cell transfusion dependent and received prior ruxolitinib (n = 38) achieved transfusion independence following treatment with luspatercept.

The phase 1/2 LIMBER study (NCT04455841) evaluated the safety and efficacy of the oral ALK2 inhibitor zilurgisertib alone and in combination with ruxolitinib in adult patients with intermediate 1 or 2 primary or secondary myelofibrosis. Among patients in the monotherapy group who were not transfusion dependent (n = 6), anemia improvement (hemoglobin increase of ≥ 1.5 g/ dL relative to baseline) occurred in 1 patient; this level of improvement was observed in 3 of 9 patients in the combination group. Zilurgisertib monotherapy or combination therapy with ruxolitinib was determined to be generally well tolerated and displayed the potential for therapeutic activity, the study authors concluded.

Another phase 1/3 trial, XPORT-MF-034 (NCT04562389) evaluated a ruxolitinibcontaining combination, this time with the selective inhibitor of nuclear export selinexor (Xpovio) in patients with JAK inhibitor–naive myelofibrosis. At week 24, efficacy-evaluable patients (n = 22) achieved spleen volume reduction of at least 35% (SVR35) from baseline at a rate of 64%. Investigators noted that the combination displayed encouraging activity, and updated data will be made available at a future date.

Finally, in a single-arm phase 2b study (NCT04217993) the oral, novel JAK/ACVR1 inhibitor jaktinib showed promising activity in patients with myelofibrosis who were intolerant to ruxolitinib. Efficacy-evaluable patients who received jaktinib (n = 44) achieved an SVR35 rate of 43% at 24 weeks, and the best spleen response rate was 55%. Notably, response was maintained for a minimum of 12 weeks in 80% of patients.

“It’s exciting to have all these non-JAK inhibitors [in the pipeline],” Rampal said in conclusion. “Ultimately, hopefully, we can figure out what the best fit is for an individual patient. We’re not there yet, but with an abundance of data, we’ll get there. It’s also important to note that there are a number of agents that are earlier on [in development] that are moving along. Even beyond this next generation of non-JAK inhibitors already in the pipeline, there is a generation beyond that that is in clinical trial development.”

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Significant progress has been made in terms of understanding myeloproliferative neoplasms and developing treatment strategies to combat them.

Vol. 24/No. 19 | Oncology Live®

EV-302 Regimen Bests Chemo in Advanced Urothelial Cancer

Development of EHR-Integrated Cancer Staging Module Identifies Barriers, Increases Discrete Capture

Addition of Tucatinib to Breast Cancer Maintenance Therapy Aims to Fill Unmet Need for Patients With Brain Metastases

TRT in Patients With Prostate Cancer on Active Surveillance: Are We Really Putting Gas on Fire?

New Developments in MPN Management Provide Additional Options for Patients

Patient and Family Interpretations of the Language of Cancer Care