This new class of immunotherapeutic antibodies, led by atezolizumab, offers patients with metastatic or locally advanced transitional cell carcinoma hope for nontoxic, durable responses.— Nicholas J. Vogelzang, MD
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The recent study by Rosenberg et al in The Lancet—summarized in this issue of The ASCO Post—is a very important paper in the field of bladder cancer therapy.1 It is the first phase II trial in metastatic transitional cell carcinoma that demonstrates the single-agent activity of the investigational programmed cell death ligand 1 (PD-L1) antibody atezolizumab.
Based on objective response rate and low level of toxicity, atezolizumab appears to be superior to all other current single agents used in second-line therapy for transitional cell carcinoma. Moreover, the trial reported by Rosenberg et al strongly confirms the activity of atezolizumab seen in the phase Ib trial of Powles et al.2
Concordant Studies
In the phase Ib trial, patients were initially selected for entry based on PD-L1 expression of 2 to 3+ on the infiltrating immune cells (IC 2/3) in the tumor (not PD-L1 expression on the tumor cells). A subsequent group of patients with IC 0/1 disease were entered on the trial. In the selected set of patients, the objective response rate was 43% (95% confidence interval [CI] = 26%–63%) in 30 IC 2/3 patients and 11% (95% CI = 4%–26%) in 35 IC 0/1 patients.
In the study by Rosenberg and colleagues with triple the number of IC 2/3 and six times the number of IC 0/1 patients, those two populations experienced objective response rates of 27% (95% CI = 19%–37%) in 100 IC 2/3 patients and 10% (95% CI = 5%–18%) in 211 IC 0/1 patients. Response duration is likely to extend well beyond 1 year.
These two studies are thus remarkably concordant, significantly narrow the confidence intervals around the response rates, and together should lead to U.S. Food and Drug Administration (FDA) approval of the agent for metastatic transitional cell carcinoma. I should note that the phase II trial was conducted in 70 centers, while the phase Ib study accrued patients from 15 centers, adding to the robustness and clinical reproducibility of the findings.
Remarkable Safety Profile
While objective response rate and durability of response are the major advantages of this drug compared to its competitors, such as docetaxel/paclitaxel, pemetrexed (Alimta), and vinflunine (approved in Europe but not in the United States), the low level of toxicity is quite remarkable. All-cause grade 1 to 4 toxicity (which was not necessarily treatment related) most commonly included fatigue (49%), decreased appetite (27%), nausea (26%), fever (22%), diarrhea (20%), vomiting (18%), arthralgias (17%), pruritus (13%), and rash (10%). However, the rate of grade 3 or 4 toxicity was mostly 1% to 2%, with fatigue at 6%.
Immune-related toxicities were equally low at 5%. No renal dysfunction was reported, and the drug can be safely given in patients with significant renal dysfunction, a common scenario in this population of cisplatin-pretreated patients, who regularly experience obstructive hydronephrosis and renal unit loss.
Predicting Response
The authors performed a number of novel exploratory translational studies to understand the characteristics of the patients responding to atezolizumab. They studied mutational load in the cancer, and the activity of the drug was clearly higher (P = 1.54 × 10-5) in patients with a high mutational load. This is reminiscent of the responses seen to pembrolizumab (Keytruda) in Lynch syndrome patients, who also carry tumors with a high mutational load (due to an inability to repair DNA damage efficiently).
They also showed that response could be predicted by the transitional cell carcinoma subtype. There are four general molecularly defined transitional cell carcinoma subtypes in The Cancer Genome Atlas (TCGA)—luminal and basal, which are then subdivided into papillary-like (luminal cluster 1), luminal cluster 2, squamous-like (basal cluster 3), and basal cluster 4. Mutational load was not related to TCGA subtype (P = .22), but response was significantly higher in luminal cluster 2 (34%) compared to the other clusters (P = .0017).
The authors concluded that “although PD-L1 immune cell status is clearly associated with atezolizumab response, incorporation of The Cancer Genome Atlas gene-expression subtype, mutational load, or both of these novel biomarkers … will allow the formal construction of … a next-generation companion diagnostic.”
I certainly hope that the FDA will approve the agent without regard to IC staining since clearly some IC 0/1 patients experience excellent remissions. Other factors such as mutational load and TCGA cluster type may be even more important in predicting response to atezolizumab.
Looking Ahead
While atezolizumab is the first immune checkpoint inhibitor to achieve this milestone of activity in transitional cell carcinoma, other checkpoint inhibitors are not far behind. Pembrolizumab has shown activity in a phase I/II trial,3 and a phase III trial of pembrolizumab vs docetaxel/paclitaxel, pemetrexed, or vinflunine has been completed. A trial of nearly identical design has been completed using atezolizumab.
Meanwhile, durvalumab (MEDI4736) was granted Breakthrough Therapy designation in February 2016 for PD‑L1–positive urothelial bladder cancer that has progressed through a prior platinum-based therapy. This was granted based on a phase I trial, with phase II testing underway and a phase III trial planned.
Nivolumab (Opdivo) has finished its phase II testing in metastatic urothelial cell cancer. The investigational agent avelumab is also showing similar activity based on a phase I trial4 and will move forward in the transitional cell carcinoma field.
In conclusion, this new class of immunotherapeutic antibodies, led by atezolizumab, offers patients with metastatic or locally advanced transitional cell carcinoma hope for nontoxic, durable responses. Over the next generation, these agents may find a role in the neoadjuvant and adjuvant therapies of muscle-invasive transitional cell carcinoma, in bacillus Calmette-Guérin (BCG)-refractory carcinoma in situ, and as maintenance therapy after chemotherapy. The future is indeed bright. ■
Disclosure: Dr. Vogelzang is a consultant and/or on speakers bureaus for Genentech/Roche, Pfizer, and Bristol-Myers Squibb.
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