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Sitravatinib Plus Nivolumab Induces Responses in Patients With Metastatic Urothelial Carcinoma

Danielle Ternyila
Published Online:6:56 PM, Wed November 27, 2019
Pavlos Msaouel, MD, PhD
Pavlos Msaouel, MD, PhD
The combination of investigational agent sitravatinib (MGCD516) plus nivolumab (Opdivo) improved responses in patients with advanced or metastatic urothelial carcinoma following progression on a prior immune checkpoint inhibitor, according to the results from a phase II trial (NCT03606174) presented at the Society for Immunotherapy of Cancer (SITC) Annual Meeting.

The options for patients with metastatic disease have been limited for many years until the evolution of immunotherapies. However, not all patients respond or have long durations of response to these treatments. By combining the oral tyrosine kinase inhibitor (TKI), sitravatinib, with immune checkpoint inhibitor nivolumab investigators, led by Pavlos Msaouel, MD, PhD, hypothesized that the combination could be beneficial in patients that have developed resistance to prior immunotherapeutic treatment.

The phase II trial evaluated objective responses, determined by 2 consecutive images, in 22 evaluable patients. Six patients achieved some kind of response, and 12 patients showed clinical benefit, including either a complete or partial response, or stable disease, meeting the primary endpoint of the study.

The toxicity profile for the combination also appeared tolerable. The toxicities noted were as expected for TKI and immune checkpoint inhibitors. Grade 3 treatment-related adverse events (TRAEs) that appeared in more than 1 patient included hypertension, fatigue, diarrhea, increased lipase, and palmar-plantar erythrodysesthesia syndrome. There were no grade 4 or 5 TRAEs.

We have ongoing cohorts that are being enrolled in multiple different settings. Some of the cohorts are receiving upfront therapy with nivolumab plus sitravatinib instead of receiving it only after they have progressed on an anti-PD-1/PD-L1 therapy. Hopefully as these data continue to mature, they will allow us to determine how to best use this regimen clinically.

In an interview with Targeted Oncology, Msaouel, medical oncologist at The University of Texas MD Anderson Cancer Center, discussed the findings from the trial evaluating sitravatinib plus nivolumab in patients with advanced/metastatic urothelial carcinoma. He also highlighted the next steps for this combination regimen.

TARGETED ONCOLOGY: What is the prognosis for patients with metastatic urothelial carcinoma? Why is there a need for novel therapies and combinations in these patients?

MsaouelFor many years, we had very limited options for patients with metastatic urothelial carcinoma. The only available options were cytotoxic chemotherapy. Thankfully with the advent of immunotherapy, we had additional therapies approved [by the FDA]. However, in patients who get treated with immunotherapy, many will not respond or in those who do respond, they will eventually develop resistance. There is a need to develop new therapies for this scenario.

TARGETED ONCOLOGY: What are the current options for patients who progress on immune checkpoint inhibitors?

MsaouelSome of the options would be chemotherapy and targeted therapies. Some chemotherapies can be tried for patients who have progressed on immunotherapy. For targeted therapies, particularly therapies targeting FGFR alterations, erdafitinib (Balversa) was recently approved by the FDA. For patients with this alteration, that can be an option. There are also other therapies that are currently under investigation for this scenario.

TARGETED ONCOLOGY: What was the rationale for evaluating sitravatinib plus nivolumab in these patients?

MsaouelSitravatinib is an oral TKI that targets multiple pathways, including what we call the TAM receptor family, TYRO3, Axl, and MERTK, as well as VGEF and c-MET. The idea is that by inhibiting these pathways, sitravatinib can modulate the immune microenvironment in a way that is beneficial to immune checkpoint therapy.

This is why we started this trial combining sitravatinib with the immune checkpoint inhibitor nivolumab. We treated patients that had progressed on previous treatment of an anti-PD-1/PD-L1 therapy. We are looking for responses in this cohort.

TARGETED ONCOLOGY: What were the results of the study that you shared at the SITC Annual Meeting this year?

MsaouelOut of 22 evaluable patients, 6 patients, which is a little more than 25%, responded. Objective responses were determined by 2 consecutive images. About 12 out of 22 patients showed clinical benefit as defined as complete response, partial response, or stable disease in at least 2 consecutive images and while being on treatment study for more than 14 weeks.

TARGETED ONCOLOGY: How does addition of sitravatinib help overcome the progression of immunotherapy in patients with urothelial carcinoma?

MsaouelThe mechanism is that sitravatinib can modulate the immune microenvironment in a way that can enhance the activity of immune checkpoint therapy. As I mentioned before, the main mechanism is the inhibition of the TAM family. We know that Axl, for example, is a pathway that plays a substantial role in the immune microenvironment. However, other pathways that sitravatinib inhibits, like the VGEF pathway or c-MET pathway, are also important in this context.

TARGETED ONCOLOGY: What toxicities were seen with sitravatinib plus nivolumab?

MsaouelThe toxicities that were seen were the typical toxicities that we see with these types of TKIs. We saw that patients could have fatigue, diarrhea, and hand-foot syndrome, as well as the typical immune-related toxicity that you would expect from nivolumab therapy. Nothing substantial stood out from this combination.

TARGETED ONCOLOGY: Do you have any next steps planned now for this combination?

MsaouelWe have ongoing cohorts that are being enrolled in multiple different settings. Some of the cohorts are receiving upfront therapy with nivolumab plus sitravatinib instead of receiving it only after they have progressed on an anti-PD-1/PD-L1 therapy. Hopefully as these data continue to mature, they will allow us to determine how to best use this regimen clinically.
 
 
Reference:
Msaouel P, et al. Abstract O23. Presented at: Society for Immunotherapy of Cancer Annual Meeting; Nov. 7–10, 2019; National Harbor, MD.


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