ASCO 2023: From Our Partners

Timely Initiation of Targeted Therapy for NSCLC Improves Outcomes, Study Finds

A retrospective study of patients with advanced non–small cell lung cancer (NSCLC) with actionable driver oncogenes found that patients treated with targeted therapy in the first line had better outcomes than those who received nontargeted therapy. The results, presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, also suggest that timely switching to targeted therapy upon receiving biomarker test results vs upon disease progression produced comparable outcomes to first-line targeted therapy.

Patients with advanced NSCLC have been shown to benefit from biomarker-driven targeted therapy vs chemotherapy in real-world clinical settings, the authors noted, but patients must first be tested for actionable driver oncogenes before initiating targeted therapy.

In recent real-world research, patients who had actionable driver oncogenes but started nontargeted therapy prior to receiving biomarker testing results showed suboptimal outcomes, explained study author Thomas Stricker, MD, of Tennessee Oncology in Nashville, while presenting the findings at the ASCO annual meeting.

The new study used electronic health record–derived deidentified patient data from the nationwide Flatiron Health database. Patients 18 years or older who received a diagnosis of advanced NSCLC between January 2015 and October 2022, had actionable driver oncogenes identified via biomarker testing within 90 days of diagnosis, and who received first-line NSCLC therapy were included in the study. Actionable driver oncogenes included ALK, BRAF, EGFR, RET, MET, ROS-1, or NTRK alterations.

A total of 5156 patients were stratified into groups based on treatments received, with cohort 1 receiving frontline targeted therapy within 42 days of biomarker test results; cohort 2 starting first-line nontargeted therapy prior to or following testing but switching to targeted therapy within 42 days of biomarker test results; and cohort 3 starting nontargeted therapy as frontline treatment and not switching to targeted therapy within 42 days.

Of the overall patient population, 79% were treated in the community setting and 56% underwent next-generation sequencing. The researchers followed up until November 2022 or patient death, and multivariate Cox regression analyses were used to evaluate real-world progression-free survival (PFS) and overall survival (OS) among the cohorts.

In cohorts 1 and 2, the most common actionable driver oncogenes were EGFR and ALK. In cohort 3, the most common were EGFR and BRAF.
Outcomes were similar between cohorts 1 and 2, with a median PFS of 10 months in cohort 1 and 13 months in cohort 2. Median OS was 28 months in cohort 1 and 26 months in cohort 2. Cohort 3 showed significantly worse outcomes vs cohort 1, with a median PFS of 6 months and median OS of 21 months.

“The importance of timely treatment decisions based on actionable driver oncogene detection in lieu of treatment switch at progression was demonstrated by the comparable outcomes observed between patients who received up-front targeted therapy and switched within 42 days of biomarker test results,” Stricker said.

Overall, the findings reiterate the importance of testing patients who receive a diagnosis of advanced NSCLC for actionable driver oncogenes and of initiating targeted therapy quickly when targetable biomarkers are found.

“I think opportunities remain to improve the utilization of NGS to identify all actionable driver oncogenes up front to inform appropriate first-line targeted therapy,” Stricker said. “I think there’s no doubt that starting targeted therapy initially as a first-line therapy in appropriate patients is the right way to go, but our data does suggest that if the results come back later than expected, you may not have missed the boat and can switch and still have good outcomes.”

Reference
Stricker T, Jain N, Yu E, et al. Clinical value of timely targeted therapy (TT) for patients with advanced non-small cell lung cancer (aNSCLC) with actionable driver oncogenes (ADO). J Clin Oncol. 2023;41(suppl 16):abstract 6507. doi:10.1200/JCO.2023.41.16_suppl.6507

SPOTLIGHT: Judy Wang, MD, Discusses the Potential of CLN-619 for the Treatment of Solid Tumors

Judy Wang, MD, medical oncologist, clinical trials investigator, and associate director of drug development at Sarah Cannon Research Institute at Florida Cancer Specialists and Research Institute, discussed with Evidence-Based Oncology (EBO) the mechanism of action and rationale for studying CLN-619, an anti-MICA/B antibody, with and without pembrolizumab in patients with solid tumors. CLN-619 is being developed by Cullinan Oncology, a biopharmaceutical company focused on modality-agnostic targeted oncology therapies.

Findings from a phase 1 dose escalation study (NCT05117476),¹ which showed tolerability at a range of doses, were presented at the recent annual meeting of the American Society of Clinical Oncology. This interview is edited lightly for clarification.

EBO: Can you discuss the mechanism of action of CLN-619, particularly the activation of receptors on both the innate and adaptive immune system? Why is this important?

