Treatment with a decreased dosing schedule of oral azacitidine (Vidaza) was consistent with previous findings for the agent in patients with lower- to intermediate-risk myelodysplastic syndrome (MDS), according to data from the phase 2/3 ASTREON trial (NCT05469737) shared at the 

“We showed that the safety profile of oral azacitidine in both 200 mg or 300 mg is identical or similar to our prior experience in other trials, such as the phase 3 AZA-MDS-003 trial [NCT01566695],” study author Guillermo Garcia-Manero, MD, Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston, said during a presentation of the data.

The primary end points in the trial were adverse effects (AEs) and complete remission (CR) within 6 cycles per International Working Group (IWG) 2006 criteria.

Regarding AEs, patients in both treatment arms experienced similar rates. Twenty-three patients (96%) in the 200-mg arm and 20 patients (87%) in the 300-mg arm reported having at least 1 treatment-related treatment-emergent AE (TEAE).

The most common treatment-related AEs patients experienced in either group were hematologic- and gastrointestinal-related.

“The most common [treatment-related toxicities] were neutropenia followed by constipation, nausea, thrombocytopenia. Prototypical hematological and [gastrointestinal] toxicity profile that we saw with this agent in the past,” Garcia-Manero explained.

Serious TRAEs occurred in 1 patient from the 200-mg arm and 3 patients from the 300-mg arm, researchers noted. There were 2 deaths that occurred in the 300-mg arm, which were treatment-related and treatment-emergent, respectively. No patients from the 200-mg arm experienced grade 5 AEs.

Of note, the rates of TRAEs of all grades leading to treatment discontinuation or dose reduction were higher in the 300-mg arm. Four patients (17%) in the 200-mg arm, Garcia-Manero said, discontinued treatment due to disease progression. Three patients (13%) in the 300-mg arm discontinued treatment due to TRAEs.

Regarding the co-primary end point, Garcia-Manero noted that none of the patients achieved a CR in either arm.

Secondary end points were achievement of overall response rate (ORR)–which included complete response (CR), partial remission, marrow CR, hematologic improvement-erythroid response (HI-E), HI-platelet (HI-P) response, and HI-neutrophil (HI-N) response per IWG 2006 criteria–as well as best OR and OR duration.

There were 6 patients from both dose arms that achieved HI-E; 0 patients in the 200-mg arm and 1 patient in the 300-mg arm achieved HI-P; and 1 patient in each dose group achieved HI-N.

Of note, HI rates within 6 cycles were calculated by investigator assessment per IWG 2006 criteria. This was calculated for patients who received at least 75% of the dose from cycle 1 and had at least 1 post-baseline efficacy assessment, which was the modified intent-to-treat (mITT) population.

In the mITT population, 8 of 22 patients in the 200-mg arm achieved any HI and 7 of 21 patients in the 300-mg arm achieved any HI.

In the trial, 47 patients with lower-/intermediate-risk MDS were randomly assigned 1:1. The study evaluated safety and efficacy of oral azacitadine with best supportive care (BSC) in this patient population. Patients were assigned to 2 arms to receive at least 1 dose of oral azacitadine at either 200 mg (n = 24) or 300 milligrams (n = 23) for 14 days per a 28-day cycle plus BSC. Eligible patients were at least 18 years old and had at least 1 cytopenia.

The phase 2 portion of the trial was an open-label, dose optimization trial to help determine the recommended phase 3 dose of oral azacitadine. Most patients (89.4%) had previously received treatment for MDS, which included but was not limited to, erythropoiesis-stimulating agents, luspatercept (Reblozyl), lenalidomide (Revlimid), and imetelstat.

Garcia-Manero G, Yee K, Hernandez F, et al. Preliminary safety and efficacy of oral azacitidine (Oral-AZA) in patients (pts) with low-/Intermediate (Int)-risk myelodysplastic syndromes (MDS): Phase 2 results from the ASTREON trial. J Clin Oncol. 2024;42(suppl 16):6509. doi:10.1200/JCO.2024.42.16_suppl.6509

Articles

The ASTREON trial evaluated the safety and efficacy of oral azacitidine in patients with lower- to intermediate-risk myelodysplastic syndrome (MDS). The study found that the safety profile of oral azacitidine at 200 mg and 300 mg doses was consistent with previous trials. Adverse effects were similar across both doses, with hematologic and gastrointestinal issues being the most common. No patients achieved complete remission, but some showed hematologic improvement. The trial aimed to determine the optimal dose for phase 3 studies.

