Combination regimens comprised of immunotherapy and TKI inhibitors have yielded significant benefits in terms of overall survival and progression-free survival with acceptable safety in patients with renal cell carcinoma; however, the cost of these regimens may negate the impact of these advances.
Combination regimens comprised of immunotherapy and TKI inhibitors have yielded significant benefits in terms of overall survival (OS) and progression-free survival (PFS) with acceptable safety in patients with renal cell carcinoma (RCC); however, the cost of these regimens may negate the impact of these advances, according to Suzanne Cole, MD, FACP.1
“Clearly, we have multiple options already available to us,” said Cole, a medical oncologist and medical director of the University Hospital Simmons Cancer Clinic at the UT Southwestern Medical Center, in a presentation during the 2020 International Kidney Cancer Symposium (IKCS). “We also have many other combinations coming our way. The winner that’s going to take the lead is also going to be the most affordable option, at least in the United States.”
The combination of pembrolizumab (Keytruda) plus axitinib (Inlyta) was investigated in the in the KEYNOTE-426 study in patients with newly diagnosed or recurrent stage IV clear cell RCC.2 To be eligible for the trial, patients needed to have a Karnofsky performance status of 70 or greater, measurable disease per RECIST v1.1 criteria, and adequate organ function. They could not have received previous systemic treatment for advanced disease.
Patients were randomized 1:1 to receive either pembrolizumab plus axitinib (n = 432) or sunitinib (Sutent; n = 429) based on International Metastatic RCC Database Consortium (IMDC) risk group and geographic region. The primary end points of the study were OS and PFS in the intent-to-treat population per blinded independent central review and RECIST v1.1 criteria. Key secondary end points comprised overall response rate (ORR), duration of response, patient-reported outcomes, and safety.
The combination was found to result in an improvement in OS compared with sunitinib, which led to the April 2019 FDA approval for its use as a frontline treatment in patients with advanced disease. Updated data presented during the 2020 ASCO Virtual Scientific Program showed that the survival benefit with the combination over single-agent sunitinib was upheld (HR, 0.68; 95% CI, 0.55-0.85; P <.001). At a median follow-up of 27 months, the median OS with pembrolizumab/axitinib was not reached (NR; 95% CI, NR-NR) versus 35.7 months (95% CI, 33.3-NR) with sunitinib. At 12 months, the OS rates were 90% with the combination versus 79% with the monotherapy; these rates were 74% versus 66%, respectively, at 24 months.
Another frontline immunotherapy/TKI combination, avelumab (Bavencio) plus axitinib, was examined in treatment-naïve patients with advanced RCC with a clear cell component in the JAVELIN Renal 101 study.3 To participate, patients needed to have 1 or more measurable lesions as defined by RECIST v1.1 criteria, have tumor tissue available for PD-L1 staining, and an ECOG performance status of 0 or 1.
A total of 886 patients were enrolled on the trial and randomized 1:1 to either the combination or sunitinib. Patients were stratified based on performance status and geographic region. The primary objective of the study was to demonstrate the superiority of the immunotherapy/TKI combination over sunitinib in terms of PFS or OS in patients with PD-L1–positive tumors.
In the PD-L1–positive population, the median PFS was 13.8 months (95% CI, 11.1–not evaluable [NE]) with the combination versus 7.2 months (95% CI, 5.7-9.7) with sunitinib, which translated to a 39% reduction in the risk of disease progression or death (HR, 0.61; 95% CI, 0.475-0.790; P <.0001). In the overall population, treatment with the combination led to a median PFS of 13.8 months (95% CI, 11.1–NE) versus 8.4 months (95% CI, 6.9-11.1) with sunitinib (HR, 0.69; 95% CI, 0.56-0.84; P <.001).
“The entire population was tested for PD-L1, but regardless of their PD-L1 status, the entire population had a benefit from avelumab and axitinib,” noted Cole.
The results from this trial led to the May 2019 FDA approval of frontline avelumab plus axitinib in patients with advanced RCC.
