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FDA Guidance for Pembrolizumab and Atezolizumab
My Thoughts on the New FDA Guidance for Pembrolizumab and Atezolizumab in Bladder Cancer

Released: August 28, 2018

Expiration: August 27, 2019

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In June 2018, the FDA and European Medicines Agency (EMA) issued an important restriction to the first-line use of immune checkpoint inhibitors (ICIs) for patients with urothelial carcinoma: Only those patients who are not eligible for cisplatin-containing therapy and whose tumors express higher levels of PD-L1 or are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status should be considered.

Both pembrolizumab and atezolizumab originally received accelerated approval in 2017 as first-line treatment for patients with cisplatin-ineligible, metastatic urothelial cancer following strong, durable responses and promising OS in 2 phase II trials: IMvigor210 (atezolizumab) and KEYNOTE-052 (pembrolizumab). Previously, options for cisplatin-ineligible patients with urothelial cancer were limited to non-cisplatin chemotherapy, typically gemcitabine and carboplatin.

Shorter Survival With Low PD-L1 Expression
However, by mid-2018, the FDA reported that early data from the subsequent phase III KEYNOTE-361 and IMvigor130 studies of chemotherapy plus ICI or ICI alone vs chemotherapy alone in patients with previously untreated advanced urothelial carcinoma showed a decreased survival signal with pembrolizumab or atezolizumab monotherapy compared with chemotherapy in patients with low PD-L1 expression.

As a result of the decreased survival signal, the FDA issued an alert and restricted first-line use of atezolizumab and pembrolizumab in cisplatin-ineligible urothelial carcinoma to those with a minimum level of PD-L1 expression as described below.

Unfortunately, there are currently no data available regarding the decreased survival described in the updated indications for these agents. Although the FDA’s and EMA’s choice to apply the restriction seems appropriate, it uncertainty will exist until these data are released publicly.

One of the results of this change is that most clinicians who treat patients with urothelial carcinoma now need to consider PD-L1 biomarker analysis as part of the standard workup for cisplatin-ineligible patients. Of note, patients who are eligible for cisplatin should continue to receive cisplatin-based chemotherapy and those who are ineligible for any platinum-based agent (ie, not just cisplatin) can receive first-line PD-1/PD-L1 checkpoint inhibitors regardless of PD-L1 expression. In addition, the existing indications for ICIs as second-line therapy for urothelial carcinoma have not changed.

Testing Recommendations for PD-L1
There are multiple FDA-approved PD-L1 companion diagnostic assays, each specific for the individual ICIs. How much the differences between these assays matter is as-yet unclear, but clinicians should send samples out for testing based on agent indications and the specific ICI they are likely to recommend. The assays use different antibodies and have different criteria for positivity.

The pembrolizumab companion diagnostic PD-L1 biomarker assay uses the murine 22C3 antibody to detect PD-L1. PD-L1 positivity, in this case, is defined by a combined positive score (CPS)—the ratio of PD-L1–expressing tumor-infiltrating immune cells relative to the total number of tumor cells—of at least 10.

The companion diagnostic PD-L1 assay for atezolizumab uses the SP142 rabbit antibody. PD-L1 staining on tumor‑infiltrating immune cells covering at least 5% of the tumor area is the criteria for positivity. I expect that PD-L1 testing will continue to be refined as results from KEYNOTE-361, IMvigor130, and other large randomized studies of ICIs become available.

Patient Eligibility Considerations
The next question is how should clinicians draw that line between patients who are eligible for chemotherapy but not eligible for cisplatin and those who are ineligible for any platinum agent? The formal cisplatin-ineligibility criteria are:

  • Creatinine clearance < 60 mL/min
  • Eastern Cooperative Oncology group performance status of 2
  • Grade ≥ 2 neuropathy or hearing loss
  • New York Heart Association class III congestive heart failure

In addition, other factors can preclude cisplatin use and/or carboplatin use, including coexisting medical problems and impaired performance status. For example, an octogenarian with multiple medical issues and a borderline performance status may not be able to tolerate any systemic chemotherapy. Additional medical comorbidities that may raise concern for the use of systemic chemotherapy in elderly patients include a limited bone marrow reserve that increases the risks from bone marrow suppression such as infection, bleeding, and anemia; the use of steroids in a patient with diabetes; polypharmacy; and risk factors like smoking that lead to vascular disease and chronic obstructive pulmonary disease. Although these are not absolute contraindications for chemotherapy use in older patients, these are genuine concerns that may preclude consideration of any platinum‑based chemotherapy in a particular individual; there is a growing recognition that we can safely treat elderly patients like this with ICIs.

Chemotherapy Continues to Have a Role in Bladder Cancer
The next question that arises is what if patients are PD-L1 negative once tested? This group can be offered either alternative chemotherapy or potential enrollment on clinical trials. Regarding chemotherapy, we typically use the standard approach of gemcitabine and carboplatin in the absence of any contraindication. The dose‑limiting toxicity of both agents is myelosuppression and usually managable. In the phase II clinical data for pembrolizumab and atezolizumab ORRs of 20% to 30% were reported. In the randomized EORTC 30986 study of gemcitabine and carboplatin vs methotrexate, carboplatin, and vinblastine (MCAVI) in cisplatin-ineligible advanced urothelial cancer, the response rate was 36%, the median OS was approximately 9 months, and the 1‑year survival rate approached 40%. Chemotherapy is certainly not perfect but does work in some patients.

Unfortunately, we do not have predictive biomarkers for chemotherapy, although recent data suggests that alterations in DNA damage repair genes may help. For example, I initially treated a patient with urothelial cancer with an ICI, but she progressed quickly. Next-generation sequencing showed a DNA damage repair gene alteration, so when she progressed, I switched her to gemcitabine and carboplatin. She had a major response to the chemotherapy and is doing well.

As mentioned, ICIs are indicated for patients with progression on chemotherapy, regardless of PD-L1 expression. But do some chemotherapies predispose patients to do better or worse with subsequent immunotherapy? This question is being looked at in clinical trials. Chemotherapy may alter the immune microenvironment such that some patients may be more likely to respond to subsequent ICI. Certain chemotherapeutic drugs (eg, oxaliplatin) may facilitate responses to subsequent ICI when otherwise the patient might not respond at all.

Combination Regimens
As mentioned, the ongoing KEYNOTE‑361 and IMvigor130 studies are evaluating combining chemotherapy with immune checkpoint blockade as first-line therapy for metastatic urothelial carcinoma. Although there appears to be an inferior survival signal associated with checkpoint inhibitor monotherapy compared with chemotherapy in this setting, the emerging data with combination chemotherapy and PD-1/PD-L1 blockade are exciting. In the setting of lung cancer, combining platinum-based doublet chemotherapy with an ICI demonstrated substantial improvement in outcome, regardless of PD-L1 expression. Another example of benefit from a combination approach is melanoma, where combined immune checkpoint blockade (PD-1/PD-L1 and CTLA-4) was superior to monotherapy. Clearly, the use of PD-1/PD-L1 checkpoint inhibitors is continuing to evolve in the setting of urothelial cancer.

Your Thoughts
How do you anticipate managing your patients with newly diagnosed bladder cancer after this new information? Please share your thoughts by joining the conversation in the comments box below and responding to the polling question at the right of your screen.

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