Treatment with a decreased dosing schedule of oral azacitidine was consistent with what has been previously known about the agent in intermediate-risk myelodysplastic syndrome.

Decreased Azacitadine Dosing Shows Consistent Safety in Lower- and Intermediate-Risk MDS

Abiraterone acetate (Zytiga) plus prednisone (AAP) and apalutamide (Erleada) administered after radical prostatectomy provided an oncologic outcomes benefit and did not lead to health-related quality of life (HRQoL) differences compared with bicalutamide (Casodex) in patients with prostate cancer. HRQoL findings from the phase 2 FORMULA-509 trial (NCT03141671) were presented during the 

2024 ASCO Genitourinary Cancers Symposium

Researchers provided validated questionnaires to patients at baseline, at the end of treatment, and 1 year after completing treatment. Questionnaires completed by patients included The Expanded Prostate Cancer Index Composite (EPIC-26), PROMIS Fatigue, and Saint Louis University Mental Status Exam (SLUMS), measuring hormone function, fatigue, and cognitive impairment.

EPIC-26 was measured based on a score from 0 to 100, with 100 as the highest function possible. PROMIS Fatigue was measured using a standardized T score, with higher scores indicating greater fatigue. SLUMS was measured based on a score from 0 to 30: 27 to 30 indicated normal scores, 21 to 26 meant mild neurocognitive disorder, and 20 or less meant a patient had dementia. A t-test was used to compare scores among each treatment arm. Furthermore, established thresholds for clinically meaningful differences were used to interpret the results (4 to 6 for EPIC-26 hormonal domain and 5 to 10 for PROMIS Fatigue).

“It is critical that we understand the impact of this more intensified ADT regimen and patient-reported health-related quality of life, as patient experience and perception can differ from physician assessment,” lead study author Karen Hoffman, MD, MHSc, MPH, FASTRO, of The University of Texas MD Anderson Cancer Center, said during the presentation.

“In the FORMULA-509 trial, health-related quality of life was assessed with validated questionnaires that were administered at baseline, at the end of treatment, and one year after completion of treatment,” she said.

Patients (n=345) were randomized 1:1 to bicalutamide (n=172) and AAP/apalutamide (n=173) and were evaluated using the 3 types of questionnaires. For EPIC-26, the completion rates were 96%, 80%, and 70% at baseline, end of treatment, and 1 year after completing treatment, respectively. The completion rates for PROMIS Fatigue were 95%, 79%, and 67%; and 96%, 80%, and 70% for SLUMS.

Both arms—from baseline to end of treatment—demonstrated meaningful improvements, specifically with declines in the EPIC-26 hormonal domain (median change -15 bicalutamide; -15 AAP/apalutamide) and an increase in PROMIS Fatigue (median change 6 bicalutamide; 7.4 AAP/apalutamide).

Patient-reported HRQoL from the end of treatment to 1 year after treatment improved to near baseline for EPIC-26 hormonal function. For EPIC-26 hormonal function, the median scores for the bicalutamide arm were 95 at baseline (range 35.0-100.0), 75 at the end of treatment (range 25.0-100.0), and 90 at 1-year follow-up (range 40.0-100.0).

In the AAP/apalutamide arm, the median hormonal ranges were 95.0 (range 50.0-100.0), 75.0 (range 25.0-100.0), and 90 (range 30.0-100.0) for baseline, end of treatment, and 1-year follow-up, respectively. P-values were 0.46 at baseline, 0.40 at the end of treatment, and 0.75 at 1-year follow-up, indicating no significant difference.

“With subsequent improvement towards baseline at one year, there was no difference in patient-reported hormonal function between the treatment arms at end of treatment, and one year after completion of treatment,” said Hoffman.

Similar to hormonal function, there was no difference in patient-reported fatigue, Hoffman said.

Median scores for PROMIS Fatigue in the bicalutamide arm were 43.1 at baseline (range 33.7-75.8), 48.6 at the end of treatment (range 33.7-75.8), and 46.0 at 1-year follow-up (range 33.7-75.8). In the AAP/apalutamide arm, the median scores were 43.1 at baseline (range 33.7-69.0), 51.0 at the end of treatment (range 33.7-75.8), and 46.0 at 1-year follow-up (range 33.7-75.8). P-values were 0.78 at baseline, 0.18 at the end of treatment, and 0.95 at 1-year follow-up.

