Anyone attending the immunotherapy sessions at ASCO earlier this month would have heard several distinct messages about PD-1 pathway inhibition in oncology. PD-1 appears to be a central control point for curtailing T cell responses in the peripheral tissues, similar to the role that CTLA4 plays in regulating initial T cell activation in secondary lymphoid organs such as the lymph nodes and spleen. Remarkable progress has been made in the 13 years since Gordon Freemen and colleagues first proposed in Nature Immunology that the PD-1 pathway was used by tumor cells as a shield against immune system attack (http://www.ncbi.nlm.nih.gov/pubmed/11224527).
It is clear that PD-1 pathway antagonists show tremendous promise in treating diverse cancers. Less clear is an understanding of why certain patients respond or don’t, what biomarkers might predict response, how to increase response rates, how to accurately measure response, and how to safely combine PD-1 pathway inhibition with other therapies.
Table 1 lists the PD-1 therapeutics in development (some of these therapeutics did not have updates at ASCO).
As the table demonstrates, the PD-1 pathway inhibitors are being developed in diverse tumor types. As late Phase 2 data and Phase 3 data are coming out we can begin to see the real promise of these drugs in clinical responses measured in large numbers of patients. The amount of data presented at ASCO was a bit overwhelming so to simplify the landscape we can address each tumor type individually, when possible. Some terms we will use are given in the table below.
Table 2 defines the RECIST1.1 clinical response parameters and their abbreviations.
To put these terms in perspective we can just consider that a meaningful clinical response is a measureable response to therapy (SD < PR < CR) that is durable and leads to an increase in PFS, which in turn allows a significant increase in OS. There are other terms used to describe clinical responses but these are the most common. We will start with some of the most recent data, and see where that takes us.
Part 1: Immune Checkpoint Combination Treatment of Melanoma
The very first trials of PD-1 pathway inhibitors began with the investigation of nivolumab in metastatic melanoma. As such, there was an impressive amount of progress reported and we now have mature data on different therapeutics. To set the stage, we can consider the benefit shown by nivolumab monotherapy compared to standard of care treatment protocols, and also to ipilimumab (brand name Vervoy) an anti-CTLA4 antibody, also from Bristol-Myers Squibb (BMY). Ipilimumab is approved for the treatment of metastatic melanoma based on Phase 3 clinical trial data in metastatic melanoma patients that had failed prior therapy (a chemotherapy regimen). The trial compared ipilimumab to a tumor vaccine targeting the melanoma antigen gp100. Ipilimumab treatment improved median OS to 10 months versus 6 months with the vaccine treatment (which was no better than standard of care). The 1 year survival rate was 45%. ORR however was low, just about 10%. Also, adverse events (AEs) were a problem, and included autoimmune manifestations (colitis, pituitary inflammation) and some treatment-related deaths (2% of patients). In a separate study of treatment-naive metastatic melanoma patients, ipilimumab therapy was associated with an OS = 11.2 months and a 1 year survival rate of 47%, falling to 21% by year 3. Patients were given ipilimumab or placebo plus chemotherapy (dacarbazine), and then moved to ipilimumab or placebo alone if there was a response measured or if the initial therapy caused toxicity. One consequence of this scheme was that AEs went up dramatically, with 38% of patients experiencing an immune related, grade 3 or 4 severe AE (SAE). We dwell on the anti-CTLA4 antibody ipilimumab because it is the benchmark for other immunotherapies such as nivolumab.
Nivolumab therapy for advanced melanoma has produced impressive data, with median OS = nearly 17 months, and 1 and 2-year survival rates of 62% and 43%. ORR was 33%. AEs were significant if less severe than those seen with ipilimumab. Grade 3-4 treatment-related AEs were seen in 22% of nivolumab-treated patients. Immune-related adverse events (all grades) were seen in 54% of treated patients, and included skin, GI and endocrine disorders. However only 5% of patients experienced immune-related SAEs of grade 3 or 4 and there were no drug-related deaths. These data from Topalian, Sznol et al. from John Hopkins University School of Medicine were presented at ASCO last year and published earlier this year (http://jco.ascopubs.org/content/early/2014/03/03/JCO.2013.53.0105.full.pdf).
So with that as our backdrop lets update the state of PD-1 pathway antagonism in melanoma. One of the obvious next steps in the development of immunotherapy is to combine treatments and we saw dramatic long-term data from the combination trial of ipilimumab plus nivolumab in advanced melanoma. Early trial results presented at ASCO last year introduced 4 cohorts of patients given different doses of nivolumab and ipilimumab in combination, with an ORR across all four cohorts of 40% and a 1 year survival rate of 82%. Median OS had not been reached. SAE rate across the 4 cohorts was 53%. This quickly gets complicated so let’s define the cohorts. Numbers are doses of nivolumab and ipilimumab, respectively, in mg/kg: Cohort 1 (0.3 + 3), Cohort 2 (1 + 3), Cohort 3 (3 + 1), Cohort 4 (3 + 3). No data were presented for Cohorts 6 and 7 so we’ll skip those. Cohort 8 is designed to mimic the dose schedule chosen for later clinical trials.
Note that after the induction phase, patients are moved onto maintenance therapy, as show below.
The slide is taken from the trial update presented at ASCO by Dr Sznol (Abstract #LBA9003). The data updates drove home several critical points. First, at the optimal dose rates of 1 + 3 and 3 + 1 the ORR ranged from 43-53%. The author’s introduce a new classification of clinical response to capture the observation that many patients are experiencing benefit while not strictly meeting RECIST1.1 criteria, this is termed “Aggregate Clinical Activity Rate” and reaches 81-83% in Cohorts 3 and 4 (note that Cohort 4 (3 + 3) was the maximum tolerated dose due to SAEs and will no longer be used). Perhaps more meaningfully, the percent of patients whose tumor burden was reduced by > 80% at 36 weeks was 42% across the cohorts. This is a remarkable number suggesting sustained clinical benefit. Indeed, in those patients who responded, the median DOR in Cohorts 1-3 plus Cohort 8 has not been reached. In Cohorts 1-3, 18/22 patients are still responding and 7 of those had discontinued therapy due to AEs (more on this below).
Dose cohorts were analyzed for impact on 1 and 2 year survival. In Cohorts 2-3 the 1 year OS = 94% and the 2 year OS = 88%. Most stunning of all was this data showing a median OS in Cohorts 1-3 of 40 months. Median OS in Cohort 3 (1 + 3) has not yet been reached.
These data are best-in-class for treating advanced melanoma, and place ipilimumab plus nivolumab at the forefront of therapeutic options for these patients. The one outstanding issue remains that of toxicity. 23% of patients had to discontinue therapy due to toxicity, and one patient died of complications resulting from treatment. While Dr Sznol repeatedly pointed out that the toxicities observed are controlled by standard interventions, the problem is that these standard interventions include cessation of therapy. We have already learned from the ipilizumab experience that responses to immune checkpoint inhibition can take time, and for those patients who have to stop treatment after 1 – 2 doses due to toxicity, time may not be kind. It will certainly be beneficial to reduce SAEs so that more patients can remain on therapy.
Tomorrow we’ll look at other PD-1 pathway therapeutics and combinations in melanoma before moving on to other tumor types.