A retrospective cohort study of the use of targeted therapies for advanced renal cell carcinoma (RCC) in patients receiving treatment through the Veterans Health Administration (VHA) reported poorer overall survival outcomes than those from clinical trials, as well as shorter treatment durations for initial therapies with more frequent adverse events, dose reductions, and discontinuations. The findings were published in Cancer Medicine in late September 2019.1

Collectively, these factors “likely erode the benefits of these agents in the real world,” the research team, led by VHA scientists, concluded. “Patients and physicians should be cognizant of, and discuss, these issues and the potential impact on survival.” 

The focus of the study was a cohort of 286 male patients who were diagnosed with advanced clear cell RCC between 2010 and 2014 and chose to receive care at 1 of 24 VHA medical centers across the country. The patients were followed through September 2016. 

Sixty-six patients (23.1%) didn’t receive medications for their advanced RCC. For the 220 remaining patients, the most common frontline therapies administered were the tyrosine kinase inhibitors sunitinib (61.8%) and pazopanib (17.3%), and the mTOR inhibitor temsirolimus (10.9%). 

The median duration of first-line therapy was 86 days, or just under 3 months, this duration was markedly different from the median times reported across many phase 3 trials. For instance, one phase 3 study in advanced RCC led by Memorial Sloan-Kettering Cancer Center (MSKCC) researchers reported a median duration of treatment of 8 months for pazopanib and 7.6 months for sunitinib.2

Notably, 62.3% of patients in the VHA study had at least 1 dose of therapy held or reduced, and many of these treatments were not administered as a result of adverse drug events (ADEs). In addition, 89.1% of patients discontinued 1 or more targeted therapies, mostly due to disease progression and ADEs. Most types of ADEs were similar to those reported in clinical trials — such as thrombocytopenia, nausea, vomiting, diarrhea, and liver toxicities — yet they occurred at higher frequencies than were seen in clinical trials, said Daniel Becker, MD, the section chief for hematology/oncology at the VA NY Harbor Healthcare System in NYC and a coauthor of the study, to Cancer Therapy Advisor.

Of concern was the finding that 22.7% of ADEs that resulted in a discontinuation of medication were severe (grades 3-5). “Most of the types of adverse events that we saw were relatively similar to what’s been seen in the clinical trials, but they seem to result in more dose reductions and stoppage of therapy more often than in the clinical trials,” Dr Becker explained.  

The results also differed from those observed in clinical studies in terms of overall survival. Of the 220 patients with RCC receiving targeted therapy at VHA medical centers, 81.4% died by the end of the study period. In contrast, 83.3% patients who received no medications for their advanced RCC died by the end of the study. 

Median overall survival for patients with RCC receiving targeted therapy was 1.28 years from the date of diagnosis. In comparison, in a phase 3 trial, median survival from the time of diagnosis was 2.36 years for those receiving pazopanib and 2.43 years for those who got sunitinib.3

“I think the biggest reason for why we saw a difference is really our patient cohort that we’re studying: they’re older, with multiple comorbid conditions — so older, sicker patients” compared with clinical trial participants, explained Francesca Cunningham, PharmD, associate chief consultant at the veterans affairs national pharmacy benefits management services and the director for the veterans affairs center for medication safety. 

The mean age of VHA patients with advanced RCC was 66.3 years (in the MSKCC study,2 median age for patients treated with pazopanib and sunitinib was 61 years and 62 years, respectively). Notably, Eastern Cooperative Oncology Group (ECOG) performance status score was poorer compared with patients in clinical trials, Dr Becker added. ECOG scores for VHA patients ranged from 0 to 4, with most falling into the categories of 0, 1, or 2. 

Meanwhile, the clinical study only accepted patients with a Karnofsky performance status score of at least 70, which typically reflects the functional status of an ECOG score of 1. “Clearly our performance status for patients was worse than that in clinical trials,” Dr Becker added. 

