Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma

Abstract

Background: Molecular intratumour heterogeneity (ITH) is common in clear cell renal carcinomas (ccRCCs). However, it remains unknown whether this is mirrored by heterogeneity of drug responses between metastases in the same patient.

Methods: We performed a retrospective central radiological analysis of patients with treatment-naïve metastatic ccRCC receiving anti-angiogenic tyrosine kinase inhibitors (TKIs) (sunitinib or pazopanib) within three similar phase II trials. Treatment was briefly interrupted for cytoreductive nephrectomy. All patients had multiple metastases that were measured by regular computed tomography scans from baseline until Response Evaluation Criteria In Solid Tumours (RECIST)-defined progression. Each metastasis was categorised as responding, stable or progressing. Patients were classed as having a homogeneous response if all lesions were of the same response category and a heterogeneous response if they differed.

Results: A total of 115 metastases were assessed longitudinally in 27 patients. Of these patients, 56% had a heterogeneous response. Progression occurred through the appearance of new metastases in 67%, through progression of existing lesions in 11% and by both in 22% of patients. Despite RECIST-defined progression, 57% of existing metastases remained controlled. The sum of controlled lesions was greater than that of uncontrolled lesions in 47% of patients who progressed only with measurable new lesions.

Conclusions: We identified frequent ITH of anti-angiogenic TKI responses, with subsets of metastases responding and progressing within individual patients. This mirrors molecular ITH and may indicate that anti-angiogenic drug resistance is confined to subclones and not encoded on the trunk of the tumours' phylogenetic trees. This is clinically important, as patients with small-volume progression may benefit from drug continuation. Predominant progression with new rather than in existing metastases supports a change in disease biology through anti-angiogenics. The results highlight limitations of RECIST in heterogeneous cancers, which may influence clinical trial data validity. This analysis requires prospective confirmation.

Trial registration: European Clinical Trials Database(EudraCT): 2009-016675-29 , registered 17 March 2010; EudraCT: 2006-004511-21 , registered 09 March 2007; EudraCT: 2006-006491-38 , registered 22 December 2006.

Keywords: Anti-angiogenic treatment; Drug resistance; Intratumour heterogeneity; Kidney cancer; RECIST.

Fig. 1

Flowchart of patient selection for radiological heterogeneity analysis. PD progressive disease

Fig. 2

Example of individual lesion response assessments within one patient. Lesion size on each CT scan relative to the size on the baseline scan was calculated until RECIST-defined progression. Based on the best response that was achieved over the treatment period, each lesion was categorised either as a Responding Lesion (RL, 30% or greater decrease in diameter compared to baseline), Progressing Lesion (PL, 20% or greater increase in diameter compared to baseline) or Stable Lesion (SL, all remaining lesions). The emergence of new lesions (NL) was also recorded

Fig. 3

Venn diagram of response patterns. Percentage of 27 patients with the indicated combination of lesion response categories based on a the assessment of the best response achieved per lesion and b assessment on the specific scan showing the best overall response. RL Responding Lesion, SL Stable Lesion, PL Progressing Lesion

Fig. 4

Best achieved response by baseline lesion size. Best response achieved by each individual lesion compared to its size at baseline. p value refers to SLs compared to RLs and PLs in ≤4 cm lesions versus >4 cm lesions. RL Responding Lesion, SL Stable Lesion, PL Progressing Lesion

Fig. 5

Patterns at progression. Examples of RECIST progression patterns. a ≥20% increase in size of existing disease from nadir defining progression. b New lesions and ≥20% increase in size of existing disease from nadir defining progression. c New lesions only defining progressive disease (R right, L left, green line responding lesion at progression, blue line stable lesion at progression, red line progressing lesion at progression, measurements as per size at baseline)

Fig. 6

Controlled versus uncontrolled lesions in patients progressing with measurable new lesions only. The sum of diameters of controlled lesions (responding and stable lesions combined) and the sum of diameters of uncontrolled lesions (progressing and new lesions combined) is shown relative to the sum of all lesion diameters for 15 patients in whom only measurable new lesions defined progression