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Depth of response predicts OS, PFS for non-small cell lung cancer
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Assessment of depth of response adequately predicted OS and PFS for patients with metastatic non-small cell lung cancer treated with a targeted therapy or immunotherapy, according to study results.
“[Depth of response] may be a useful clinical endpoint to more efficiently evaluate activity of new drugs or assist in the early evaluation of new combination therapies to determine if there is the potential for increased benefit over existing single-agent therapies,” Caroline E. McCoach, MD, internist in the division of medical oncology at University of Colorado, and colleagues wrote.
Response Evaluation Criteria in Solid Tumors, or RECIST, is frequently used to categorize patient response; however, it does not specify the full spectrum of benefit patients might receive from specific therapies.
With increased use of targeted therapies and immunotherapies, more outcome measures to directly identify outcomes of therapy are needed. McCoach and colleagues sought to evaluate whether depth of tumor response — defined as the percent of maximal tumor reduction from baseline — provided a more granular view of response.
Researchers separately pooled and evaluated data from two randomized controlled clinical trials of patients who received an ALK inhibitor (n = 305; median age, 51 years; 43% men) and two trials in which patients received a PD-1 inhibitor (n = 355; median age, 61 years; 62% men).
Among the ALK inhibitor-treated group, 63% were never smokers and 94% had a ECOG performance status score of 0 or 1. Among the PD-1-treated group, 83% were current or former smokers and all had ECOG performance status score of 0 or 1.
Researchers grouped patient responses to therapy into depth of response quartiles based on reduction in tumor size: Q0 indicated no shrinkage, Q1 indicated 1% to 25% shrinkage, Q2 indicated 26% to 50% shrinkage, Q3 indicated 51% to 75% shrinkage, and Q4 indicated 76% to 100% shrinkage.
Researchers conducted a retrospective exploratory responder analysis to determine association between depth of response and OS or PFS via HRs developed by the Cox proportional hazards model.
In the targeted therapy analysis, 12 patients were in Q0, 39 patients were in Q1, 70 patients were in Q2, 144 patients were in Q3 and 40 patients were in Q4.
The HRs for depth of response compared with PFS or OS were 0.19 vs. 0.94 for Q1,0.11 vs. 0.56 for Q2, 0.05 vs. 0.28 for Q3, and 0.03 vs. 0.05 for Q4.
Greater depth of response was associated with a significant improvement in OS for patients in Q3 (adjusted HR = 0.28; 95% CI, 0.11-0.73) and Q4 (HR = 0.05; 95% CI, 0.01-0.28).
In the anti-PD-1 analysis, 168 patients were in Q0, 70 patients were in Q1, 44 patients were in Q2, 45 patients were in Q3 and 28 patients were in Q4.
The HRs for depth of response compared with PFS or OS were 0.3 vs. 0.52 for Q1, 0.22 vs. 0.47 for Q2, 0.09 vs. 0.07 for Q3, and 0.07 vs. 0.14 for Q4.
Adjusted analysis showed a relationship between OS and depth of response for all quartiles. Q1 had similar survival curves as Q2, as did Q3 with Q4, which indicated patients with more than 50% tumor burden made up one response group and patients with less than 50% tumor burden served as an alternate group.
Limitations of the study included the use of one type of targeted therapy and potentially unbalanced prognostic values between quartiles.
Although the study points out different associations between targeted therapies and immunotherapies for depth of response, it did not establish a strong association at the clinical trial level needed to establish a surrogate endpoint, Everardo D. Saad, MD, from the International Drug Development Institute in Louvain-la-Neuve, Belgium, and Marc Buyse, ScD, chief scientific officer at the International Drug Development Institute in San Francisco, wrote in a related editorial.
“The current work ... does not address this issue, precluding any tentative conclusions about the worth of [depth of response] as a novel endpoint for clinical trials,” they wrote. “Despite this limitation ... this work is a step in the search for other metrics, such as [depth of response], that can potentially circumvent limitations from the use of RECIST responses as endpoints in clinical trials.” – by Melinda Stevens
Disclosures: The study authors report no relevant financial disclosures. Buyse reports employment with and stock ownership in IDDI, Belgium. Saad reports no relevant financial disclosures.
Perspective
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In this analysis, McCoach and colleagues demonstrate that the depth of overall response with ALK tyrosine kinase inhibitors and PD-1 inhibitors in metastatic NSCLC correlates with improvement in PFS and OS, implying a role for depth of overall response as an alternate and earlier readout of drug efficacy in clinical trials. However, in this analysis — unlike with ALK TKIs — the increase of survival did not demonstrate a stepped increase with increasing depth of overall response among patients treated with PD-1 inhibitors.
This observation raises the possibility that mechanism of drug action and the availability of a biomarker for patient selection are likely to influence the value of depth of overall response as an endpoint. Nevertheless, it is possible that this discrepancy can be explained by limitations of the study itself, such as the post hoc nature of this analysis, as well as differences in subsequent treatment options available for patients and sample size between both groups.
Additionally, tumors with ALK rearrangements carry identical driver alterations and are, therefore, more likely to constitute a homogenous group from a standpoint of tumor biology and clinical and demographic factors. On the other hand, patients who receive PD-1 inhibitors constitute a highly heterogeneous group. The inaccuracy of RECIST criteria for identifying patients who benefit from PD-1 inhibitors also is likely to explain this discrepancy.
Finally, these results clearly indicate increased survival benefit among patients demonstrating greater than 50% depth of overall response, irrespective of the choice of therapy. One can speculate that, with deeper responses, a substantially lower number of cancer cells serve as a substrate for natural selection for the emergence of treatment resistance, resulting in durable responses and better outcomes.
These findings are hypothesis generating and additional studies are required to determine if these observations can be therapeutically exploited. If reproducible in the prospective setting, these findings could pave way for the integration of surgery, radiation or other ablative techniques into the management of patients with metastatic NSCLC for inducing deeper responses, with the objective of improving survival.
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