The median scores for SLUMS were 27 in both the bicalutamide (range 16.0-30.0) and AAP/apalutamide (range 17.0-30.0) arms, 28 for both arms at the end of treatment (range 13.0-30.0; 17.0-30.0, respectively), and 27 in both arms at 1-year follow-up (range 14.0-30.0; 21.0-30.0). P-values were 0.22 at baseline, 0.41 at the end of treatment, and 0.76 at 1-year follow-up.

“Given these favorable patient-reported health-related quality of life outcomes, 6 months of intensified ADT with next-generation anti-androgens is an attractive treatment alternative to long-duration ADT for patients with rising PSA and unfavorable features after prostatectomy,” Hoffman concluded.

FORMULA-509 is a randomized, phase 2 study evaluating the safety and effectiveness of 2 newer anti-hormonal drugs, abiraterone acetate and apalutamide with luteinizing hormone-releasing hormone agonist, a standard form of ADT.

All patients in the study had histologically confirmed prostate cancer, had a PSA ≥ 0.1 after receiving radical prostatectomy, and had at least 1 unfavorable risk factor, including—but not limited to—a Gleason score between 8 and 10, a PSA > 0.5, pathologically positive lymph nodes, negative margins, and/or local or regional recurrence on imaging.

The trial included two experimental arms: GnRH plus bicalutamide and GnRH plus abiraterone with apalutamide and prednisone.

Hoffman K, Nguyen P, Rathkopf D, et al. Patient-reported health-related quality of life (HRQoL) in the randomized FORMULA-509 trial of salvage radiotherapy and the 6 months of GnRH agonist with either bicalutamide or abiraterone acetate plus prednisone (AAP) and apalutamide (Apa) after radical prostatectomy (RP). 

Randomized Phase II Study of Salvage XRT + ADT +/- Abiraterone and Apalutamide for Rising PSA after RP (FORMULA-509). ClinicalTrials.gov. Accessed January 25, 2024. https://clinicaltrials.gov/study/NCT03141671

Abiraterone acetate/prednisone/apalutamide after radical prostatectomy did not lead to quality of life differences vs bicalutamide in prostate cancer. 

Abiraterone Acetate/Prednisone/Apalutamide Maintains HRQOL Outcomes in Prostate Cancer

 fusion–positive gastrointestinal cancers who received larotrectinib (Vitrakvi) experienced long-lasting responses, encouraging survival, and a favorable safety profile, according to updated data from the phase 2 NAVIGATE basket trial (NCT02576431) presented during the 

. Findings included the overall response rate (ORR) assessed by independent review committee (IRC) RECIST v1.1.

“Larotrectinib is the first-in-class, highly selective, central nervous system-active TRK inhibitor approved for tumor-agnostic use in adult and pediatric patients with TRK fusion cancer; approval was based on tumor response and durable efficacy,” the study authors wrote in the poster presentation.

At the cutoff date of July 20, 2023, 43 patients were IRC-eligible; the ORR was 28% (95% CI, 15%-44%). In particular, there were 3 complete responses (CR; 7%), 9 partial responses (PR; 21%), 19 patients with stable disease (SD; 44%), 5 with progressive disease (PD; 12%), and 7 not evaluable (16%). At 24 weeks, the disease control rate was 47% in all patients (95% CI, 31%-62%).

In this patient population, the median time to response was 1.8 months (range, 1.7-11.1). The median duration of response (DoR), progression-free survival (PFS), and overall survival (OS) were 27.3 months (95% CI, 5.6-not estimable [NE]), 6.1 months (95% CI, 4.8-9.2), and 12.5 months (95% CI, 6.8-29.4), respectively.

Among the 25 IRC-eligible patients with colorectal cancer, the ORR was 44% (95% CI, 24%-63%): 3 CR (12%), 8 PR (32%), 11 SD (44%), 1 PD (4%), and 2 not evaluable (8%). The 24-week disease control rate was 56% in these patients (95% CI, 35%-76%).

The median DoR, PFS, and OS for all IRC-eligible pts with CRC were 27.3 months (95% CI, 5.6-NE), 7.4 months (95% CI, 5.5-NE), and 29.4 months (95% CI, 6.8-NE), respectively. The duration of treatment ranged from 0 to 56 or more months.

“At data cutoff, 28 (64%) [total] patients had progressed on treatment, with 8 (18%) continuing treatment post-progression per investigator assessment,” the authors wrote.

