Figlin Explains the Many Factors that Dictate Second-Line Treatment Options in mRCC

Robert A. Figlin, MD, Steven Spielberg Family Chair in Hematology-Oncology, professor of medicine, and director, Division of Hematology/Oncology, Cedars-Sinai Medical Center, recently discussed the cases of 2 patients with metastatic renal cell carcinoma.

Robert A. Figlin, MD

Robert A. Figlin, MD, Steven Spielberg Family Chair in Hematology-Oncology, professor of medicine, and director, Division of Hematology/Oncology, Cedars-Sinai Medical Center, recently discussed the cases of 2 patients with metastatic renal cell carcinoma (RCC).

Case 1

January 2014

A 48-year-old Caucasian man presented to his physician complaining of right upper quadrant discomfort and back pain. CT scans of the abdomen and pelvis showed a large right renal mass with retroperitoneal node biopsy. He was diagnosed with stage IV RCC, clear-cell histology, with metastases to the bone and contralateral adrenal gland.

After radiation therapy to T8, he was started on pazopanib (Votrient) 800 mg. The first follow-up scan showed a decrease in size of the adrenal lymph node. The patient reported moderate diarrhea and mild fatigue which was controlled with antidiarrheal medication and rest. He continues to do well with improved tolerance after a dose adjustment to 600 mg.

April 2016

The patient complains of increasing back pain and pain in multiple other bony sites. He reports nausea and rapid weight loss during the last 3 weeks. Imaging showed slow but steady progression in the adrenal lesion and new bone lesions in the thoracic lumbar spine.

Targeted Oncology™: How do you define progression in patients with mRCC?

Figlin:Progression in patients with metastatic kidney cancer is classically defined as RECIST growth with growing existing lesions or the appearance of new lesions consistent with their cancer. In patients with kidney cancer, the problem is that clinical trials often define progression in a strict way, and oftentimes in clinical practice, there is modest growth of the tumor that does not justify a change in treatment unless there is evidence that quality of life, performance status, or new disease presents itself. Also, one needs to understand that new areas of involvement, because of the heterogeneity of cancer, might sometimes be treated with techniques, such as stereotactic body radiation therapy [SBRT], while the systemic therapy is continued.

Targeted Oncology™: How do the following factors affect your decision-making for second-line therapy?

Figlin:Response and tolerance to upfront VEGF tyrosine kinase inhibitor (TKI) therapy: The literature, unfortunately, does not support that prior response and tolerance to therapy from VEGF receptor TKIs predicts outcome to the next sequence therapy. While we hope that prior responding patients will benefit again, or if we think there are specific adverse events [AEs] that appear from prior therapies, although those can be used in a general sense, there is not strong literature to support using that as a criteria for the choice of next sequence of treatment.

Aggressiveness of recurrence; symptoms and tempo of progression: Clearly, when cancer patients have progressing disease, especially when they are symptomatic, one would like to use agents that have a potential rapid response to treatment. Agents such as TKIs, including some of the newer agents like cabozantinib [Cabometyx], lenvatinib [Lenvima], and everolimus [Afinitor], have the ability to produce a rapid symptom and tumor response, whereas immuno-oncology [IO] agents may take a bit longer to show benefit for patients.

Disease burden and the sites and number of metastases: Unfortunately, those are not criteria that predict outcome. Clearly, when a patient's disease is growing, when there are an increasing number of sites and metastases, those patients require systemic therapy, but those are not criteria that help us choose between level 1 and level 2a evidence agents available for choices.

Toxicities for TKIs versus immunotherapy: When one thinks about toxicities for TKIs versus immunotherapy, one recognizes that they have different toxicity profiles and must be tailored to the patient. You also recognize that the toxicities from TKIs can affect quality of life, especially early in the course of treatment. Immunotherapy by and large has low levels of toxicity, but in individual cases can produce immune-related AEs that can be life threatening.

Targeted Oncology™: What factors would weigh into the decision to switch therapies versus treating beyond progression?

Figlin:I think the key to that is to recognize that imaging, while helpful, must be balanced by how the patient is experiencing the treatment. Oftentimes, with minimal volume disease, slow progression, long predominant cancer, or growing cancer may be supported by continuing therapy as opposed to switching; or else if there is rapid growth of tumor, appearance of new unequivocal areas of involvement, and new symptoms related to the cancer, that certainly justifies a change in the treatment paradigm.