Wang: The study of CLN-619 was a phase 1 study; [CLN-619 is a] fully human monoclonal antibody to what we call stress-induced ligands, MICA and MICB. In normal settings, MICA and MICB are receptors that are present on the surface of stressed cells. [Stress can be caused] not only [by] infections, but also cancer. And they act as a means of addressing cells that need to be purposefully removed, proteolytically destroyed through our innate cellular immunity.

However, tumor cells have a way of eliminating presentation of MICA and MICB by proteolytically cleaving them with proteozymes that are present within the tumor microenvironment. And when MICA and MICB are not present on the surface of tumor cells, they’re not able to engage an activating receptor called NKG2D, which is a means of activating not only NK, or natural killer cells, but [also] cytotoxic T cells that are a big part of our cellular immunity. And when they’re not able to bind, it acts as a means of immune evasion. Therefore, these tumors are allowed to propagate and progress in the face of an active immune system.

So, what CLN-619 strives to do is to restore that MICA and MICB expression, by not only anchoring it and binding to the surface of these tumor cells, but helping to engage receptor binding to NKG2D, so that we can have both cellular innate and adaptive immune killing through our NK and T cells. As you can imagine, both of these prospects of immune activation—both innate and adaptive immunity—are important in the sense that they are complementary aspects of our immune system, but particularly adaptive immune activation can lead to, for example, memory cells that may be able to provide prolonged and lasting immunity, following an active treatment with these agents. 

Reference
Wang JS, Gutierrez M, Rasco DW, et al. A phase 1 dose-escalation study to investigate the safety, efficacy, pharmacokinetics, and pharmacodynamic activity of cln-619 (anti-MICA/B antibody) alone and in combination with pembrolizumab in patients with advanced solid tumors. J Clin Oncol. 2023;41(suppl 16):abstr 2532. doi:10.1200/JCO.2023.41.16_suppl.2532

Dose Rounding Can Reduce Drug Waste Costs Associated With Reference, Biosimilar Bevacizumab

Dose rounding of biological antineoplastic agents, such as reference bevacizumab (Avastin) and its FDA-approved biosimilars (n = 4), was shown to offset the impact of drug waste and reduce the total cost of care for value-based programs, according to a recent analysis of Oncology Care Model (OCM) practices by authors from The US Oncology Network. The results were presented at the 2023 American Society of Clinical Oncology Annual Meeting.

The OCM was a 6-year long Medicare value-based care program that offered practices rewards for decreasing total cost of care (TCOC) compared with a benchmark price without impacting the ability to maintain high-quality cancer care. Drug waste from partially used single-dose vials of expensive biologics is considered to be a leading contributor to TCOC expenditures for payers.

Dose rounding (DR), whereby doses of anticancer treatments are rounded up or down between 5% and 10% of the ordered dose in line with recommendations from the Hematology/Oncology Pharmacy Association and endorsed by the National Comprehensive Cancer Network, is a common approach to mitigate the impact of drug waste.

In 2018, many OCM practices adopted a DR program for biologic agents as a strategy to reduce drug waste and TCOC; however, whether the strategy worked remained to be seen. The investigators assessed claims data for 14 practices in The US Oncology Network participating in the OCM. The data included drug administration data for reference bevacizumab and bevacizumab biosimilars (Vegzelma, Mvasi, Zirabev, and Alymsys) to evaluate drug waste, total dose, TCOC, DR, and the financial impact of drug waste reduction on TCOC from 2017 to 2021.

Prior to implementing DR, an average 5.3% (range, 4.6%-5.5%) of the total dose of bevacizumab products was wasted, with approximately 25% of bevacizumab administrations having wasted more than 10% of the total dose.

A DR initiative led to a reduction of waste for 30% of the total number of bevacizumab administration across all 14 practices. As a result of DR, bevacizumab drug waste decreased by 55% to an average 2.5% (range, –2.3% to 2.7%) of the total dose in 2021. The decreased waste resulted in TCOC reduction of approximately $100 per member episode per month (0.97% of TCOC) for episodes with a bevacizumab administration.

The highest waste reduction was seen in situations where the patient was receiving bevacizumab as a treatment for gastrointestinal cancer (colon, rectal, anal, gastroesophageal, or pancreatic) compared with other cancer types (eg, lung, brain, ovarian). Additionally, there was approximately a 50% reduction in cases where bevacizumab drug waste was more than 10% of the total dose.

The authors noted that a similar DR approach could be adopted for other high-cost originator and biosimilar biologic agents where drug waste results from partial use of single-dose vials.

Reference
Indurlal P, Alam N, Garey JS, Wilfong LS. Dose rounding bevacizumab and its biosimilars to reduce drug waste in the oncology care model in a community oncology network. J Clin Oncol. 2023;41(suppl 16):1529. doi:10.1200/JCO.2023.41.16_suppl.1529