ASCO 2024 From Our Partners

Selected Abstracts Highlight Research by FCS Scientists

Sixteen investigators from Florida Cancer Specialists & Research Institute (FCS) were first authors or coauthors on 37 abstracts presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting¹; the findings presented ranged from phase 1 to phase 3 trial results to post hoc analyses of disparities seen in larger studies.

Promising Phase 1 Results for Oral Chimeric ER Degrader in Metastatic Breast Cancer
Manish R. Patel, MD, director of drug development at FCS, was the first author on an abstract featuring preliminary data from a phase 1 study

Manish R. Patel, MD | Image: Florida Cancer Specialists & Research Institute

(NCT05654532) of AC699, described as “an orally bioavailable chimeric estrogen receptor degrader,” in patients who had advanced or metastatic breast cancer.² FCS collaborated with Sarah Cannon Research Institute in Nashville, Tennessee, which authors said seeks to find a therapy that could affect up to 200,000 patients diagnosed each year with estrogen receptor (ER)–positive, HER2-negative breast cancer.³

AC699 seeks to improve upon the mechanism of selective ER degraders (SERDs), which have produced some improvements in progression-free survival among these patients. The drug works by binding and degrading ERα by bringing it into close proximity with an E3 ligase. According to the investigators, this approach “may result in greater specificity and more complete target blockade compared [with] SERDs.”

Patel reported initial results from the ongoing first-in-human dose-escalation study using a 3 + 3 design. Patients must have received at least 2 prior lines of endocrine treatment, or 1 prior line and a CDK4/6 inhibitor. AC699 was administered orally in 28-day cycles, and tumor responses were assessed every 2 cycles. In addition, the relationship between ESR1 mutational status and the drug’s effectiveness against the tumor was evaluated. Results for 22 patients in 3 cohorts showed the following:

• Patients were divided into cohorts receiving doses of 100 mg, 200 mg, or 300 mg.
• Median age was 61 years, and the median number of lines of prior therapy was 5 (range, 2-10). All patients had received a CDK4/6 inhibitor, 91% had taken an aromatase inhibitor, 82% had fulvestrant, 23% had a novel oral SERD or covalent antagonist, and 14% had received an ER chimeric degrader.
• Eighteen patients had measurable disease and 4 had bone lesions only.
  Patients receiving AC699 had no dose-limiting toxicities, dose reductions, or discontinuations for treatment-related adverse events (AEs), and the maximum tolerated dose was not reached.
• Common treatment-emergent AEs were fatigue (23%), dehydration (18%), and nausea (18%); all were grade 1 or 2.
• Among 12 evaluable patients at data cutoff, 4 (33%) had a partial response; 3 were confirmed. The clinical benefit rate (CBR), which includes patients with stable disease at 24 weeks or more, was 42% (5 of 12).
• Among evaluable patients with a confirmed ESR1 mutation, the overall response rate was 67% (4 of 6), the CBR was 83% (5 of 6), and the median time on treatment was 168 days (range, 56-336).

Investigators concluded that the results showed “promising safety, tolerability, and antitumor activity, at doses up to 300 mg orally once daily.” Enrollment is under way for a phase 2 study of AC699.

Oral Utidelone Shows Antitumor Activity in Phase 1 Study
Judy Wang, MD, associate director of drug development, was the lead author for an ASCO 2024 abstract featuring phase 1 results for utidelone, a novel oral microtubule inhibitor now being given as a capsule (Patel was a coauthor). Utidelone injection is approved in China to treat advanced breast cancer in combination with capecitabine.⁴

Judy Wang, MD | Image: Florida Cancer Specialists & Research Institute

This dose-escalation study (NCT05681000) is the first study of the capsule in humans in the US. Eligible patients are at least 18 years of age and have an ECOG performance status of 0 or 1, life expectancy of at least 12 weeks, adequate organ functions, and a pathologic confirmed advanced solid tumor that is refractory to prior standard therapies.

The study seeks to determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives include efficacy, pharmacokinetic profile, and a phase 2 dose recommendation. Patients in the study receive oral utidelone as monotherapy. The starting dose is 25 mg/m2/d/5-day, with escalation to 50, 75, or 100 mg/m2/d/5-day; 70 mg/m2/d/7 day, and 85 mg/m2/d/7-day for a 21-day cycle.