Forty-four patients were included in the analysis; next-generation sequencing determined that all patients included had 

 gene fusions. The median age was 67.0 years (range 32-90). Tumor types included colorectal (n=26), pancreatic (n=7), cholangiocarcinoma (n=4), gastric (n=3), and 1 each of appendiceal, duodenal, esophageal squamous cell carcinoma, and hepatocarcinoma. Among the patients with colorectal cancer, 15 were microsatellite instability-high (MSI-H), 9 were undetectable MSI-H (including microsatellite stable), and 2 had unknown microsatellite status.

Thirty-eight patients (86%) had received prior systemic therapy, 37 (84%) had prior surgery, and 4 (9%) had prior radiotherapy. The average number of prior systemic regimens was 2 (range 0-4); 6 patients (14%) had 0 prior lines of systemic therapy, 13 (30%) had 1 prior line, 16 (36%) had 2 prior lines, and 9 (20%) had 3 or more prior lines. Of the best responses to prior systemic therapy, 1 patient (2%) had a CR, 2 (5%) had a PR, 11 (25%) had SD, and 10 (23%) had PD.

At the data cutoff, adverse events (AEs) occurred in ≥15% of all patients with TRK fusion GI cancers. Treatment-related adverse events (TRAEs) were “predominately grade 1 or 2,” the authors wrote.

Grade 3 or 4 TRAEs were reported in 7 (16%) patients, in which the 2 most common AEs were increased alanine aminotransferase and aspartate aminotransferase. Other AEs included nausea, vomiting, anemia, diarrhea, decreased neutrophils, decreased white blood cells, fatigue, weight decrease, dizziness, and constipation. None of the patients discontinued treatment due to TRAEs.

“These data support the wider adoption of next-generation sequencing panels that include 

gene fusions to identify patients with GI cancer who may benefit from treatment,” the study authors wrote.

Shen L, Andre T, Chung HC, et al. Updated efficacy and safety of larotrectinib (laro) in patients (pts) with TRK fusion gastrointestinal (GI) cancer. 

 2024;42(suppl 3):109. doi:10.1200/JCO.2024.42.3_suppl.109

Larotrectinib led to long-lasting responses, encouraging survival, and a favorable safety profile in TRK fusion-positive gastrointestinal cancers.

Larotrectinib Displays Efficacy, Tolerability in TRK Fusion+ Gastrointestinal Cancers

Treatment with asciminib (Scemblix) elicited greater efficacy and had a more tolerable safety profile compared with bosutinib (Bosulif) for patients with chronic myeloid leukemia in chronic phase (CML-CP) following treatment with 2 or more tyrosine kinase inhibitors (TKIs), according to data from the phase 3 ASCEMBL trial (NCT03106779) presented at the 2023 ASH Annual Meeting.

“Most patients with chronic phase CML on long-term TKI therapy do have the potential for long-term chronic health issues,” lead study author Michael Mauro, MD, leader of the Myeloproliferative Neoplasms Program and hematologist at Memorial Sloan Kettering Cancer Center, said in a presentation of the data. “And those with treatment failure of at least 2 prior TKIs face additional challenges, such as high frequency of resistance causing mutations as well as toxicity.”

“Now, results from the ASCEMBL trial demonstrated superior efficacy and favorable safety at 24 and 96 weeks with asciminib versus bosutinib in these patients with chronic phase CML, previously treated with at least 2 TKIs,” said Mauro.

The major molecular response (MMR) rate for asciminib (33.8%) at week 156 (end of study) continued to be higher than with bosutinib (10.5%). After adjusting for baseline, the difference for major cytogenic response was 23.2% (95% CI, 13.1%-33.2%; 2-sided 

.001). The BCL-ABL1 ≤1% rate at week 156 in patients without the major cytogenic response of 23.2% at baseline continued to be higher when treated with asciminib than bosutinib (43.0% vs 11.1%). 

In terms of progression-free survival (PFS) and overall survival (OS), the investigators found that the PFS rate at 3 years was 85.2% (95% CI, 76.8%-90.7%) with asciminib and was 84.0% 95% CI; 67.5%-92.6%) with bosutinib. The 5-year OS rate was 87.8% (95% CI, 78.7%-93.1%) with asciminib and was 89.7% (95% CI, 76.3%-95.7%) with bosutinib.

