Practicing medicine today requires balancing cost, treatment timing, and access to the best therapies for patients. This is especially critical in cancer, where the costs of newer agents have entered the stratospheric range, and where more narrowly defined treatments based on molecular selection are optimal. This competing need—to control costs while preserving good care—is understandable, and one way to address this challenge is to limit access to more expensive treatments.
Recently, the Centers for Medicare & Medicaid Services (CMS) announced that Medicare Advantage programs are now allowed to require step therapy for physician-administered and patient self-administered agents under Medicare Part B and Part D.[1]
Cancer, however, is likely to be far less forgiving.
This is just such a strategy. Step therapy is a type of prior authorization for drugs that gives patients access to more expensive treatments only if they have previously received and had a poor outcome on a lower-cost therapy. The American Society of Clinical Oncology (ASCO) immediately expressed opposition, with ASCO President Monica Bertagnolli, MD, arguing that “this not only delays patient access to proper treatments, it potentially leads to irreversible disease progression and other significant patient health risks.”[2]
These concerns are well founded. Patients with elevated blood pressure or cholesterol levels have the opportunity to refine treatment options toward the most cost-efficient but effective antihypertensive and lipid-lowering agents, respectively, targeting outcomes over years or even decades. Cancer, however, is likely to be far less forgiving.
We don’t need to look far to find examples in which deferring treatments until later translates to inferior survival. A study from Europe and Canada known as TORCH randomly assigned patients with advanced non–small cell lung cancer (NSCLC), not selected by molecular markers or clinical factors, to receive either first-line cisplatin/gemcitabine or erlotinib, then switch to the other treatment upon progression.[3] This study terminated early on the basis of a review of results by the Data Safety Monitoring Committee, which demonstrated a significantly worse progression-free survival (PFS) and overall survival (OS) in the recipients of first-line erlotinib (who we may assume were very unlikely to have a cancer harboring an EGFR mutation in this unselected broad population).
Notably, not only were PFS and OS significantly worse with the suboptimal treatment of erlotinib in an unselected patient population, but 41.7% of the patients assigned to first-line erlotinib did not receive second-line chemotherapy despite this being built into the protocol, “mostly because of worsening conditions or death.” And among those who were able to receive second-line cisplatin/gemcitabine, their objective response rate (ORR) was far less than half that obtained with this same regimen administered first-line (10.5% vs 25.6%).
With life-threatening lung cancer, at least, we learned that suboptimal treatment administered up front leads to fewer patients available for the best treatment later, and inferior outcomes among those who were able to receive it.
Several years later, at the 2018 ASCO annual meeting, we saw results from the Japanese randomized phase 3 NEJ009 trial of gefitinib alone versus gefitinib administered concurrently with carboplatin/pemetrexed chemotherapy as first-line treatment for patients with EGFR mutation-positive advanced NSCLC.[4]Despite EGFR tyrosine kinase inhibitor (TKI) therapy being a current standard and platinum doublet chemotherapy—most commonly the same carboplatin/gemcitabine regimen employed on the concurrent arm—being the recommended subsequent treatment approach for recipients of gefitinib, the trial demonstrated that concurrent targeted therapy and chemotherapy led to a significantly longer PFS (median, 20.9 vs 11.2 months) and OS (median, 52.2 vs 38.8 months).
The only way to ensure that patients receive beneficial therapies is to “front-load” them.
The more recent NEJ009 recapitulates some of the themes of the TORCH trial: Patients who received an EGFR TKI alone were more likely to have more extensive spread of disease and a performance status of 2-4 at the start of chemotherapy than those patients in whom chemotherapy was moved into the first-line setting, while 25.6% of the recipients of first-line gefitinib alone failed to receive chemotherapy later.
Similarly, we’ve seen several trials now demonstrating a survival benefit with a combination of platinum doublet chemotherapy and immunotherapy, and in which crossover rates are typically less than 50%. We have also seen similar results in other settings such as prostate cancer, in which early administration of docetaxel[5,6] or abiraterone/prednisone[7] is associated with significantly longer OS than subsequent treatment.
Beyond these specific examples, the improvements in clinical outcomes in patients who receive maintenance therapy in many cancer settings are likely predicated largely on this proactive approach. It ensures that patients receive the benefit conferred by a therapy without the risk that a higher tumor burden and/or declining performance status will compromise the ability to deliver the same treatment later.
The converging evidence clearly demonstrates that the only way to ensure that patients receive therapies that are beneficial for them is to “front-load” them. This doesn’t mean that every patient should receive all of their effective treatments in combination as first-line treatment. However, we see a recurring theme: For patients with aggressive cancers, progression and the potential clinical decline that may accompany it are associated with both a lower probability of receiving effective therapies subsequently and also potentially suboptimal results even when these treatments are administered. For many cancers, this inevitable attrition with step therapy will save money at the cost of worse clinical outcomes for patients.
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