Biomarker or bust? Does PD-1 therapy need a biomarker to hit the big time in NSCLC?

by Debbie Warner | Aug 7, 2015

Opdivo (nivolumab, Bristol-Myers Squibb) is approved for the treatment of patients with squamous cell non-small cell lung cancer (NSCLC) who have relapsed on platinum-based chemotherapy. Based on the clinical trial that served as the basis for approval, Opdivo did not stratify response rates based on PD-L1 levels, and the approved label does not have a biomarker requirement. Uptake for Opdivo in second-line NSCLC has progressed briskly since its launch in March 2015, with revenue of $35 million in May, nearly triple March sales of $12 million (Symphony, accessed July 14, 2015). Analysts had forecasted approximately $349 million in U.S. sales for Opdivo in second-line NSCLC (Evaluate Pharma, accessed June 3, 2015).

Clinicians are becoming more comfortable with using Opdivo in second-line squamous NSCLC but eagerly awaited data from the Checkmate-057 trial at the recent annual meeting of the American Society of Clinical Oncology (ASCO) before considering expanding use of Opdivo into the more prevalent non-squamous NSCLC (Kantar Health oncologists interviews conducted from April to May 2015). According to one community oncologist interviewed, “It’s always exciting to have things for melanoma, but we’re very excited to think about nivolumab in squamous cell carcinoma of the lung, because we don’t have many options. Those patients are usually sicker… so to be able to use this as second-line would be great, since it is a bit easier than most chemos.”

Looking to where will PD-1 blockade fit in the treatment of NSCLC

Opdivo is representative of a host of immunotherapies, including Keytruda (pembrolizumab, Merck), already approved for metastatic melanoma, in clinical development targeting PD-1/PD-L1 in first- through third-line NSCLC. Current standard of care in first-line, non-squamous, non-EGFR-positive patients is platinum-based doublet chemotherapy. While second-line treatment is highly variable, docetaxel dominates (Kantar Health CancerMPact 2015, accessed June 9, 2015). These relatively low-cost, generic regimens are poised to be overtaken by more effective, better tolerated, but significantly more expensive immunotherapy therapy.

ASCO presenter Leonard Saltz, M.D. of Memorial Sloan Kettering praised the clinical value of an Opdivo + Keytruda combination as being “truly, truly remarkable,” but he added that with the combination costing nearly $300,000 (if continued for 11 months) “these drugs cost too much – unsustainable.” While Dr. Saltz is an unabashed critic of cancer drug prices, $300,000 would give most people pause. Concern about the increasing cost of breakthrough cancer treatment heightens when one considers the number of immunotherapies – like Opdivo and Keytruda – in development for a broad range of solid tumors as well as hematologic malignancies. In fact, at least 33 of the 279 trials studying immune therapies are for combinations with each other and/or in combination with other novel agents. Cost of novel therapy combinations may be the most important factor in limiting these treatments moving forward, and it’s no surprise that discussions of the game-changing nature of immunotherapy are often accompanied by questions of cost sustainability.

While the easiest way to address the issue of cost may be to dramatically cut prices, development and innovation would no longer flourish. A more realistic approach would be to limit treatment to those patients most likely to respond, as assessed by some objective biomarker. Payers and providers would agree that this makes sense in principle. After all, retrospective analyses of data from clinical trials have shown positive correlations between PD-L1 expression and efficacy. However, researchers are unanimous that there is too much scientific evidence that PD-L1 expression is not an appropriate biomarker for it to be used for patient selection. Further, payers seem unconvinced that biomarkers are the solution. In an April 2015 Kantar Health Oncology Market Access survey, commercial payers expressed tepid enthusiasm about the value of biomarkers.

With no clear biomarker to determine whom to treat with PD-1 drugs, payers will find it difficult to implement prior authorization criteria or treatment pathways that can limit use of PD-1 to patients who are most likely to benefit. For example, the current treatment pathway created by the health plan Anthem Blue Cross® for second-line NSCLC does not specify treatment options for squamous histology by PD-L1 status. For that matter, Opdivo is not included as a treatment on their pathway at all (https://anthem.aimoncology.com/pdf/pathways/Cancer_Pathways_Clinical_Detail.pdf, accessed on June 3, 2015). National Comprehensive Cancer Network (NCCN) guidelines version 5.2015 recommend nivolumab for only for squamous cell NSCLC after progressing on platinum-based chemotherapy. However, release of these data at ASCO is expected to lead to a revision of these guidelines and possible recommendation (based on Level IIB evidence) for expanded use of Opdivo in the non-squamous setting. As NCCN guidelines underpin most oncology treatment pathways, their broader inclusion into these guidelines will likely increase pressure to include PD-1 drugs on treatment pathways. Even if the Food and Drug Administration (FDA) does not mandate it in the label, payers may still require PD-L1 testing for non-squamous patients as part of their pathways or prior authorization process. However, they will likely be compelled to exhibit significant flexibility in the PD-L1 levels required to authorize coverage. It is more likely that, at least initially, payers could deny reimbursement for patients with ALK or EGFR mutations and a negative smoking history, based on the lack of efficacy demonstrated in those patient populations in the CheckMate studies while they wait for broader consensus from the scientific community on the use of PD-L1 testing.

Moving forward…now that we know that PD-1 and PD-L1 drugs are here to stay!

Although the title of the ASCO Special Session was “Immunotherapy for every patient, Check your enthusiasm,” perhaps oncologists and the investment community may find a hard time not to, and payers will need to check their blood pressure moving forward.

The data presented for the PD-1 and PD-L1 drugs during ASCO in numerous tumor types was impressive. From renal, bladder, small cell lung cancer, liver cancer, and exploratory combinations, PD-1 drugs may literally transform the treatment of oncology from a chemo/targeted therapy approach to an immunotherapy one. As Michael B. Atkins, M.D., of Georgetown University Medical Center discussed at the plenary session at ASCO, “In order to increase effectiveness of PD-1 treatment, they may need to be combined with drugs that increase the movement of T-cells into the tumor (drugs like Yervoy can help with this) and creating more T-cells (CAR-T, TCR, chemo and vaccines).” However, when combined with PD-1 drugs, the costs of the combinations may be the most important factor in limiting these treatments moving forward.

Leave a comment

More than one Google Analytics scripts are registered. Please verify your pages and templates.