Other PD-1 pathway therapeutics in advanced melanoma therapy.
Yesterday we focused on nivolumab, particularly in combination with ipilimumab, for the treatment of advanced melanoma. There are competing PD-1 pathway inhibitors that have now reported out substantial trial data. See part 1 for a list of PD-1 pathway therapeutics in development. Much attention has gone to Merck’s pembrolizumab, formally called MK-3475. The activity of pembrolizumab in melanoma is very similar to that of nivolumab, so it’s worth taking a closer look at the characteristics of the antibodies. Included here is pidilizumab, another anti-PD-1 antibody, developed by CureTech.
Attributes of note include the different sources of the antibodies (fully human vs humanized murine antibody), different isotypes (IgG4 vs IgG1) and affinities ranging more than 200-fold from sub-100pM to 20nM. However, this is a small number of antibodies and it will be hard to discern how each of these attributes contributes to efficacy. Pembrolizumab closely resembles nivolumab except that the affinity for PD-1 is as much as 10 fold better. At the doses given it is difficult to know if this makes any difference, as drug levels may be saturating. We’d have to dig out target occupancy data from the trials to figure this out, but let’s look at the pembrolizumab results first, as it will become clear that this antibody has similar efficacy as nivolumab. How these therapeutics are being developed is different, as we’ll see.
The pembrolizumab (“pembro”) data reported at ASCO are from a huge Phase 1 clinical trial in advanced melanoma. Importantly, Merck made the strategic decision to stratify patients by prior exposure to the anti-CTLA4 antibody ipilimumab (“ipi”), from Bristol-Myers Squibb. This gave the company a jump on the field, allowing them to pursue FDA approval first for ipi-refractory patients. Due in part to the toxicity associated with ipi therapy, there are a lot of these patients. First, though, a brief look at the data, which has been widely reported. The data are compared to published data for nivolumab (“nivo”) treatment of ipi-naive advanced melanoma patients (http://jco.ascopubs.org/content/32/10/1020.long). A guide to the clinical abbreviations is included in part 1.
If we focus on the ipi-naive ORR and 1 year survival data I think we have to conclude that these drugs are pretty comparable, and we’ll wait for additional data before trying too hard to differentiate these. That data will have to come from longer duration of ongoing trials and various combination studies. It is clear from the monotherapy data is that for advanced melanoma patients, anti-PD-1 therapeutics offer a chance at extended benefit. If we look more closely however,we see that in the nivo trial referenced above, half of the responding patients stopped therapy for reasons other than disease progression, most likely dropping off study due to AEs. It is true that 3/4s of the nivo patients stopping therapy maintained a response, some for extended periods. In the pembro study, the SAE rate was 12% but only 4% of patients discontinued therapy as a result of AEs, so that’s good. The catch is that in order to move ORR higher than 40%, combination therapy may be needed. As we saw with the ipi/nivo combo, this comes with much higher toxicity and drop-out rates. Of course the hope is that moving to earlier line therapy will boost response rates with the same or less toxicity and that data will come with time. As an aside, the question of ORR is the reason we have basically ignored the anti-PD-1 antibody pidilizumab, which had a 5-6% ORR. The 1 year OS was similar to the other anti-PD-1 therapeutics, but with such a low ORR it’s hard to believe this therapeutic from Curetech will gain much traction.
Anti-PD-L1 antibodies constitute the second class of therapeutics targeting the PD-1 pathway. These are in early clinical development in multiple tumor types, and will be addressed later. PD-L1 is also important in the context of predicting response to therapy in melanoma, and the utility of this marker as well as PD-1 is the subject of considerable discussion. When the ORR is 40%, it is helpful to select patients prospectively. We can take a close look at one of the smaller cohort studies to get a good look at this. In a study of responsiveness to pembro, Richard Kefford et al (abstract #3005) used an analysis of PD-L1 expression to demonstrate a remarkable difference in clinical response between patients who had > 1% tumor PD-L1 expression versus those who were PD-L1 negative. Biopsy was required in the 2 months preceding the start of pembro therapy; tumor PD-L1 expression was assessed by immunohistochemical staining. Patients received pembro at either 10 mg/kg Q2W, 10 mg/kg Q3W or 2 mg/kg Q3W. With a median treatment time of 23 weeks and ≥13 months follow-up, ORR was 41%, median PFS was 31 weeks and median OS was not reached. The 1-year survival rate was 81%, so this was a terrific cohort within the larger pembro study, likely due to the higher doses used. PD-L1 expression was associated with improved ORR by (51% vs 6%), PFS (median 12 vs 3 months) and 1-year survival rate (84% vs 69%). Note that while there were no treatment-related deaths; 14% of patients experienced drug-related SAEs (grade 3/4) again reflecting the aggressive dosing schedule.
In the large trial of ipi-naive patients treated with nivo, PD-L1 positive tumor staining was associated with ORR, but only weakly with PFS and OS. Why the data are less robust than the Kefford study is unclear. What is abundantly clear however is that there were profound responses in patients scored as PD-L1 negative, as shown in this screen grab from Dr Weber’s Discussant review of the melanoma oral poster session:
These data suggest that caution should be exercised in the use of PD-L1 staining as a prognostic tool, and the search for better biomarkers of response continues.
We will revisit some of these issues as we move on to NSCLC, RCC, bladder, ovarian and solid tumors more generally.