Time on Therapy for at Least Three Months Correlates with Overall Survival in Metastatic Renal Cell Carcinoma

Abstract

With 15 drugs currently approved for the treatment of metastatic renal cell carcinoma (mRCC) and even more combination regimens with immunotherapy on the horizon, there remains a distinct lack of molecular biomarkers for therapeutic efficacy. Our study reports on real-world clinical outcomes of mRCC patients from a tertiary academic medical center treated with empirically selected standard-of-care therapy. We utilized the Stanford Renal Cell Carcinoma Database (RCCD) to report on various outcome measures, including overall survival (OS) and the median number of lines of targeted therapies received from the time of metastatic diagnosis. We found that most metastatic patients did not survive long enough to attempt even half of the available targeted therapies. We also noted that patients who failed to receive a clinical benefit within the first two lines of therapy could still go on to experience clinical benefit in later lines of therapy. The term, "clinical benefit" was assigned to a line of therapy if a patient remained on drug treatment for three months or longer. Moreover, patients with clinical benefit in at least one line of therapy experienced significantly longer OS compared to those who did not have clinical benefit in at least one line of therapy. Developing biomarkers that identify patients who will receive clinical benefit in individual lines of therapy is one potential strategy for achieving rational drug sequencing in mRCC.

Keywords: IMDC criteria; RCC; favorable-, poor-, and intermediate-risk prognosis RCC; immunotherapy; kidney cancer; metastatic renal cell carcinoma; systemic treatment; targeted kinase inhibitors; therapy sequencing.

Figure 1

Heatmaps clustered by sequential therapy benefit showing a lack of cross-resistance among targeted therapies in mRCC (stratified by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score). Individual patients could still derive a clinical benefit despite failure in a previous line of therapy. (a) Favorable-risk prognosis treatment courses (21 patients); (b) intermediate- and poor-risk prognosis treatment courses (173 patients). Each row illustrates a single patient’s treatment course through a sequence of red and blue boxes from left to right. Each box shows one line of treatment (box size independent of therapy duration). Colors indicate therapy benefit (blue), lack of clinical benefit (red), or no further lines of treatment (gray) (for definitions, see “Materials and Methods”).

Figure 2

The clinical benefit in any given line was independent of the IMDC prognostic risk group. A chi-square analysis comparing treatment response in favorable- and intermediate- or poor-risk prognosis groups. In this analysis, intermediate and poor risk patients were combined; the combined group is labeled as, “Poor”.

Figure 3

A greater number of total therapies received correlated with longer OS. Kaplan–Meier curves of OS are graphed. Patient cohorts in this figure are defined by the total number of treatment lines received (ranging from one to six). As only three patients received more than six lines of therapy, these patients were excluded. Subpanel: Pairwise statistical comparison of the length of OS between the four subgroups receiving one, two, three, and four lines of therapy.

Figure 4

A greater number of beneficial therapies received correlated with longer OS. Kaplan–Meier OS curves for patient cohorts defined by the total number of beneficial lines of treatment received (independent of total number or duration of treatments). Subpanel: Pairwise statistical comparison of the duration of OS between the five subgroups receiving zero, one, two, three, and four beneficial lines of therapy.

Figure 5

The number of beneficial lines of treatment and the IMDC risk prognostic score were both significantly correlated with OS. Cox regression multivariate testing of the relationship between the following factors: Age, number of treatment lines, number of beneficial lines of treatment, and intermediate- or poor-risk versus favorable-risk prognosis.

Figure 6

Patients maintained on a drug for at least three months in any line of therapy (within the first two lines) showed longer OS. Kaplan–Meier OS curves for all patients who received a minimum of two lines of targeted therapy stratified by timing of first clinical benefit (none, first-, or second-line). Subpanel: Statistical analysis showing no difference in the length of OS between first- and second-line therapies, but worse OS if patients could not be maintained on at least three months of drug treatment.