Targeted Oncology™: In which patients do you consider this option?

Figlin:I consider the option of treating beyond progression in patients with low-volume, slowly growing, non-life-threatening disease that usually is seen primarily in the lung, not in the bone, for example, where they are still asymptomatic from the disease. It is still low volume, and giving them some additional time to prove the path the cancer is taking that will allow for the next decision-making process.

Pazopanib was discontinued and the patient was started on cabozantinib 60 mg.

Targeted Oncology™: What is the rationale for choosing cabozantinib in this patient?

Figlin:Cabozantinib is one of several agents used in the second-line that has demonstrated clinical benefit for patients with respect to objective response, progression-free survival [PFS], and overall survival [OS]. It has the advantage of also targeting a resistance pathway from VEGF receptor TKIs, which is the MET pathway. The choice in this patient is 1 of many possibilities suggesting that level 1 and 2a evidence supports the use of 60 mg of cabozantinib when switching from a first-line TKI.

Case 2

December 2002

A 64-year-old man presented with left-sided back pain. A CT scan showed an 8.5 cm left renal mass. He underwent laparoscopic radical nephrectomy; pathology confirmed diagnosis of RCC Fuhrman III.

January 2013

Surveillance CT showed a 4.5-cm mass in the left renal bed. The patient underwent metastatectomy, distal pancreatectomy, and splenectomy. Pathology showed RCC with positive resection margins.

July 2014

CT showed new hepatic metastases. The largest was 5.9 cm; RP nodules; omental mass was 16.3 x 5.2 cm; pelvic mass, 6.3 cm.

Targeted Oncology™: How would you treat the patient?

Figlin:We have a wide variety of choices in the frontline setting. Generally, I would not use high dose interleukin-2 (IL-2) in such a patient, because of the performance status and their risk factors. Agents such as sunitinib (Sutent) or pazopanib would be considered standard of care in the previously untreated patient looking to receive a TKI.

Cabozantinib does have experimental data that is currently being reviewed by the FDA in the frontline setting when compared with sunitinib and might become an option in the future, if approved by the regulatory bodies as demonstrating improvement with respect to PFS and OS when compared with sunitinib. I would certainly always use and consider a clinical trial with either PD-1 pathway blockade alone or in combination with a VEGF receptor, as I think clinical trials still remain a standard for patients that have that treatment option available to them, as long as it's FDA approved and IRB [International Review Board] approved. It could be a checkpoint inhibitor as monotherapy in combination with other checkpoint inhibitors or in combination with VEGF-targeted agents. Those therapies are currently still considered experimental as we wait for the evolution of that data to mature. Absent a clinical trial, I think the standard of therapy in such a patient would be sunitinib or pazopanib.

September 2014

He was enrolled onto a phase I trial of axitinib (Inlyta) plus pembrolizumab (Keytruda). Treatment was associated with >50% reduction in tumor volume. The patient developed hypertension, diarrhea, and dry cough; otherwise he tolerated the treatment well.

January 2016

He presented with headaches and visual problems.

Axitinib was held and the patient was started on rivaroxaban (Xarelto). CT scans showed rapid progression of liver metastases with new lesions and peritoneal carcinomatosis.

Targeted Oncology™: How would you manage his disease progression?

Figlin:In a patient that starts on an IO, either alone or in combination, we don't have a great deal of level 1 and 2a evidence to make choices, because most of the level 1 and 2a evidence was in the setting of prior VEGF receptor TKIs. Certainly, there is little evidence of using an IO in patients who have previously progressed on an IO, so I would not use nivolumab [Opdivo]. I think switching to a VEGF receptor TKI that is different than axitinib would be prudent, and those agents that we have in the second-line setting that have a demonstrated clinical activity would be agents such as cabozantinib, lenvatinib, or everolimus. In my own practice, I would use cabozantinib in this setting.

Axitinib was restarted with concomitant anti-coagulation. The patient had immediate resolution of disease symptoms. He remained performance status 0 with a stable partial response, now 14 months after resuming axitinib.