Sumanta Pal, MD, medical oncologist at City of Hope, Duarte, California, who wasn’t involved in the new research, isn’t surprised that a real-world study of treatment outcomes would yield inferior results to those seen in phase 3 clinical studies, which tend to exclude patients with certain comorbidities and select for best-performing patients who tend to be healthier and younger. Other population-based studies of targeted therapies in metastatic RCC have also noted differences in overall survival between population-based data and trial data.4 

Yet the VHA team also found discrepancies between treatment outcomes of VHA patients and patients in other real-world analyses. For instance, a study of overall survival associated with targeted therapies in metastatic RCC using the Surveillance, Epidemiology, and End Results (SEER) cancer registry reported a median survival of 20 months.5

This figure may be overstated because survival was measured from the date of diagnosis, rather than the date of the start of treatment, Dr Becker and his colleagues explained. Nevertheless, the SEER figure “is longer than what we found, even when starting with the diagnosis date,” they wrote, concluding that this discrepancy in overall survival may reflect differences in the patient populations. 

“Certainly, the [VHA] population represents a unique pool of patients with perhaps more extensive comorbidity and certainly a variety of issues [that] could potentially confound the results,” Dr Pal noted. Both biological and psychological factors may help explain the rationale for dose reductions and discontinuations, and in addition, timely recognition of the disease could also play a role, he said. “I think that this study really prompts the need to understand why patients in the [VHA] setting have such inferior outcomes,” Dr Pal added. 

Che-Kai Tsao, MD, oncologist and medical director of the Derald H. Ruttenberg Treatment Center at the Tisch Cancer Institute, Mount Sinai Hospital, NYC, noted that the study cohort was relatively small, and only enrolled male patients — a limitation the authors acknowledged. 

Another limitation of the VHA study is that the authors didn’t report the patients’ risk scores according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), which is often used to evaluate a patient’s prognosis. As a result, “it could have been that they had a very high number of poor-risk disease [patients], which led to the poor outcomes that we’re seeing,” explained Dr Tsao, who wasn’t involved in the study.  However, the authors weren’t able to obtain the data needed to assess prognosis, they wrote.  

Dr Tsao also noted that he considers the results of the study somewhat dated, as combination immunotherapies or immunotherapies combined with targeted therapies have moved closer to the frontline standard of care for advanced RCC. 

Following the release of the results of several trials suggesting such combination treatments are more efficacious than targeted therapy alone, the FDA has approved several combination treatments in the past 2 years, including the anti–PD-1 immunotherapy pembrolizumab in combination with the tyrosine kinase inhibitor axitinib, the anti–PD-1 immunotherapy avelumab combined with axitinib, or the immunotherapies nivolumab and ipilimumab.

However, the VHA team’s results still carry relevance, as targeted therapies are still used following progression with immunotherapy, and therefore, still play a significant role in the management of advanced RCC, Dr Becker said. 

Ultimately, to Dr Becker, his and his colleagues’ findings underscore the limited generalizability of clinical trial results to patients in the real world. “One of the ways that you can consider dealing with that is to broaden the inclusion criteria in clinical trials so that they are more generalizable.” Although he concedes that loosening the enrollment criteria may have some drawbacks, “a significant advantage would be that the clinical trial results would be a little more informative about what patients can expect,” he said. 

References

  1. Aspinall SL, Zhao X, Geraci MC, et al. Use of targeted therapies for advanced renal cell carcinoma in the Veterans Health Administration [published online September 19, 2019]. Cancer Med. 2019;8(15):6651-6661.
  2. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722-31.
  3. Motzer RJ, Hutson TE, McCann L, et al. Overall survival in renal-cell carcinoma with Pazopanib versus sunitinib. N Engl J Med. 2014;370:1769-1770.
  4. MacLeod LC, Tykodi SS, Holt SK, et al. Trends in metastatic kidney cancer survival from the cytokine to the targeted therapy era. Urology. 2015;86(2):262-268.
  5. Vaishampayan U, Vankayala H, Vigneau FD et al. The impact of targeted therapy on overall survival in advanced renal cancer: A study of the National Surveillance Epidemiology and End Results Registry Database. Clin Genitourin Cancer. 2014;12(2):124-129.