Finally, the combination of nivolumab (Opdivo) plus cabozantinib was compared with sunitinib in patients with previously untreated advanced or metastatic RCC in the phase 3 CheckMate-9ER study.4 A total of 651 patients were enrolled to the trial; all patients had to have a clear cell component but they could fall within any IMDC risk group. Patients were randomized 1:1 to the combination or sunitinib. Stratification was based on IMDC risk score, PD-L1 expression, and geographic region. The primary end point of the trial was PFS, while key secondary end points included OS, ORR, and safety.
Results from the trial were presented during the 2020 Virtual ESMO Congress and showed that at a median follow-up of 18.1 months, the median PFS was 16.6 months with nivolumab plus cabozantinib versus 8.3 months with sunitinib (HR, 0.51; P <.0001). The median OS had not yet been reached in either arm (HR, 0.60; 98.89% CI, 0.40-0.89; P =.0010).
“Although neither arm has OS data, at the 18-month mark, we are seeing that there has been a 40% risk reduction in death,” Cole said. “Nivolumab/cabozantinib has received a priority review designation by the FDA. We are hoping that this [regimen] will receive an approval within the next year.”
To put the data into perspective, Cole examined results with immunotherapy/TKI combinations alongside that of doublet immunotherapy combinations. She emphasized that while combinations such as nivolumab and ipilimumab (Yervoy) have 4 years of OS data, immunotherapy/TKI combinations are relatively new, with younger trials; therefore, longer-term data are not yet available.
“It is interesting that the immunotherapy/TKI [combinations] have a 12-month OS [rate] that is 6% to 10% higher than [what we saw with] ipilimumab plus nivolumab,” Cole noted. “The hazard ratio for that first year is about equivalent and hard to interpret, but there [are] PFS [data] that [are] in favor of immunotherapy/TKI combinations. The ORRs are much more significant with the immunotherapy/TKI combinations.”
She did note, however, that the combination of ipilimumab plus nivolumab has yielded very deep and long-lasting responses, with a great cure fraction. Currently, it’s not clear whether this will prove to be true with immunotherapy/TKI combinations.
In her presentation, Cole raised the concern regarding the safety profiles of these combination regimens and the need to weigh whether the benefit outweighs the risk in each patient. With immunotherapy agents, Cole explained, there is always the possibility that the patient will experience a severe immune-related adverse effect (AE). TKIs are additionally accompanied by a chronic AE that needs to be taken into consideration. Some of the AEs that are present across all 3 regimens include diarrhea, hypertension, and fatigue.
Cole also discussed the concerns associated with the financial toxicity of these regimens. Estimates for 1 year of treatment with an immunotherapy/TKI regimen range between $300,000 to $500,000, depending on the treatment. While some health insurances may be able to cover these costs, Cole said that high co-pays and deductibles often put the financial burden on patients who are often not able to work due to their disease. Even with health insurance, out-of-pocket costs for these drugs can climb to as high as $25,000 per year.5
“Patients with stage IV cancer are having to come up with this kind of money and it’s outrageous,” stressed Cole. “When you’re thinking about the oral TKI component mechanism, which is much more burdensome to the patient, it’s very hard to actually get these drugs into the hands of the patients.”
In 1 paper, investigators examined how cost may negate the impact of treatment advances in RCC in patients with low-income Medicare and high-income Medicare.5 Low-income patients had a subsidy that brought the copay for their treatments down to $7, while high-income patients needed to pay $2800 per month for their oral chemotherapy medications. Results from the study indicated that patients with a $7 co-pay were more likely to fill their medications within the first 200 days of receiving a prescription compared with patients who had a $2800 co-pay.
“Although we have these amazing trials where we’re giving free drugs to our patients and proving that we have these huge survival benefits, if when these drugs come to market, they are so expensive and the co-pays are so high that the patients who have cancer cannot actually get the medications, it doesn’t matter how great these drugs are,” Cole asserted. “If they can’t get to the patients, we’re not being effective.
“If pharma is listening, if our government is listening, or our healthcare organizations are listening, we have to do something to lower the costs of these drugs or our patients are going to die and all the work that we’re doing to improve survival is meaningless,” concluded Cole.