Results as of data cutoff on January 22, 2024, are as follows:

• Ten patients with advanced solid tumors enrolled with a median age of 62.5 years (range, 52.0-81.0); 5 women and 5 men.
• All had received prior treatments in advanced settings. The cohort receiving 100 mg/m2/d/5-day is under evaluation.
• The first 8 patients were evaluated for efficacy, with 1 complete response (CR), 5 with stable disease, and 2 with progressive disease.
• Patients had a variety of solid tumor cancer types.
• Five patients are still on treatment.
• The patient who experienced CR, with ovarian cancer, was enrolled to the lowest dose cohort and is still on treatment. She is heavily pretreated with multiple prior lines including chemotherapies.
• Most treatment-emergent AEs were grade 1 and 2 and manageable; they included diarrhea, nausea, and alopecia. Two grade 3 incidents of diarrhea were downgraded to grade 1 with dose reductions.
• No DLTs or MTDs have been reached.
  

“This study has demonstrated encouraging antitumor activity with good tolerance and manageable safety profile of [oral utidelone] in patients with heavily pretreated advanced solid tumors,” the authors wrote.

Biostar Pharmaceuticals is sponsoring the trial.

No Differences in Outcomes for Black Patients in Phase 3 OUTBACK Trial
Black patients were not found to have “discernible disparities” from White patients when overall survival (OS) outcomes were compared among patients in an international trial studying primary treatment for locally advanced cervical cancer.

Bradley Monk, MD | Image: Florida Cancer Specialists & Research Institute

Bradley Monk, MD, who joined FCS at the start of the year as director of late-phase trials, was a coauthor on a poster at ASCO 2024 featuring an evaluation of racial disparities and survival outcomes in the phase 3 OUTBACK trial (NCT01414608, ANZGOG 0902, RTOG 1174, NRG 0274), an international multicenter study investigating adjuvant chemotherapy following definitive chemoradiation in locally advanced cervical cancer.⁵

For this study, the authors wrote, “We analyzed [whether] baseline characteristics were associated with survival outcome. More specifically, we determined whether race held prognostic significance relative to established clinical factors.”

Results did not show race to be a prognostic factor, although study authors said being in a clinical trial could have affected any gap between racial groups.

The analysis incorporated demographics, biomarkers, and participants’ self-ratings on the European Organisation for Research and Treatment of Cancer QLQ-C30, a validated quality-of-life assessment. Investigators explored relationships between baseline characteristics and survival outcomes. Black patients accounted for 13% of the OUTBACK study population. Most Black patients in the study lived in the US.

When examining the impact of race on survival outcomes in locally advanced cervical cancer, the investigators found “no evidence associations” with OS (HR, 1.2; 95% CI, 0.84-1.72; P = .32), or progression-free survival (HR, 1.29; 95% CI, 0.95-1.75; P = .10).

Multivariable analysis identified several independent prognostic factors for OS, including the following:

• performance status (HR, 1.43; 95% CI, 1.04-1.95; P = .03);
• FIGO stage, based on criteria from the International Federation of Gynecology and Obstetrics (HR, 2.02; 95% CI, 1.48-2.75; P < .01);
• nodal involvement (HR, 1.59; 95% CI, 1.18-2.14; P < .01), and
• elevated white blood cell count (HR, 1.68; 95% CI, 1.21-2.33; P < .01).

Factors including social function, financial difficulties, and estimated glomerular filtration rate showed significance in the univariable analysis for OS but were not shown to be significant in the multivariable analysis, investigators reported.

“No discernible disparities in survival outcomes were observed between Black or African American participants and other racial groups undergoing primary treatment for locally advanced cervix cancer,” the authors wrote.

“The primary prognostic determinants for this disease continue to be cancer staging and clinical performance status.”

