ACCC: What do you see as the standout developments in immuno-oncology in 2018?
Dr. Schwartzberg: I think the high-level standout development is the continued remarkable rollout of programmed-death-1 (PD)-1 and PD-L1 antibody therapies for a variety of diseases. There’s been no slowing down of the number of indications for now-established drugs, as well as new drugs, in the clinical armamentarium to treat a variety of diseases.
For example, we now have approval for the use of pembrolizumab in cervical cancer for PD-L1 positive disease. We also have the approval of nivolumab in small cell lung cancer, the first indication in that disease for late-line therapy. In September, cemiplimab-rwlc, a new anti-PD-1 inhibitor, was approved for metastatic or locally advanced cutaneous squamous cell carcinoma (cSCC). This is the first drug that’s been approved for metastatic squamous cell cancer. In stage III unresectable non-small cell lung cancer (NSCLC) we now have the approval of durvalumab.
Then, we have the additional uses of both PD-1 and PD-L1 antibodies either as single agents or in combination therapy. For instance, the combination of nivolumab and ipilimumab is approved as first-line treatment for renal cancer and that same combination is approved for microsatellite instability-high (MSI-H) colorectal cancer. The effectiveness of combination therapy with two checkpoint inhibitors raises the promise of 800-plus studies being done with a range of combination therapies including immune system agonists and antagonists.
Finally—and I think this is really important—we now have very, very solid data for the combination of chemotherapy and anti-PD-1 therapy in non-small cell lung cancer (NSCLC). Just this month, the United States Food and Drug Administration (FDA) approved atezolizumab in combination with bevacizumab, paclitaxel, and carboplatin for first-line treatment of metastatic non-squamous non-small cell lung cancer (NSq NSCLC) with no EGFR or ALK genomic tumor aberrations. From a clinical perspective, we’re now seeing that almost all patients with NSCLC are likely to receive in the first-line setting either monotherapy or combination therapy including a PD-L1 inhibitor. It’s been a remarkable three-year journey from the first data in 2016 showing that single agent checkpoint inhibitor monotherapy would help patients in the second-line setting. Now, in just a few short years, it’s become the standard of care for virtually all patients in the first-line for NSCLC.
ACCC: What progress have you seen in the search for biomarkers in 2018?
Dr. Schwartzberg: Biomarkers remain a quest in immunotherapy, particularly in relation to checkpoint inhibitors. PD-L1 remains an important biomarker, although admittedly far from perfect. We have some debate in NSCLC about stratifying patients to monotherapy vs. combination chemotherapy and checkpoint inhibitor. In patients who have very high expression of PD-L1 we do not yet have data to support direct comparison, but in cross-trial comparisons—with all the usual caveats about making cross-trial comparisons—we see very good response data for monotherapy with pembrolizumab in that high expresser range, such that people who have higher PD-L1 levels in NSCLC tend to get more benefit from the addition of the checkpoint inhibitor. However, even patients with low or no expression also seem to get some benefit, so we need to tease out the subgroups that derive the best benefit and try to develop other approaches for those who get minimal or very modest benefit. While there is variation from disease to disease, there’s clearly still an important role for PD-L1 expression as a relatively easily-measured biomarker with some discriminatory power in terms of predicting response to therapy or benefit from therapy.
Microsatellite instability (MSI), or mismatch repair deficiency (dMMR), and tumor mutational burden (TMB) are two biomarkers that are becoming more important. Looking back to 2017, one of the big stories was the first FDA pan-tumor approval based on a biomarker (MSI or dMMR) versus tumor location. That excitement continues today. I think most physicians are now more routinely measuring the presence of MSI in a variety of cancers where there isn’t other therapy, or standard therapy has been exhausted. We have approval in colorectal cancer for the combination of ipilimumab plus nivolumab, and pembrolizumab as a monotherapy in all cancers for dMMR or MSI-high. So, testing is becoming more ubiquitous. Close behind as an emerging biomarker—although less data driven so far, but with tantalizing data—is tumor mutational burden (TMB), which is now also being more commonly reported in comprehensive molecular profiling. While there is a lot to learn about TMB—who truly benefits and even standardizing it across tumor types—there are already many hints that high TMB is predictive of response to checkpoint inhibitors across tumor types.
ACCC: Do you see sequencing tumor DNA as becoming standard of care for many tumor types?
Dr. Schwartzberg: I believe it already has and it’s going to continue. Increasingly, community-based providers will be doing comprehensive molecular profiling. You can make the case to test a patient with sequencing if there is no standard therapy left to treat them. Most of the laboratories that are now doing molecular profiling are including MSI-high or dMMR and TMB in their reports. It makes a pretty compelling argument to increase the frequency of DNA sequencing and perhaps move testing up earlier into the treatment paradigm of when you test if the patient has metastatic disease.
ACCC: Are reimbursement and payer policies lagging behind in this area?
Dr. Schwartzberg: My sense is that payers are becoming more comfortable with paying for MSI or dMMR testing because it does yield some pretty rich information. Although it’s expensive, the cost of testing is really dwarfed by the potential benefit or the cost of the drugs; so I see change driven in part by the FDA approval of these tests. I think we’ve reached an inflection point where over the next year or two we will see less payer pushback to doing molecular profiling.
ACCC: What other policy concerns are a focus for the ACCC IO Institute?
Dr. Schwartzberg: The cost of drugs is a big focus of concern in the country right now. IO drugs are quite expensive, and they are given a for prolonged period. The cost of treating patients for years at time is unsustainable, despite the fact that you can make a very strong case that the value of using IO agents is higher than that of using many other expensive oncology drugs that provide a few months of progression-free survival.
There is still a lack of consensus regarding a value structure to which all stakeholders can agree and what the metric should be for measuring value—particularly as it relates to IO. From both a federal perspective and Medicare, current and planned proposals for reimbursement are uncertain. A concern that many practices have with the impending changes being considered is that any reduction in the slender margin that supports the entire community infrastructure will be a challenge.
ACCC: Final thoughts as 2018 winds down and we move into the New Year?
Dr. Schwartzberg: Immunotherapy is assuming an even greater importance in the treatment of multiple cancers, and it’s very clear that IO will become a standard in the majority of cancers in a variety of settings—potentially even moving into early treatment, that is, adjuvant treatment in the next few years. IO is not only a new pillar in the armamentarium of cancer treatment, it may well become the dominant pillar as things go forward.
As we enter 2019, it’s important to remember that we’re still really at the very beginning of this journey. We understand a lot about the checkpoint inhibitors, but the immune system is so complex. We have so many other different agents that could enhance the immune response, given either with a checkpoint inhibitor or alone. Cellular therapies are also clearly established as effective therapies that. as currently constituted, come with an enormous cost. We have challenges at the payer level and the federal level to figure out how this new class of therapies can be integrated into real-world practice.
Despite these challenges, the future looks extremely broad and bright for immunotherapy.