Second-Line Treatment Approaches for mRCC

Robert Alter, MD: When patients present to me and are of intermediate or poor risk, I have to go back to the days of high-dose IL-2 in trying to achieve a complete remission in our patients, where our therapies can actually be quite tolerable and durable. If patients are appropriate candidates, without contraindications to receiving immunotherapy, I like to treat our patients at the John Theurer Cancer Center with a combination of ipilimumab-nivolumab, then sequence to nivolumab after 4 doses of ipilimumab-nivolumab combination.

It gives us the ability to have our patients come to the office. We can monitor the patients. Tolerability seems to be quite good. Patients are having an enjoyable time out of the office. Oral therapies may be beneficial. However, I do get concerned about some of the chronic toxicities of oral therapy, not only the physical toxicities but also the financial toxicities.

There’s a presentation at the International Kidney Cancer Symposium that discusses the cost of the agents in combination. It appears that the combinations of I/O [immuno-oncology]–I/O or ipilimumab-nivolumab seem to be almost $100,000 cheaper over the course of a year compared with using I/O–TKI [tyrosine kinase inhibitor] therapy. In this time of the year, when the Medicare drug plan doughnut hole might be quite concerning to patients, out-of-pocket expenses may be significant. It is important to recognize the financial toxicities as well.

Dr Nizar Tannir presented information on the CheckMate 214 trial at ASCO GI [American Society of Clinical Oncology Genitourinary Cancers Symposium] in 2020. This involved looking at the 59 patients who were in a complete remission. There were percentages of patients who had been taken off therapy, who were now on active surveillance post-therapy, who remained in a complete remission years after receiving therapy. Some patients had to come off the study because of toxicity and remained off therapy, still in a complete remission.

Our goals when providing treatment are having patients experience improved quality of life, long-term survival, complete remissions, or partial remissions that are durable, where patients can remain off therapy. In the appropriate patient population, ipilimumab-nivolumab seems to be an excellent first-line therapy.

If the patients are having a more aggressive disease, visceral involvement, or disease that needs reduction because of patient symptoms in a short period, I would use the combination of axitinib and pembrolizumab as a first-line therapy. Tolerability is excellent. Axitinib’s short half-life allows us to adjust doses based on toxicity. We have become very familiar with utilizing immunotherapy, and after evaluating the response or efficacy data on the KEYNOTE-426 trial, one feels very confident patients should have not only good tolerability but effective therapy as well.

Second-line therapy depends on first-line therapy. If the patient received I/O–I/O as first-line therapy, we consider using the single-agent cabozantinib. If the patient received axitinib-pembrolizumab and had recent, dramatic disease, I would consider using lenvatinib and everolimus as a second-line therapy. There is still the ability to utilize immunotherapy as a third line.

Robert Motzer, MD: In terms of the standard management for RCC [renal cell carcinoma], as newer drugs were studied and found to be effective, most treatment plans consisted of sequence therapy, where we treat a patient with drug A to maximum benefit, and then when the patient progresses, go to drug B, and drug C. That scenario comprised patients treated with TKIs or MTOR inhibitors. One of the points that has not been appreciated is that some of the studies that showed a benefit for sequence therapy—say, for drug C—seemed to provide a small benefit. But in the conglomerate, when we started out with drug A, then drug B, and then drug C, the benefits for the patient were fairly dramatic overall, with improvement in survival and good quality of life over the period of the treatment. With the advent of I/O therapies, our paradigm has been changed, and that is going to need to be revisited in defining what the paradigm is for sequencing therapy, since I/O treatments are really 1 of 2 main types of treatments we use to treat advanced RCC.

Robert Alter, MD: We do see our patients often. We do speak to them on the phone, which is a significant delight that we do not have to have our patients come to see us often as often, especially during this concerning time of COVID-19. When it comes to the communication with the patient, one can definitely assess tolerability of therapy. Sometimes dose adjustments have to be incorporated, or at times therapies have to be discontinued.

If tolerability and toxicity seem to be more secondary, we think mostly about disease progression as being the benchmark indicating that it is time to change therapies. We forget sometimes about the tolerability issue. We think more about dose adjustments rather than believing that a therapeutic benefit may be offered; a big difference can occur if therapy is utilized. If cost becomes an issue, it is unfortunate and it is rare, but it should be always considered. To me, if a patient is having a disease progression but a nominal progression of disease, I may just continue therapy. Despite the fact that we believe that we have a large menu of options of therapy, at times the therapies have been tolerated well and are durable with little progression.

There is no harm in maintaining the initial therapy, in monitoring the patients closely again for disease progression at the next set of studies, allowing the patients still to derive a benefit from the therapies. Ultimately, it comes down to patients adjusting to therapies and changing therapies, but one should be cognizant of the fact that we have many means of drugs; the mechanisms seem to be quite important as well.

Having a patient come off and go on therapy freely because of a nominal change should be delayed until progression is noted. Then, because of immunotherapy, we have to be aware of pseudo-progression. At times, the disease may appear to flare; if the first scan is done, we may see a little progression. I assess the patients, looking at their symptoms, and if they are relatively asymptomatic or patient symptoms are actually improving, then we would continue immunotherapy for 2 or 3 more doses and repeat scans. If there is progression at that time, changing therapies would be appropriate, but there are times subsequent scanning shows disease regression, and maintaining additional therapies with immunotherapy will be quite important.

Transcript edited for clarity.