It was hard to miss the news recently about survival rates for lung cancer patients who incorporate immune therapy into their treatment. The New York Times ran a story titled “Lung Cancer Patients Live Longer With Immune Therapy.” The opening of the story caught my eye: “Odds of survival can greatly improve for people with the most common type of lung cancer if they are given a new drug that activates the immune system along with chemotherapy, a major new study has shown.”
That was pretty strong, but then this quote about the new treatment really made me stop and read the article from end to end: “What it suggests is that chemotherapy alone is no longer a standard of care.”
Whenever I hear “standard of care” I immediately think InterQual®, because InterQual is all about supporting clinicians with the most current, evidence-based clinical criteria that are the standard of care for a given medical condition or treatment plan. So I fired off an email to share the story with some of my colleagues and see where we’re at around this particular therapy. We talk a lot about how InterQual synthesizes the latest, best medical evidence into clinical criteria at your fingertips. Here was an opportunity for me to put that concept to the test.
There was good news: The response I got is that we already cover multiple indications for several immunotherapy drugs (including the one mentioned in the Times article) and that we were indeed adding clinical evidence regarding new CAR-T therapy (Kymriah) to InterQual in our September 2018 release. It was a pretty fast turnaround for a new, breakthrough treatment. But what were the steps to get from breakthrough treatment to InterQual?
While I know the answer to this, you, dear reader, may not, so I want to share with you how that process operates. Before we do that, let’s talk a little about what this therapy is and why it’s so interesting. (I’m sure many of the clinicians in our audience already know this, so you can skip ahead to the next section.) But for those of you who aren’t familiar with this therapy, let me tell you what it is and how it works.
A Fast Education
You may have seen the advertisement on TV where the woman thanks her doctors for giving her Keytruda, a new immunotherapy, for her non-small-cell lung cancer (NSCLC). The use of immunotherapy is pricey (Keytruda costs approximately $13,000 per month or $150,000 per year), but studies have shown that these drugs significantly prolong progression-free and overall survival when compared with chemotherapy used alone.
Although immunotherapies have been approved by the FDA for quite some time (the first immunotherapy drug, ipilimumab [Yervoy], was approved for the treatment of metastatic melanoma in 2011), immunotherapy has shown such great promise that the FDA approved 18 immunotherapy drugs in the period from January 2015 to June 2018 alone. Immunotherapy includes monoclonal antibodies, vaccines, oncolytic virus therapy, and T-cell therapy. These medications work by attacking cancer, or by boosting or replacing the patient’s immune system. Uses for immunotherapy continue to expand to many cancer types (e.g., lung, breast, head and neck, skin, kidney, liver, stomach, bladder). Let’s review this treatment for lung cancer.
Immunotherapy was introduced in the treatment of lung cancer in 2015. Immune checkpoint inhibitors, such as Keytruda (pembrolizumab), have transformed treatment for advanced NSCLC. A checkpoint inhibitor is a type of drug that blocks the programmed cell death protein 1 (PD-1) protein on T cells or the programmed death-ligand (PD-L1) protein on tumor cells. These checkpoint proteins help keep immune responses in check.
The American Society of Clinical Oncology’s (ASCO) clinical practice guideline for advanced NSCLC was revised in 2017 to add immunotherapy as a standard treatment approach for either first-line or second-line settings (Hanna et al., J Clin Oncol 2017; 35:3484-3515). ASCO estimates that, in the United States alone, 250,000 years of life would be saved if all eligible patients received a checkpoint inhibitor. An estimated 25% of people who receive checkpoint inhibitors as initial treatment and 10% of those who receive them as second-line treatment may live longer than five years after treatment initiation, in comparison to an average of 2.5 years with standard treatment.
