Oncologists generally prescribe adjuvant therapy to patients who not only have been diagnosed and treated for their disease but, also have a high probability that the disease will return. For example, in women with hormone-receptor-positive (HR+), the most common type of breast cancer, tamoxifen given for five years has demonstrated a reduction in the risk of recurrence of disease in early-stage breast cancer patients by 40% and a reduction in the risk of death by 30%, with manageable side effects (mostly hot flashes).
With respect to kidney cancer, a number of agents were tested in the era of targeted therapies (sunitinib, pazopanib, axitinib, and sorafenib), but, with the exception of the S-TRAC trial of sunitinib versus placebo, none met the desired endpoint of improved disease-free survival. The S-TRAC trial showed an improvement of disease-free survival of 6.8 years in the sunitinib group versus 5.6 years in the placebo group, but sunitinib showed no benefit in overall survival. Sunitinib also delivered more toxic side effects and a lower quality of life. Although it was approved by the FDA, it was not given approval by the European Medicines Agency (EMA), and it is not used much as adjuvant therapy.
Keynote-564 Phase III Trial
Due to the lack of effectiveness of targeted therapies, oncologists have been looking forward to testing immunotherapy agents for adjuvant efficacy in kidney cancer. Given the benefit of the combination therapy of pembrolizumab (Keytruda) and axitinib (Inlyta) outperforming sunitinib in the treatment of metastatic kidney cancer, Dr. Toni Choueiri of the Dana Farber Institute chose to test pembrolizumab as an adjuvant monotherapy in kidney cancer. Dr. Choueiri became the primary investigator in a Phase III, multi-institution trial using pembrolizumab versus placebo in clear cell kidney cancer patients with high risk of return. Pembrolizumab was given, for one year, on a 1:1 basis versus placebo to 500 patients in each arm, who had undergone a nephrectomy (and possibly also a metastasectomy) and were disease-free at the start of the trial. Dr. Choueiri reported at the June 2021ASCO Conference, with data from 24 months follow-up from date of nephrectomy, that the pembrolizumab arm of the trial showed a significant benefit in disease-free survival of 32% over placebo (hazard ratio of 0.68). Median overall survival was not reached in either group, although 18 patients died in the pembro arm versus 33 in the placebo arm. On the other hand, 150 pembro patients (32.4%) had Grade 3 or 4 Adverse Events versus 88 patients in the placebo arm. However, the use of pembro did not affect quality of life as much as sunitinib did.
There was no subgroup analysis done on which type of patients would most benefit from adjuvant therapy. It is also an open question as to whether it is better to treat patients with the adjuvant monotherapy of pembrolizumab or to wait until recurrence and treat them with a combination of therapies.
Based on this trial result, on November 17, 2021, the Food and Drug Administration approved pembrolizumab for the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy,or following nephrectomy and resection of metastatic lesions.
Update: At the 2022 ASCO Genitourinary Cancers Symposium, held in February 2022, Dr. Choueiri gave a 30-month update to the pembrolizumab trial. In the additional six months, the hazard ratio for usage of pembrolizumab versus placebo went from 0.68 to 0.63 so the statistically significant benefit favoring pembrolizumab for disease-free survival went up from a 32% advantage to a 37% advantage. The subgroup analysis showed a 32% benefit for pembrolizumab compared to placebo in the intermediate risk patients, a 40% advantage for patients with high risk for recurrence, and a whopping 72% advantage for patients originally diagnosed as M1, which in the TNM Cancer Staging System, refers to a cancer that has already spread to other parts of the body. See “Cancer Staging” on the NCI website https://www.cancer.gov/about-cancer/diagnosis-staging/staging
To be eligible for an adjuvant trial, a patient must be cancer-free or NED (no evidence of disease). Therefore, an M1 participant in the Keynote-564 trial will have had a nephrectomy to remove the primary tumor in the kidney plus additional surgery, called a metastasectomy, to resect the metastatic lesion found in another part of the body. These surgeries leave the patient cancer-free and eligible to participate in the trial. Note that neither the principal investigator nor anyone else who commented on the trial could explain why patients who were already metastatic would have longer disease-free survival than others who were not metastatic at the time of diagnosis.
Hazard Ratio
When talking about hazard ratios, we are speaking about survival curves. But the discussion is also applicable to other indicators such as disease-free survival. The slope of a survival curve is the probability of dying within a short period of time. So, say, for example, 20% of a group of patients with metastases are expected to die this year. Then the hazard is 20%. A second group of metastatic patients is treated with a therapy where 10% of the patients are expected to die this year. The hazard ratio is the probability of the treated patients dying this year divided by the probability of the untreated patients dying this year, which, in this case, is 10/20 = 0.5. Thus, in this example, the hazard of the treated patients is one-half that of the untreated patients, or those taking a placebo.
By convention, the treated patients’ hazard is the numerator and the untreated patients’ hazard, or the hazard of those treated with a standard therapy against which you want to compare a new therapy, is the denominator.
For example, If the hazard ratio is 0.7, then the probability of relapsing for Therapy A’s group is 1 minus 0.7 which equals 0.3, or 30% less of a chance of Therapy A’s group relapsing at any given point in time compared to the group to the control group.
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