References
1. Sixteen researchers from Florida Cancer Specialists & Research Institute share cancer care discoveries at 2024 ASCO Annual Meeting. News release. Florida Cancer Specialists & Research Institute. May 29, 2024. Accessed June 26, 2024. https://flcancer.com/articles/asco2024/
2. Patel MR, Layman RM, Danso MA, et al. Preliminary results from a phase 1 study of AC699, an orally bioavailable chimeric estrogen receptor degrader, in patients with advanced or metastatic breast cancer. J Clin Oncol. 2024;42(suppl 16):3074. doi:10.1200/JCO.2024.42.16_suppl.3074
3. Wang JS, Van Tine BA, Patel MR, et al. A novel oral microtubule inhibitor utidelone capsule (UTD2): a phase 1 clinical study to assess the tolerability, safety, and efficacy in advanced solid tumors. J Clin Oncol. 2024;42(suppl 16):e15014. doi:10.1200/JCO.2024.42.16_suppl.e15014
4. Lee YC, Castellano T, Myers TKN. Racial disparities and survival outcome of patients with locally advanced cervix cancer in the international randomised phase 3 OUTBACK trial (ANZGOG 0902, RTOG 1174, NRG 0274). J Clin Oncol. 2024;42(suppl 16):1594. https://ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.1594

At 5 Years, “Unprecedented” PFS Outcomes for Lorlatinib in ALK+ Advanced NSCLC

Median progression-free survival (PFS) had not been reached at 5 years for patients treated with lorlatinib, according to a post hoc analysis of the CROWN study (NCT03052608),¹ marking the longest PFS reported in a study of advanced non–small cell lung cancer (NSCLC).

Todd M. Bauer, MD | Image: Tennessee Oncology

Over the length of the study period, lorlatinib offered an 88% PFS advantage over crizotinib for treatment-naive patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-positive NSCLC, as well as a 94% advantage in preventing brain metastases. The senior author of the analysis, reported at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, is Todd M. Bauer, MD, of Tennessee Oncology.

CROWN was a global phase 3 randomized study to evaluate the safety and efficacy of lorlatinib (Lorbrena; Pfizer Inc), a brain-penetrant, third-generation ALK tyrosine kinase inhibitor. The trial demonstrated improved PFS and intracranial (IC) activity compared with crizotinib (Xalkori: Pfizer) in the treatment-naive population with advanced ALK+ NSCLC.
At ASCO 2024, investigators reported long-term efficacy and safety outcomes after 5 years of follow-up for 296 patients randomized 1:1 receive 100 mg of lorlatinib once daily or (n = 149) or 250 mg of crizotinib twice daily (n = 147).

Results showed the following:

As of October 31, 2023, 74 of 149 patients taking lorlatinib (50%) vs 7 of 142 patients taking crizotinib (5%) were still receiving their respective treatments.
Lorlatinib had a median duration of follow-up for PFS (95% CI) of 60.2 months (57.4-61.6), while crizotinib had a median PFS of 55.1 months (36.8-62.5).

Median PFS (95% CI) was not reached (NR; 64.3-NR) with lorlatinib; median PFS was 9.1 months (7.4-10.9) with crizotinib. The hazard ratio (HR) was 0.19 (95% CI, 0.13-0.27) with a 5-year PFS of 60% for lorlatinib and 8% for crizotinib.

Median time to IC progression (95% CI) was NR (NR-NR) with lorlatinib and 16.4 months (12.7-21.9) with crizotinib, for an HR of 0.06 (95% CI, 0.03-0.12).

Adverse events. Patients receiving lorlatinib were more likely to experience grade 3/4 adverse events (AEs); these occurred in 77% of patients receiving the study drug compared with 57% taking crizotinib. Treatment-related AEs led to treatment discontinuation in 5% and 6% of patients in the lorlatinib and crizotinib arms, respectively. Investigators stated that new ALK mutations were not detected in circulating tumor DNA collected at the end of lorlatinib treatment.

“After 5 years of follow up, the median PFS in the lorlatinib arm has yet to be reached, corresponding to the longest PFS ever reported in advanced NSCLC,” the investigators concluded. “Coupled with prolonged IC efficacy and absence of new safety signals, these results indicate an unprecedented improvement in outcomes for patients with advanced ALK+ NSCLC.”

Reference
Solomon BJ, Liu G, Felip E, et al. Lorlatinib vs crizotinib in treatment-naive patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. J Clin Oncol. 2024;42(suppl 17): Abstract LBA8503.

Remote Pharmacy Model Relieves Burdens on Community Oncologists

A poster presented during the 2024 American Society of Clinical Oncology Annual Meeting showed how a remote pharmacy model could identify opportunities to modify treatment choices based on clinical criteria, waste reduction, or cost.