A total of 233 patients in the study with CML-CP following ≥2 prior TKIs, experiencing intolerance or lack of efficacy according to 2013 ELN recommendations were randomized 2:1 into the asciminib cohort (n = 156) or bosutinib cohort (n = 76). Patients either received 40 mg of asciminib twice daily or received 500 mg of bosutinib once daily.

The investigators noted that if patients receiving bosutinib did not meet the treatment criteria according to 2013 ELN recommendations, they could switch to asciminib and were analyzed separately. Patients who were intolerant to bosutinib and discontinued the treatment could not switch to asciminib.

Of the 28 patients who discontinued bosutinib because of lack of efficacy, 25 switched to asciminib. Almost every patient who switched (96%) had previously received a BCL-ABL1 >10% before switching. None of the switch patients achieved an MMR at or by week 48 after switching. At week 48, 24% of patients achieved BCL-ABL1 ≤10% and 8% achieved BCL-ABL1 ≤1%.

At the end of study treatment cutoff date, there were 77 (49.4%) and 8 (10.5%) patients who were still receiving asciminib and bosutinib, respectively. Patients who experienced beneficial activity after the end of the study, after investigator assessment, continued receiving the treatment posttrial. 

Common reasons for discontinuation of treatments were because of the lack of efficacy in 40 patients (25.5%) receiving asciminib and 28 patients (36.8%) receiving bosutinib.

Although asciminib had a longer median duration of exposure (156.0 [0.1-256.3] weeks) compared with bosutinib (30.5 [1.0-239.3] weeks) the safety profile and tolerability of asciminib demonstrated better results vs bosutinib, remaining consistent with prior analyses.

Two patients in the study discontinued treatments because of adverse events (AEs) following the week 96 cutoff. One patient who had received asciminib reported pregnancy and the other patient who had received bosutinib reported diarrhea. Rates of discontinuation were lower for asciminib (8.3%) vs bosutinib (27.6%).

The most common (≥10%) grade ≥3 AEs for asciminib vs bosutinib were thrombocytopenia (22.4% vs 9.2%), neutropenia (18.6% vs 14.5%), diarrhea (0% vs 10.5%), and increased alanine aminotransferase (0.6% vs 14.5%). Most of the AEs occurred within the first 6 months of treatment.

“During the survival follow-up, 6 additional deaths occurred with asciminib due to CML in 3 patients and hemorrhagic stroke, multiple organ dysfunction syndrome, and COVID-19 and 1 patient each. And 3 with bosutinib treatment, 1 due to CML, 1 respiratory distress, and 1 due to COVID-19,” Mauro reported.

The safety profile for ascliminib in patients who switched treatments remained consistent when compared with patients receiving ascliminib during the randomized period. The most frequent (≥10%) grade ≥3 AEs were neutropenia (32.0%) and thrombocytopenia (24.0%). Eight percent of switch patients experienced AEs and discontinued treatment.

Since the week 96 cutoff, exposure-adjusted incidence rates of arterial occlusive events (AOEs) with asciminib decreased from 3.0 to 2.2 per 100 patient years, and no new AOEs occurred with the respective drug, which emphasized that the risk of AOEs did not increase over time. No new mutations occurred for patients since the week 96 cutoff who discontinued treatment due to lack of efficacy or disease progression.

“By the end of study, newly emerging mutations did not change since week 96, occurring in 7.6% of patients with asciminib and 2.6% with bosutinib,” Mauro noted.

Mauro M, Minami Y, Hochhaus A, et al. Sustained efficacy and safety with asciminib after almost 4 years of median follow-up from Ascembl, a phase 3 study of ASC vs bosutinib in patients with chronic myeloid leukemia in chronic phase after ≥2 prior tyrosine kinase inhibitors: an end of study treatment update, including results from switch population. 

https://doi.org/10.1182/blood-2023-186854

Treatment with asciminib elicited greater efficacy and had a more tolerable safety profile compared with bosutinib for patients chronic myeloid leukemia in chronic phase following treatment with 2 or more TKIs.

Ashley Chan

Articles

Decreased Azacitadine Dosing Shows Consistent Safety in Lower- and Intermediate-Risk MDS

Abiraterone Acetate/Prednisone/Apalutamide Maintains HRQOL Outcomes in Prostate Cancer

Larotrectinib Displays Efficacy, Tolerability in TRK Fusion+ Gastrointestinal Cancers

Asciminib Elicits Safe and Durable Responses in Previously Treated CML