The first-line treatment strategy for metastatic bladder cancer, where chemotherapy has been the standard of care for the past 30 years, has recently shown signs of rapid reorienting toward immunotherapies and antibody-drug conjugates (ADCs).
In particular, the leading anti-PD-1 immunotherapies Keytruda (pembrolizumab) and Opdivo (nivolumab) are demonstrating their value as first-line treatment options in combination with different partner drugs and maintenance therapy, which will likely erode the position of the anti-PD-L1 immunotherapy Bavencio (avelumab) rapidly.
The European Society for Medical Oncology Annual Congress (ESMO 2023), held in Madrid, Spain, from Oct. 20-24, saw many key data on new drugs for treating metastatic bladder cancer.
Most notably, data from the EV-302/KEYNOTE-A39 study, which evaluated the combination of Keytruda and Padcev (enfortumumab vedotin) in first-line treatment compared to conventional platinum-based chemotherapy, showed that Keytruda plus Padcev nearly doubled median progression-free survival (mPFS), the primary endpoint, and reduced the risk of disease progression or death by 55 percent (12.5 months vs. 6.3 months).
The combination also nearly doubled median overall survival (mOS) (31.5 months vs. 16.1 months) and lowered the risk of death by 53 percent compared to conventional platinum-based chemotherapy.
Other highlighted data included results from the CheckMate 901 study, which evaluated Opdivo plus platinum-based chemotherapy (gemcitabine/cisplatin) vs. platinum-based chemotherapy alone in first-line treatment.
The study showed that Opdivo plus chemotherapy improved the primary endpoints of PFS and OS by 28 percent (7.9 months vs. 7.6 months) and 22 percent (21.7 months vs. 18.9 months), respectively, with a significant prolongation of median PFS in the Opdivo arm of 37.1 months vs. 13.2 months.
These two studies were selected side-by-side for the society's Presidential Symposium, recognizing the value of innovation in first-line treatment dominated by chemotherapy for the past 30 years.
However, these two therapies are expected to significantly impact subsequent treatment strategies once they reach the clinic following regulatory approval.
The first to be hit will be the maintenance regimen of Bavencio. This is because Bavencio has become the first immunotherapy to demonstrate a survival benefit in first-line maintenance therapy, setting a new global standard over the past two to three years.
In the JAVELIN Bladder 100 study, the mOS of the Vavencio maintenance arm was 29.7 months, more than nine months longer than the optimal supportive care arm (20.5 months), and all patients showed an improvement in survival of more than eight months compared to the control arm, regardless of their first-line chemotherapy treatment option.
This effectiveness has been recognized in Korea, and insurance benefits have been applied to Bavencio maintenance therapy since August.
The reimbursement of Bavencio in the Korean treatment environment, where “reimbursement means treatment,” has also led to significant changes in follow-up care.
Initially, when only platinum-based chemotherapy was available for first-line treatment, Keytruda monotherapy could be used for second-line treatment. However, using the same immunotherapy as maintenance therapy earlier, immunotherapies could not be used again in patients with advanced disease.
Fortunately, with the recent introduction of Padcev in Korea, there is a new follow-up treatment option for patients who have failed the maintenance therapy of Bavencio. Still, it is not yet covered by insurance, which limits its actual use. The same applies to the recently introduced Valvesa (uldapitinib), the first FGFR inhibitor.
This is compounded if Keytruda, Opdivo, and Padcev emerge as first-line treatment options.
Since most of the follow-up treatment options developed to date have been tested in patients who have failed platinum-based chemotherapy, a shift in first-line therapy toward immunotherapies and ADCs could lead to a significant lack of evidence for their use in follow-up.
That also explains why experts and patients are not exactly overjoyed smiling, although the surge of positive data is writing new history in treating metastatic bladder cancer for the first time in 30 years, medical sources said.