Pavlos Msaouel, MD, PhD, discusses a study of panitumumab-based EGFR blockade in SMARCB1-deficient RMC.
Treatment with panitumumab (Vectibix)-based regimens displayed unprecedented response rates in patients with SMARCB1-deficient renal medullary carcinoma, opening the door for the approach to become a potential new standard-of-care therapy in this setting, according to Pavlos Msaouel, MD, PhD.
“[An] important [remaining] question is: How do we scale up this paradigm, not just in RMC?” Msaouel said an interview with OncLive®. “It is very exciting that now we have tailored, targeted therapies for RMC that can produce such efficacy, and this is only the beginning. We have other targets that we have identified for this disease, and we have ongoing clinical trials.”
Msaouel is an associate professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, in Houston.
In the interview, Msaouel discussed data from a study evaluating the prospective clinical activity of panitumumab-based EGFR blockade in SMARCB1-deficient RMC, the present and future role of this approach in RMC, and safety management considerations with the approach.
Msaouel: In our preclinical models, we tested the efficacy of the monoclonal antibody panitumumab against wild-type EGFR vs erlotinib [Tarceva] vs vehicle control.1,2 We found, both in our patient-derived xenograft models and our cell line–derived xenograft models, that the efficacy of panitumumab was much higher than that of erlotinib. Before that, we had already published data that are included in the guidelines showing that erlotinib [plus bevacizumab (Avastin)] produced some responses, even in heavily pretreated RMC, in the range of [approximately] 20%.3
As soon as we made those preclinical discoveries, we quickly repurposed a clinical regimen that had been developed for inflammatory breast cancer, a different type of rare cancer that also expresses wild-type EGFR. We repurposed it for our patients with RMC, and the initial results were profound. As soon as we realized the potency of that regimen, we started a prospective registry.
We do have clinical trials dedicated to RMC, but those trials use novel agents or strategies that are not available outside of the clinical trial setting. Panitumumab, however, has been available in oncology for decades, and so what we did instead was take advantage of the ability to repurpose that therapy across the world.
We utilized the flexibility of health systems in the United States, Canada, and Europe, and tested that regimen in patients with RMC [n = 26], prospectively gathered the data, and found a very exciting objective response rate [ORR] of [53.9%] with a complete response [CR] rate of [15.4%].1 That is much better than the historical data in the first-line setting, where CR rates are less than 5% and ORRs are less than 30%.
Keep in mind that the patients we tested this regimen in were heavily pretreated, with a median of at least two prior lines of therapy, which made that signal even more impressive. The progression-free survival [PFS] with this regimen was 5.8 months [95% CI, 4.0-8.2], which was much better than anything else we have seen in this disease.
This may not sound impressive for some other cancers, but when we have a disease in which our best first-line regimen barely produces 4 months of PFS, seeing a PFS of 5.8 months in the third line and beyond is impressive. The median overall survival [OS] from the study was 9.5 months [95% CI, 7.6-not evaluable]. For a cancer with a median OS of 13 months, adding 9.5 months of median survival in the third-line setting and beyond essentially almost doubles the median OS with this regimen.
That is exactly what everyone has asked us once individuals around the world started seeing these results. They said we need to bring it into the first-line setting, and indeed the first step was to present and publish the current data from the 26 patients around the world. However, we do not just have data from those 26 patients, we now have data from across the world, including South America, from more than 40 patients. These data include more patients receiving this therapy in the first-line setting, and we are learning and generating the information to find out which patients would benefit from bringing this powerful therapy earlier.
One way we are accounting for this is by developing a prognostic score using data from 180 patients with RMC, historical data we have at MD Anderson, to identify which patients have the most aggressive disease. For these patients, if the first therapy does not work, we are likely to lose them because of how aggressive the disease is. For those patients, we believe we should give our strongest therapy upfront, which does include EGFR targeting with panitumumab. That is one strategy through which we will tailor bringing panitumumab-based therapy into the first-line setting.
Another strategy applies to certain patients who, for all practical purposes, have stage IV disease. RMC is so aggressive that it is extremely rare for it to be contained to the kidney. However, for some of these patients, even though the cancer has spread, it has not spread to multiple areas, and because of that we may be able to debulk the disease with first-line therapy and then proceed with definitive nephrectomy with curative intent. Perhaps in those scenarios, panitumumab-based therapy could be used to debulk the tumor and sterilize it from the body before proceeding to surgery.
