Jason Broderick

Patients who had BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) and were urinary minimal residual disease (uMRD)-negative after treatment of Adstiladrin (nadofaragene firadenovec) did not experience cancer recurrences, according to a phase 2 trial.

Findings from the phase 2 trial were presented in a poster at the 2024 

Beyond being highly predictive of future recurrence, uMRD was also shown to enable quantitative evaluation of molecular response to Adstiladrin, according to first author Dr. Vikram M. Narayan and co-investigators. Narayan is an assistant professor in the department of urology at Emory University School of Medicine.

“uMRD profiling uses next-generation sequencing to identify mutations associated with urothelial carcinoma and can be used to predict recurrence and assess response to therapy,” Narayan and co-investigators wrote on their poster.

Patients with a specific type of non-muscle invasive bladder cancer (NMIBC) called BCG-unresponsive, who were treated with Adstiladrin, showed no cancer recurrences if they were urinary minimal residual disease (uMRD)-negative after treatment.

The study used a technique called uMRD profiling, which used advanced genetic analysis to identify mutations associated with the cancer, helping predict the likelihood of recurrence and assess the response to Adstiladrin therapy.

The uMRD analysis involved 43 patients in a phase 2 trial, with urine samples collected before treatment and at three months follow-up. The primary goal of the study was to achieve high-grade recurrence-free survival at one year.

The analysis found that patients with uMRD-negative status had significantly better recurrence-free survival rates compared to uMRD-positives, indicating the potential effectiveness of Adstiladrin in preventing cancer recurrence.

The researchers’ uMRD analysis was from the phase 2 trial that included 43 patients with BCG-unresponsive (relapsed/refractory) NMIBC treated with the novel intravesical therapy Adstiladrin. To enroll in the trial patients had to have an ECOG performance status of 2 or lower, meaning eligible patients were able to perform tasks independently. Patients with upper tract bladder cancer were not eligible.

The uMRD analysis included all patients in the trial who had been treated with at least one dose of Adstiladrin, which included 35 patients. Urine samples were collected from patients before induction and at three months follow-up.

The primary endpoint (main result measured at the end of a study to see if treatment worked) of the study was high-grade recurrence-free survival (RFS; time after primary treatment when cancer does not return) at one year.

Initial pathological stages for the 35 evaluable patients were Ta in three patients, T1 in nine patients and Tis in 23 patients. Six patients also had concomitant carcinoma in situ (CIS). For the 32 patients with pre-treatment urine samples available, the most frequently mutated genes included TP53, TERT, PIK3CA, ARID1A, PLEKHS1, ELF3 and ERBB2. CNVs occurred most in SOX4and NIT1.In both pre- and post-induction collections, “uMRD identified patients with high (72%) and low (28%) recurrence risk,” the authors wrote.

The12-month pre-induction RFS rates were 71% and 20% for MRD-negatives and MRD-positives, respectively.Also at 12 months, the post-induction RFS rates were 100% and 20% for MRD-negatives and MRD-positives, respectively.

The researchers measured quantitative drug response using pre- and post-induction urine in 15 patients and categorized patients’ MRD status as negative (7%), complete responder (13%), partial responder (27%), stable (20%) or refractory (33%).The researchers then determined a broad correlation between recurrence and response groups, with no recurrence in the MRD negative and complete responder groups and recurrence in seven of the 12 patients that comprised the other groups.

“uMRD enables quantitative assessment of molecular response to drug treatment. uMRD-determined pre-treatment disease burden assessment can support stratification of control and intervention arms in future treatment trials,” the authors wrote in their poster conclusion.

Earlier this month, Ferring Pharmaceuticals, the developer of Adstiladrin, announced that the therapy is now fully available across the United States for the treatment of adult patients with high-risk BCG-unresponsive NMIBC with CIS with or without papillary tumors. In December 2022, the 

 Adstiladrin for use in this patient population.

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Urinary minimal residual disease-negative status was related to preventing the return of cancer when certain patients with bladder cancer received Adstiladrin.

Adstiladrin Leads to Beneficial Outcomes in Some Bladder Cancers

At a median follow-up of approximately 50 months, treatment with Lenvima plus Keytruda led to a 21% reduction in the risk of death compared with Sutent. 

Survival benefits from treatment with Lenvima (lenvatinib) and Keytruda (pembrolizumab) were sustained compared with Sutent in pateints with advanced clear cell renal cell carcinoma (RCC) after four years of follow-up, according to updated study results.

These findings from the phase 3 CLEAR study were presented at the 2023 ASCO Annual Meeting.

At a median follow-up of approximately 50 months, treatment with Lenvima plus Keytruda led to a 21% reduction in the risk of death compared with Sutent. The median overall survival (the time when a patient with cancer is still alive) was 53.7 months with the combination versus 54.3 months with Sutent. The overall survival rates at 24, 36, and 48 months all favored the combination arm versus the control arm at 80.4% versus 69.6%, 66.4% versus 60.2%, and 55.9% versus 52.5%, respectively.

