Receptor Tyrosine Kinase Inhibitors Show Only Modest Potential in Sarcoma

Gary K. Schwartz, MD

Research is making only modest progress in the discovery of receptor tyrosine kinase (RTK) inhibitors that show benefit in the treatment of sarcomas, Gary K. Schwartz, MD, argued during a presentation at the 2016 ASCO Annual Meeting.

“There are multiple receptor tyrosine kinases across multiple cell lines and multiple tumor types that are not equally expressed. And this is the challenge in developing an inhibitor that blocks not 1 but multiple receptor tyrosine kinases for growth development,” Schwartz emphasized.

Schwartz, chief of hematology and oncology, Herbert Irving Comprehensive Cancer Center, Columbia University School of Medicine, presented findings for trials exploring RTK inhibitors pazopanib (Votrient), regorafenib (Stivarga), and anlotinib in the treatment of patients with non—gastrointestinal stromal tumor (GIST) soft tissue sarcomas.

The phase II PAPAGEMO trial of single-agent pazopanib compared with pazopanib in combination with gemcitabine in patients with refractory soft tissue sarcoma showed no overall survival (OS) benefit for the combination.¹

“One of the questions we don’t know from the study is how many of these patients on pazopanib crossed over to gemcitabine and how this could’ve affected overall survival. In fact, I suspect this did have an effect on showing no benefit in overall survival. It raises questions about combinations of drugs versus sequential therapy of the same drugs in terms of survival benefit,” said Schwartz.

The median progression-free survival (PFS) for pazopanib monotherapy was 2 months (range, 1.6-3.2 months) versus a median PFS of 5.6 months (range, 4.2-8.1 months) for the combination therapy, for a difference of 3.6 months.

The benefit of the gemcitabine addition could be solely based on each patient’s ECOG performance status score. Gemcitabine has shown better results in patients with lower ECOG scores. In patients with an ECOG score of 0 the PFS was 5.0 months and the PFS was 2.5 months for patients with a score of ≥1.²

In the PAPAGEMO study 90% of the 43 patients receiving combination gemcitabine and pazopanib had an ECOG score of 0/1 and 10% had a score of 2. Ninety-five percent of the 43 patients receiving pazopanib monotherapy had a score of 0/1 and 5% had a score of 2.

It is very difficult to justify the use of pazopanib in combination with gemcitabine for patients with advanced soft tissue sarcomas based on this data, Schwartz said.

In addition, the liposarcoma stratification did not include enough data to produce a statistically significant benefit to support the use of the doublet in patients with liposarcoma. For 9 patients with liposarcoma receiving gemcitabine and pazopanib there was a mPFS of 8.6 months (range, 5.1-11.9 months) and median PFS of 1.5 months (range, 1.0-2.0 months) for 7 patients receiving pazopanib alone (P= .99).

RTK inhibitor regorafenib was studied in a phase II trial with cohorts for sarcoma subtypes. Overall, regorafenib showed a median PFS of 4 months (range, 2.6-6.5 months) versus a median PFS of 1 month (range, 1.0-1.8 months) on placebo.³

Regorafenib did not show any survival benefit in patients with liposarcoma. On regorafenib, patients had a median PFS of 1.1 months (range, 0.9-2.3 months) versus a median PFS of 1.7 months (range, 0.9-1.8 months) on placebo (P= .7).

Yet it did show notable signals of response in synovial sarcoma with a mPFS of 5.6 months (range, 1.4-11.6 months) versus median PFS of 1 month (range, 0.9-1.4 months) on placebo (P<.00001). In comparison, an older study of pazopanib showed a median PFS of approximately 5 months in the treatment of patients with synovial sarcoma.⁴

These drugs are particularly effective in synovial sarcoma, Schwartz said, &ldquo;presumably because of a high expression in PDGFRA that is a target for both of these drugs in this particular disease.&rdquo;

Regorafenib also showed a similar toxicity profile and median overall survival benefit to pazopanib.

&ldquo;Though regorafenib could be considered a treatment alternative, there is no compelling data at this time, in my opinion, indicating that regorafenib should replace pazopanib in patients with non-adipocyte soft tissue sarcomas who progress on prior chemotherapy,&rdquo; Schwartz noted.

In a phase II study of recurrent advanced soft tissue sarcoma subtypes, the PFS rate at 12 weeks among all 166 evaluable patients was 57.23% with an overall response rate (ORR) of 11.45%.⁵

The median PFS of 4.3 months for patients on anlotinib was comparable to results from RTK inhibitor pazopanib, which had a median PFS of 4.6 months.⁶The toxicity profile for anlotinib was also similar to that of regorafenib and pazopanib, except that anlotinib also showed cases of pneumothorax.

Interestingly, patients with alveolar soft part sarcoma on anlotinib showed a promising ORR of 46.15% and a PFS rate at 12 weeks of 76.92%, the highest rate of all subtypes.

Further data is needed before direct comparisons between each of these 3 RTK inhibitors can be made. However, as of now, none of these inhibitors has shown sufficient survival benefit across sarcomas.

&ldquo;Our goal must be to develop drugs that broadly target the complex array of RTKs that exist in the cell surface. We need to develop personalized therapies to recognize the RTKs unique to each person&rsquo;s individual sarcoma,&rdquo; Schwartz said.

References:

1. Schmoll H, R&uuml;ssel J, Reichardt P, et al. Pazopanib vs pazopanib + gemcitabine in refractory soft tissue sarcoma: A randomized phase II trial of the AIO.J Clin Oncol34, 2016 (suppl; abstr 11004).
2. Maki RG, Wathen JK, Patel SR, et al. Randomized phase II study of gemcitabine and docetaxel compared with gemcitabine alone in patients with metastatic soft tissue sarcomas: results of sarcoma alliance for research through collaboration study 002 [corrected].J Clin Oncol.2007;25(19):2755-2763.
3. Penel N, Mir O, Italiano A, et al. Regorafenib (RE) in liposarcomas (LIPO), leiomyosarcomas (LMS), synovial sarcomas (SYN), and other types of soft-tissue sarcomas (OTS): Results of an international, double-blind, randomized, placebo (PL) controlled phase II trial.J Clin Oncol34, 2016 (suppl; abstr 11003).
4. Sleijfer S, Ray-Coguard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European organisation for research and treatment of cancer-soft tissue and bone sarcoma group (EORTC study 62043).J Clin Oncol.2009;27(19):3126-3132.
5. Chi Y, Sun Y, Cai J, et al. Phase II study of anlotinib for treatment of advanced soft tissues sarcomas.J Clin Oncol34, 2016 (suppl; abstr 11005).
6. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.Lancet.2012;379(9829):1879-1886.