The Evolving Role of PD-L1 Testing in Immunotherapy of Metastatic Melanoma and Non-Small Cell Lung Cancer
By Bill Bowman, J.D.
The Treatment of Cancer is Becoming More Precise
The movement toward precision medicine in oncology has accelerated over the past few years, driven by the emergence of multiple agents that target specific biomarkers across a wide array of malignancies, as well as the availability of companion diagnostics used in molecular testing. The standard of practice has evolved such that most oncologists routinely test their patients for the more established biomarkers in certain tumor types, e.g., EGFR mutations and EML4-ALK in metastatic non-small cell lung cancer (mNSCLC) and BRAF mutations in metastatic melanoma (mM).1
The Emergence of Immuno-Oncology
More recently, immunotherapy – unleashing the body’s immune system to attack malignant cells – has risen to the fore as the latest exciting development in the treatment of cancer. The introduction of the PD-1 checkpoint inhibitors Opdivo® (Bristol-Myers Squibb) and Keytruda® (Merck) over the past year has already had a major impact on the market dynamics for mM and mNSCLC. Both Opdivo and Keytruda work by blocking PD-1 on the surface of immune cells, disrupting its interaction with PD-L1 on cancer cells. This lifts a natural brake on the immune system (i.e., PD-1), allowing it to kill cancer cells.
To date, each of these brands has captured a large share of the mM market, particularly among pre-treated patients.2 Opdivo was just recently cleared for use in combination with Yervoy® for frontline treatment of mM. In the mNSCLC arena, Opdivo has leveraged its FDA approval for treatment among second-line or greater squamous cell patients to become the dominant player in this segment. Both PD-1 inhibitors gained full approval for second-line or greater NSCLC in October 2015 and early tracking data indicate that both brands (particularly Opdivo) have already made substantial inroads in the non-squamous market.3
Yet, the early commercial success of these PD-1 inhibitors has been accompanied by uncertainty and questions with respect to patient selection.
In what types of patients should they be used?
Can these agents be prescribed to “all comers” regardless of PD-L1 status?
Should their use be restricted to patients who express PD-L1?
If the approach is to administer these agents only to patients who are “PD-L1 positive”, how is this defined?
And further, how does the level of PD-L1 expression correlate to efficacy?
Clinical Trial Data Based on PD-L1 Status
> PD-L1 Expression in mNSCLC
As illustrated in Table 1, data from the KEYNOTE-001 trial involving Keytruda in patients with advanced NSCLC demonstrated the highest overall response rate (ORR) of 45.2% among patients with high levels of PD-L1 (defined as >50% of tumor cells expressing PD-L1).4 Results from the CHECKMATE-057 trial of Opdivo vs. docetaxel in pre-treated patients with non-squamous cell NSCLC also demonstrated a benefit among patients expressing PD-L1, albeit at lower levels. On the other hand, in the KEYNOTE-001 study, clinical activity was observed in a smaller group of patients who were PD-L1-negative or who expressed only low levels of this protein; and in the CHECKMATE-017 and 063 trials, patients with previously treated squamous cell NSCLC derived a benefit from Opdivo regardless of PD-L1 status.5