When presenting these data at the ASCO meeting, study author Thomas E. Hutson explained that the reason the overall survival outcomes for the two study arms appeared to come closer together at the four-year time point was due to subsequent anticancer medications.

“Sixty-nine percent of patients who received (Sutent) went on to receive subsequent anticancer therapy, including anti-VEGF therapy in 45% and PD-1/L1 checkpoint inhibitors in 55%. This is comparted to only 51% of patients moving on to additional anticancer therapy in the (Lenvima)/(Keytruda) group, with only 16% receiving PD-1/L1 checkpoint inhibitors,” said Hutson, who is director of the urologic oncology program and co-chair of the Urologic Cancer Research and Treatment Center at Baylor University Medical Center.

Hutson said the investigators adjusted data in the study to account for the potential impact of subsequent anticancer medications, which suggested “that the (overall survival) analysis was indeed impacted by the imbalance in the use of subsequent anticancer medication in the (Sutent) group versus the (Lenvima)/(Keytruda) group.”

Regarding progression-free survival (the time during and after treatment when a patient with cancer lives with the disease without worsening), Hutson said that with an additional 23 months of follow-up, the median progression-free survival was 23.9 months with Lenvima plus Keytruda compared with 9.2 months with Sutent, translating to a 53% reduction in the risk of disease progression or death. The progression-free survival rates at 24, 36, and 48 months all favored the Lenvima/Keytruda versus the Sutent group at 49% versus 23.4%, 37.3% versus 17.6%, and 24.5% versus 13.1%, respectively.

Overall, the three-arm CLEAR study randomized patients to receive Lenvima plus Keytruda (355 patients), Lenvima plus everolimus (357 patients) or oral Sutent (357 patients). Updated findings for the everolimus arm were not presented at the ASCO meeting.

Baseline characteristics showed that the median patient age was 64 years in the combination arm and 61 years in the Sutent arm. In the combination arm, 27% of patients had favorable risk, 64% had intermediate and 9% had poor risk disease.

The objective response rate (the percentage of patients with a partial or complete response to treatment) was 71.3% with Lenvima plus Keytruda compared with 36.7% for Sutent. The rate of complete responses (the disappearance of all signs of cancer as a result of treatment) was 18.3% with the combination compared with 4.8% for Sutent. The median duration of response (the time from when a response to treatment was observed to progression or all-cause death, whichever occurred first) was 26.7 months with Lenvima/Keytruda compared with 14.7 months with Sutent.

Regarding safety, Hutson said, “No new safety signals were identified; adverse events were managed with dose modifications as necessary.”

After a median follow-up of four years, the survival benefit, including progression-free survival persisted in patients with advanced clear cell renal cell carcinoma treated with Lenvima plus Keytruda compared with those treated with Sutent.

Survival Benefit With Lenvima/Keytruda for Advanced Clear Cell RCC Continues After 4 Years

Data from a recent study demonstrated that increased prostate-specific antigen (PSA) screening was associated with improved outcomes in younger Black patients with prostate cancer.

Among this patient population, an increased frequency of PSA screening was linked to a nearly 25% reduction in prostate cancer–specific mortality and an approximately 40% lower risk of having metastatic disease at the time of a prostate cancer diagnosis.

“We found that PSA screening was associated with a decreased risk of … metastatic disease at diagnosis, as well as prostate cancer–specific mortality. Taken together, these results would suggest that [increased] PSA screening may improve cancer outcomes for young African American men,” said lead study author Edmund M. Qiao, of the University of California San Diego, during a presentation of the data on a news briefing held ahead of the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

A blood test and PSA screening may indicate the presence of prostate cancer. However, other conditions, such as an inflamed prostate, can increase PSA levels, which is why there is conflicting advice involving screening.

Overall, the study included 4,726 Black men (mean age, 51.8 years) diagnosed with prostate cancer. The “high PSA screening” group had received an average of three prior screening tests and the “low PSA screening” group had received an average of 0.5 prior screening tests.

Regarding disease severity at diagnosis, all important metrics showed that the high PSA screening group had lower severity. The rate of metastatic disease at diagnosis was 4.2% versus 1.4%, respectively, translating to a 39% risk reduction.

“In our statistical model, controlling for the confounders, we found that PSA screening was associated with about a 25% reduction in prostate cancer–specific mortality,” noted Qiao. The confounding factors controlled for in the statistical model included primary care visit rate, age at diagnosis, year of diagnosis, employment, marital status, college education and income.

Black men have the highest mortality rate in prostate cancer, Qiao noted. Prior to this research, he highlighted, there has been limited data on PSA screening in this patient population.

“The data for PSA screening includes very few African American men (in general) and no young African American men between the ages of 40 and 55,” he said. “This has led to discordant PSA screening recommendations for these patients and as a result, young African American men are an at-risk group that needs additional research to help guide their clinicians and themselves when deciding when to start PSA screening.”