Andrea Roman, PharmD, BCOP | Image: Andrea Roman

Andrea Roman, PharmD, BCOP, senior clinical pharmacist for McKesson and The US Oncology Network, presented results from the yearlong implementation of the model, which produced benefits while also eliminating burdens for physicians in local clinics.

For this initiative, oncology-trained pharmacists remotely reviewed therapeutic regimens across 12 community oncology practices in The US Oncology Network. Pharmacists identified opportunities for changes, which were then presented to the treatment team and made based on practice-approved policies.

Between January 1 and December 31, 2023, a total of 27,938 reviews were documented for 19,962 patients. These included 14,572 (73%) that called for a modification by the pharmacist; 3005 (21%) were clinically significant. Common interventions were as follows:

• changes to anticancer drug doses (1155, 38%),
• modifications to supportive care (742, 25%), and
• recommendations for additional monitoring (426, 14%).

Investigators reported that across 12 practices, 63 drug-related workflow policies were implemented, allowing pharmacists to autosubstitute products, adjust doses, and order laboratory tests without prior authorization—saving 600 hours of physician time. The pharmacists generated $9.3 million in savings based on these medication margins and $4.3 million in savings in total cost of care.

“The cost of the pharmacists during this period was $1.4M, equating to a 560% return on investment compared to margin improvement,” the investigators wrote.

“As invaluable members of the care team, pharmacists identified opportunities to significantly enhance clinical care by focusing on medication safety, dosing, and regimen optimization, while demonstrating a tremendous financial impact on small-scale budgets,” the investigators said. “Oncology-trained pharmacists play a vital role in alleviating care burden of the clinical team by collaboratively developing practice-approved policies and reviewing clinical orders in a high-risk patient population.”

Change in Prompt Protocol Boosts Biomarker Documentation
An abstract at ASCO 2024 from authors at McKesson and The US Oncology Network found that use of a clinical decision support (CDS) tool could boost documentation of biomarkers in cancer care. According to the authors, having biomarker results available at the right time is a key factor in using precision medicine-based treatment options. However, poor documentation may limit the use of biomarker testing.²

Daniel Rubin, PharmD, BCOP | Image: McKesson

The authors, led by Daniel Rubin, PharmD, BCOP, state that an examination of CDS data showed that too many biomarker results are documented as “unknown,” which could be related to the availability of these results.
For this project, providers answered prompts related to the patient’s disease stage, treatment needs, and biomarker results. The prompts contained in the CDS were aligned with guidelines from the National Comprehensive Cancer Network. Changes were made to make it easier for providers to add documentation of biomarker results.

The abstract noted changes in 3 common areas: adjuvant non-small cell lung cancer (NSCLC), metastatic NSCLC (mNSCLC), and metastatic castrate resistant prostate cancer (mCPRC), where authors said, “some biomarkers are only needed after a patient has received prior docetaxel and hormone therapy, thus prompts were moved to that scenario.”

The changes to the CDS also added a prompt to document biomarker status for later therapies of the initial provider response was recorded as “unknown.” In an evaluation that covered 85,493 biomarkers, across all 3 disease areas, biomarker documentation increased pre- and post-implementation of this initiative. Increases from pre- and post-implementation were as follows:

• Adjuvant NSCLC, from 69% (1228/1791) to 78% (1751/2245)
• Metastatic NSCLC, from 59% (28,607/48,140) 79% (16,938/21,473)
• Metastatic CPRC, from 34% (2,945/8,627) 61% (1,949/3,217)

Increases were seen in documentation of all common biomarkers—ALK and EGFR in NSCLC and BRCA1/2, MSI, and MMR in mCPRC. According to the authors, “Based on these findings, similar changes are being implemented for other cancer types in the CDS tool.”

References
1. Roman A, Cho J, Jovani J, et al. Clinical impact and financial feasibility of remote oncology pharmacists’ roles in community oncology practices. J Clin Oncol. 2024;42(suppl 16). Abstract 1545. doi:10.1200/JCO.2024.42.16_suppl.1545
2. Rubin D, Handy V, Gilmore S, et al. Impact on biomarker documentation in community oncology by optimizing clinical decision support. J Clin Oncol. 2024;42(suppl 16): Abstract 11182. doi: 10.1200/JCO.2024.42.16_suppl.11182