Facts first, then comments.
Keynote -189: This phase III trial compared pembrolizumab (pembro), or placebo, plus pemetrexed and carboplatin as first-line therapy for metastatic NSCLC.
Presenter of Keynote–189, Leena Gandhi, MD, PhD, Director of Thoracic Medical Oncology at the Laura and Isaac Perlmutter Cancer Center, NYU Langone Health: The rationale of the study was not to see what IO might add to chemo, but rather to see if chemotherapy – which can be immunogenic – can add or expand the benefit of IO monotherapy in patients that might not have high PD-L1 expression; and this is indeed what we are seeing.
Alice T. Shaw, MD, PhD, Director of the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center: “This landmark study establishes the triplet as a new standard of care for advance non-squamous lung cancer – the improvement in OS with the addition of pembro to standard chemo across all patients, regardless of PD-L1 status, is really striking.”
Checkmate 227: Nivolumab (nivo) plus ipilimumab (ipi) vs. platinum-doublet chemotherapy as first-line treatment for advanced NSCLC
Note: This study was amended to include a co-primary endpoint based on a proposed new biomarker – tumor mutational burden (TMB). High TMB was defined as greater than 10 mutations per megabase (10mut/Mb). This interim report is related to those patients for whom TMB status was available; N=193.
Presenter of Checkmate -227, Matthew Hellmann, MD, Memorial Sloan Kettering Cancer Center: “Overall, my sense is that this study has the opportunity to introduce two new standards of care for patients with NSCLC, the first is that the study demonstrates the clinical value of nivo plus ipi as a treatment option for patients that are TMB high, with durable benefit, while sparing 1st-line chemo and thereby preserving effective 2nd-line options. Second, the study validates TMB as an important and independent biomarker to be routinely tested in treatment naïve advanced NSCLC patients.”
Commenting at an investor event, sponsored by Bloomberg Intelligence, just a few days prior to the AACR conference, John Heymach, Chair of the Thoracic Cancer Program at MD Anderson Cancer Center, speculated on the outcomes from these two trials.
Regarding Keynote 189: “This is already a widely used regimen, because we have the Keynote – 21G result, which reported a really surprising 0.53 hazard ratio for PFS. So for the 189 results, we’re not looking for a practice changing result, we’re looking for practice confirming results (21G was not powered for survival).”
“For 189, if it confirms a PFS of 0.6 or below – that would solidify this regimen as front line. (The HR reported today was 0.49.)”
Regarding when to use front-line in PD-L1 high expressers: “(Community) oncologists have less experience with nivo/ipi outside of melanoma. Yes, it’s manageable – there’s no chemotherapy side effects, so there’s a good chance patients will prefer IO first and delay chemo until later. But there is more unease with IO/IO (as in Checkmate) versus pembro by itself – it’s easy to give. The question is, if you are a high PD-L1 expresser and you qualify for both IO/IO, and pembro monotherapy, what are people going to give? That’s where there will be a battle.”
Regarding the use of TMB in treatment management decisions:“Cost is a major issue. If (the use of TMB) is approved, it will be interesting to see how. A lot of different assays can produce TMB. Many centers are doing smaller panels – ours included – we’re typically running 100-plus genes, maybe 150, but that isn’t enough right now to get good TMB data. So does that mean all the centers are going change what they do and use Foundation Medicine? This is a significant potential barrier to adoption.”
A View from The Street
A quick Q&A with Patrick Rivers, Vice President of Research, Aquillo Capital
OBR: Of all the results out today, what was the most striking finding?
Rivers: The HR of 0.49 for KN-189 is really impressive. The strength of the phase II data in a much smaller group of patients was enough to get this regimen approved for first-line non-squamous NSCLC, but these results substantiate this as a go-to regimen in a broad number of patients. I was surprised that they were able to demonstrate benefit in EGFR and ALK mutant patients as well.
OBR: The results today don’t’ really suggest a “winner”. What would you need to see - as yet unseen - that would be a true differentiator between the two PD-1 drugs?
Rivers: I don’t believe that nivolumab and pembrolizumab are appreciably different in terms of the actual drug properties. They have been tested in different clinical settings with different patient selection strategies, and that has likely given rise to the different results that we have observed. The only way to truly differentiate them would be to test them head-to-head, and we all know that isn’t going to happen. One question that hasn’t been answered, which may be critical moving forward, is how much benefit is observed for PD-1 plus chemo when you look at TMB stratification. We only have this for ipi plus nivo vs chemo.
OBR: Given your science background (Rivers came from the bench) - TMB vs. PD-L1 staining – any opinion on which has the most utility?
Rivers: They are independent variables, so they both play an important role and may represent different biological principles – PD-L1 being a marker of inflammation and TMB being a surrogate for neoantigen burden. I am surprised that they show no correlation with one another, but because they independently predict likelihood of response in different populations, they will both have to be examined. The key distinction now is that PD-L1 staining is cheaper, faster and more well-integrated into routine pathology so it currently has more utility. It will be several years before next-gen sequencing panels that give you a TMB read-out are as routine in clinical practice.
OBR: Do these data swamp out any conceivable me-too? Is there a reason to pursue a next-gen anti PD-1?
Rivers: I don’t believe there is any reason to pursue any additional generations of PD-1 monovalent antibodies. What we do still need to explore further is additional combinations that reveal new elements of biology. There are many other environmental factors in the tumor that are not being properly addressed by PD-1, CTLA-4 and chemotherapy alone. Bi-specific antibodies that bind PD-1/L1 with one arm and another target with another arm may also yet reveal interesting new approaches that do not overlap with current PD-1 use cases.
A final word on Pepsi vs. Coke from Dr. Hellman:
“The results of these two studies are not zero sum. This is a huge step forward for patients – anyway you look at it. Two positive phase III studies, with different but complimentary messages about the use of anti PD-1 therapy in the first-line setting is a huge advance. Although now there are new questions to be answered about how we make the best decisions in the first-line setting, but these are great questions to have to grapple with. So I’m really pleased that we have all this data together.”
By Neil Canavan, Solebury Trout