In 2012, the U.S. Preventive Services Task Force (USPSTF) issued a grade D recommendation against the use of PSA screening in the general U.S. population, regardless of age. The current USPSTF PSA screening policy is slightly changed, with a grade C recommendation for men aged 55 to 69 years, meaning in this population, an individual decision on screening should be made based on a physician-clinician discussion of the potential benefits and risks.

While the USPSTF acknowledges that family history and Black race are two of the most significant risk factors for developing prostate cancer, the panel maintains that there is insufficient evidence to issue individualized screening recommendations in any age group based on those factors.

“We know African American men are nearly one-and-a-half times more likely to develop prostate cancer and more than twice as likely to die from prostate cancer as White patients,” ASCO President Dr. Lori J. Pierce said during the news briefing. “And despite this, young African American men are poorly represented in PSA studies from which evidence-based guidelines are developed. So, this really limits proper PSA guidance screening guidance for African American patients, especially for those who are younger than 55. And so, because we don't have adequate screening data, there are differences in opinion as to what the guidelines should be. And so, this abstract makes a very strong statement to discuss screening at a younger age in African American men.”

The study results lend strength to discuss prostate cancer screening in younger Black men, according to an expert.

Increased Screening Associated with Improved Outcomes in Younger Black Patients with Prostate Cancer

Sprycel (dasatinib), an oral medication that helps reduce the production of damaged white blood cells in the body, has been approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP).

The approval is based on results with Sprycel demonstrated in 97 pediatric patients with CP-CML enrolled across two studies, an open-label, nonrandomized, single-arm phase 2 trial and an open-label, nonrandomized, dose-ranging phase 1 trial. Fifty-one patients (all from the single-arm trial) were newly diagnosed, and the remaining 46 (29 from the single-arm study and 17 from the dose-ranging trial) were intolerant or resistant to prior Gleevec (imatinib).

At a median follow-up of 4.5 years, more than half of the responding patients in the treatment-naïve cohort had not progressed at the time of the data cutoff, so the median duration of complete cytogenetic response (CCyR), major cytogenetic response (MCyR), and major molecular response (MMR) could not be estimated. The same was true at the median follow-up time of 5.2 years for the previously treated cohort.

The range of duration of response (DOR) for the newly diagnosed patients was 2.5+ to 66.5+ months for CCyR, 1.4 to 66.5+ months for MCyR, 5.4+ to 72.5+ months for patients who achieved MMR by month 24, and 0.03+ to 72.5+ months for patients who achieved MMR at any time. The ‘+’ denotes a censored observation. Among the Gleevec-intolerant cohort, the DOR ranges were 2.4 to 86.9+ months for CCyR, 2.4 to 86.9+ months for MCyR, and 2.6+ to 73.6+ months for MMR.

“Options for pediatric patients with chronic myeloid leukemia are limited, and it is challenging to conduct clinical trials investigating potential new treatments in this small patient population,” Lia Gore, M.D., University of Colorado School of Medicine and Children’s Hospital Colorado, said in a statement. “Dasatinib is an important new option to help address the unmet needs of children with Philadelphia chromosome-positive CML in chronic phase.”

The 3-, 6-, 12- and 24-month CCyR rates among newly diagnosed patients were 43.1 percent, 66.7 percent, 96.1 percent and 96.1 percent, respectively. In the previously treated group, the corresponding rates were 45.7 percent, 71.7 percent, 78.3 percent and 82.6 percent, respectively.

The 3-, 6-, 12- and 24-month MCyR rates among treatment-naive patients were 60.8 percent, 90.2 percent, 98.0 percent and 98.0 percent, respectively. The corresponding rates in the Gleevec-intolerant group were 60.9 percent, 82.6 percent, 89.1 percent and 89.1 percent, respectively.

The 3-, 6-, 12- and 24-month MMR rates among newly diagnosed patients were 7.8 percent, 31.4 percent, 56.9 percent and 74.5 percent, respectively. The corresponding rates in the previously treated group were 15.2 percent, 26.1 percent, 39.1 percent and 52.2 percent, respectively.

Across both patient groups, 14.4 percent experienced treatment-related serious adverse events (AEs). AEs occurring in 15 percent or more of patients included myelosuppression, headache, nausea, diarrhea, skin rash, pain in extremity and abdominal pain.

“While chronic myeloid leukemia is rare in children, accounting for less than three percent of all pediatric leukemias, it is often more aggressive in younger patients than in adults and until recently, there have been few available treatment options,” Vickie Buenger, President, Coalition Against Childhood Cancer, said in a statement. “The FDA’s decision to approve the expanded use of Sprycel in children with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase may bring new hope to these patients and their families.”

Sprycel (dasatinib), an oral medication that helps reduce the production of damaged white blood cells, has been approved by the Food and Drug Administration for the treatment of pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.
 

Jason Broderick

Adstiladrin Leads to Beneficial Outcomes in Some Bladder Cancers

Survival Benefit With Lenvima/Keytruda for Advanced Clear Cell RCC Continues After 4 Years

Increased Screening Associated with Improved Outcomes in Younger Black Patients with Prostate Cancer

Sprycel Approved for CML Subset

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