In real-world studies, time to treatment discontinuation (TTD) may be a viable end point to use in lieu of progression-free survival (PFS) to evaluate therapies in metastatic non-small cell lung cancer (mNSCLC), an analysis published in the Annals of Oncology revealed.1 The analysis was conducted, in part, by members of the Center for Drug Evaluation and Research and Oncology Center of Excellence at the US Food and Drug Administration (FDA). If validated in other studies, TTD could be used to help determine a therapy’s efficacy among mNSCLC patients in the postmarketing setting.

“The ideal way of evaluating the efficacy of a therapy would be to evaluate those patients’ radiographs, but there are many impediments to that [in the real-world],” Edward Garon, MD, told Cancer Therapy Advisor. He was not involved in the study. He is associate professor of hematology and oncology at the David Geffen School of Medicine at University of California, Los Angeles.

The problem, Dr Garon explained, is that one may not have access to all of the radiographic reports to determine disease progression, and even if one does, the scans themselves may not be accessible. In addition, unlike a traditional clinical trial, the timing of the radiographic assessments is not fixed in the real world. Some practitioners may order scans after 6 weeks of treatment and others after 3 months.

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Data on when a patient started and stopped a drug — that is, TTD — are fairly easy to capture, according to Dr Garon, because it’s documented in the patient’s record.

To determine whether TTD could be used as a surrogate for PFS in the real-world setting, study researchers reviewed 18 clinical trials that began after 2007 and were submitted to the FDA. The trials evaluated targeted therapies, immune checkpoint inhibitors, and chemotherapy in patients with mNSCLC.

TTD was compared with PFS and overall survival (OS) both for the entire population of patients and treatment subgroups. Subgroups included EGFR-mutation–positive patients treated with a tyrosine kinase inhibitor (TKI), EGFR wild-type patients treated with a TKI, ALK-positive patients treated with a TKI, patients treated with an immune checkpoint inhibitor, patients treated with chemotherapy doublet with maintenance, and patients treated with chemotherapy alone.

The retrospective analysis included 8947 patients and revealed that TTD was associated with PFS (r=0.87; 95% CI, 0.86-0.87). The weakest association occurred for chemotherapy alone (r=0.78; 95% CI, 0.77-0.79) and the strongest association for EGFR wild-type patients who received a TKI (r=0.98; 95% CI, 0.98-0.98). Dr Garon said it makes sense that TTD would be correlated with PFS because treatment discontinuation often happens when progression occurs.

Overall, a low proportion of patients (7.7%) had a TTD that was more than 3 months shorter than their PFS and a similarly low proportion (6%) had a TTD that was more than 3 months longer than their PFS. The median TTD was, in fact, longer than the median PFS for patients who were EGFR positive (13.4 months and 14.1 months, respectively) or ALK positive (11.4 months and 11.3 months, respectively), suggesting that patients who received targeted therapies tend to continue treatment beyond progression.

TTD weakly correlated with OS (r=0.68; 95% CI, 0.67-0.69), and this result, Dr Garon explained, could be a result of the fact that some of the therapies themselves haven’t been found to improve OS in trials. Furthermore, PFS had a similarly weak correlation with OS (r=0.65; 95% CI, 0.64-0.66).

While the findings are “not definitive,” they are still “helpful” in determining the utility of TTD as an end point, Dr Garon said. “It’s not the same as having a hard radiographic end point in a randomized controlled study and certainly not like overall survival either, but I think that the fact that, in the context of a study, the time to treatment discontinuation correlated [with PFS] is encouraging.”


  1. Blumenthal GM, Gong Y, Kehl K, et al. Analysis of time to treatment discontinuation of targeted therapy, immunotherapy, and chemotherapy in clinical trials of patients with non-small cell lung cancer
  2. . Ann Oncol. doi: 10.1093/annonc/mdz060