There are currently four FDA-approved checkpoint inhibitors for previously treated NSCLC (nivolumab, pembrolizumab, atezolizumab [Tecentriq], and durvalumab); pembrolizumab can also be used as initial therapy in select patients (Brahmer et al. Journal for Immunotherapy of Cancer 2018; 6:75). In a double-blind, phase III, randomized study, overall survival was nearly 70% in the pembrolizumab-chemotherapy combination group versus 50% in the placebo-chemotherapy cohort. Median progression-free survival was 8.8 months versus 4.9 months, respectively (Gandhi, N Engl J Med 2018; 378:2078-2092). An international phase III clinical trial is underway, with a completion date of April 2019, to confirm these findings (ClinicalTrials.gov identifier: NCT02578680).
Outcomes when giving nivolumab (Opdivo) after standard treatment of early-stage lung cancer are being studied in the ALCHEMIST immunotherapy trial (ClinicalTrials.gov identifier: NCT02595944).
In a clinical trial of patients with Stage III, locally advanced NSCLC, durvalumab (Imfinzi) demonstrated a median time until cancer worsening of 16.8 months, while disease worsened at 5.6 months in those given placebo; the median time until patients died or the cancer metastasized was 23.2 months versus 14.6 months, respectively (Antonia et al., N Engl J Med 2017; 377:1919-1929).
How It All Gets into InterQual
The use of checkpoint inhibitors has revolutionized the treatment of lung cancer. The optimal chemotherapy regimens to combine with this medication need additional study, however. To aid physicians in decision-making, InterQual has provided Specialty Pharmacy Oncology Criteria for these drugs since early 2017. The criteria now cover pembrolizumab for 30 cancers and nivolumab for 15 cancers. Ipilimumab is now being offered for a total of five indications. InterQual guidance for the genetically modified drug Kymriah (tisagenlecleucel) is currently under development for release this year and Yescarta (axicabtagene ciloleucel) will follow.
Because this is so new and not yet the standard of care, when reading this news, InterQual clinical developers research the validity of the results (e.g., critically appraise published articles and trial results), and then develop guidance for our users. For example, they look at the appropriateness of using “XYZ” drug—which conditions it is effective in treating, comorbid conditions and/or adverse effects which would limit use of the drug, and short-term outcomes, among other factors. Our interpretation of these guidelines is then validated by external experts in the field.
There could potentially be new drug treatments released daily, so the decision on which to add to the InterQual Criteria is driven by market demand for the content coupled with critically appraised evidence. Priority for adding new guidance would be given to drugs that could have the greatest impact on patient outcomes; those drugs that replace standard treatment; medications that are costly and need support for initiating or continuing their use; and drugs that may be restricted to select patient populations (for example, the elderly, HIV patients, diabetics).
The InterQual team works closely with our expert consultant panel of more than 950 practicing clinicians dispersed across the country, as well as in-house librarians, and uses alerts from our proprietary surveillance system that monitors over 3,000 guidelines for notification of new publications. New studies that are published are rigorously appraised by the InterQual clinicians, all extensively trained in concepts and methods of evidence-based medicine (EBM) and value-based clinical improvement, as well as critical appraisal based on AHRQ Methods, Cochrane and NICE development, and the GRADE methodology; the criteria are then updated accordingly. Therefore, the content is up to date and reflects the latest evidence to support the use of these new drug therapies.
As mentioned earlier, both immunotherapy drugs pembrolizumab (Keytruda), and nivolumab (Opdivo) have shown tremendous promise in the treatment of NSCLC. Because of that, InterQual Criteria now cover Keytruda used as first-line and subsequent therapy of Stage IV or Recurrent NSCLC, while Opdivo is appropriate for use for first-line NSCLC therapy.
In short, that’s how the magic happens. We continually monitor the published literature for the latest best evidence, then vet that evidence. If it meets evidentiary standards, we fast-track it into the InterQual Criteria. Case in point: immunotherapy. It was talked about in The New York Times in the spring and integrated into InterQual criteria by the summer. By keeping abreast, we stay ahead.
Lynanne B. Morganstern, MD, MBA, is Medical Director, InterQual, for Change Healthcare