This article is a Clarivate Analytics Market Insight report, an ongoing series featuring expert reviews of hot topics in the pharma/biotech field, with analysis and discussion on the factors currently affecting the industry. Data leveraged for this analysis was gathered both onsite at ASCO and from Clarivate Analytics Cortellis.
The American Society for Clinical Oncology (ASCO) held its annual meeting in Chicago in June, and it was typically industrious with cancer drug developers presenting their latest clinical and translational science as part of ongoing efforts to produce powerful new cancer therapies. In addition, as in the past few ASCO meetings, the deepening knowledge of the biological mechanisms that cause and maintain cancer provided exciting preludes of where the next blockbusters might emerge.
Among the numerous themes at this year’s meeting, CAR-T cell therapies were named by ASCO as the oncology advance of the year.
Among the numerous themes at this year’s meeting, CAR-T cell therapies were named by ASCO as the oncology advance of the year and there was no shortage of presentations involving this important new therapy option. This is a review of what we consider to be some of the most key data presented, notably in lung cancer and in CAR-T cell research, as well as a discussion on their broader implications.
NSCLC: the end for chemotherapy in the first-line?
Two of the heavyweights in the immuno-oncology field continued their marketplace battle as Merck and Roche revealed positive data in first-line NSCLC for the PD-1/PD-L1 checkpoint inhibitors Keytruda and Tecentriq, respectively.
Merck’s phase III KEYNOTE-042 trial compared Keytruda monotherapy versus doublet chemotherapy in squamous and non-squamous advanced NSCLC patients with PD-L1 expression of >1%, and the most pertinent question was whether patients with lower tumor PD-L1 expression achieved benefit or if the effect was driven by patients with higher PD-L1. This will be critical for prescribers deciding whether to treat with first-line chemotherapy followed by second-line immunotherapy or with competing options of first-line immunotherapy.
The data demonstrated Keytruda to be effective even in patients with minimal PD-L1 expression; in patients with only 1% or greater PD-L1 expression overall survival was increased from 12.1 to 16.7 months (HR = 0.81). Although survival was most improved in patients with PD-L1 > 50% (12.2 to 20 months), the fact that safety and tolerability with Keytruda was better than with chemotherapy, with 17.8% Grade 3 adverse events compared to 41% for chemotherapy, this is likely to spell the end of the use of chemotherapy as a first-line treatment in NSCLC in favor of immunotherapy.
Squamous cell lung cancer – an unusual contender
In a year that was unusual compared with previous meetings, for once ASCO featured squamous cell lung cancer data as strongly as non-squamous histology. The data presented in this setting which had the most impact was that from the IMpower131 trial, which compared Tecentriq + doublet chemotherapy followed by Tecentriq maintenance versus doublet therapy alone in first-line advanced squamous NSCLC.
The risk of progression or death was reduced by 29% with the addition of Tecentriq to first-line chemotherapy, with a progression-free survival (PFS) of 6.3 versus 5.6 months. The PFS was observed in all PD-L1-expressing subgroups. At the first interim overall survival analysis, the median overall survival was 14 months with the Tecentriq triplet versus 13.9 months for chemotherapy alone, although the data are immature. With similar data presented in squamous NSCLC for Keytruda (KEYNOTE-407) and the fact Keytruda has become the dominant PD-1/PD-L1 in lung cancer, competition for Tecenrtiq in this setting will be fierce, but with less use of immunotherapy currently in squamous NSCLC, sales for Tecentriq will likely be meaningful nevertheless.
RET+ NSCLC – soon to be approvable datasets in the first-line?
Finally, a perhaps more nuanced battle in lung cancer was also being played out elsewhere among earlier-stage RET inhibitors. RET+ NSCLC patients derive only modest benefit from current multi-target kinase inhibitors, and both LOXO Oncology and Blueprint Medicines are currently developing phase I programs of specific RET inhibitors. Presented at ASCO was LOXO’s LOXO-292, which showed robust efficacy in RET+ patients with KIF5B-RET fusions (PFS 50%), and impressive dose escalation datasets. Assuming the durability data matures favorably, the drug appears likely to be approved as first-line therapy in this setting.
CAR-T – durability and depth
As cell therapies continue to be integrated into oncology treatment protocols, interest in durability and deepening responses remains paramount. The most interesting of the CAR-T updates on show at this year’s ASCO meeting were for Yescarta, bb-2121 and JCAR-017.
As cell therapies continue to be integrated into oncology treatment protocols, interest in durability and deepening responses remains paramount.
Bluebird and Celgene’s bb-2121 is an autologous T-cell therapy engineered to express a B-cell maturation antigen (BCMA) chimeric antigen receptor. Since the companies’ last update at ASH in December 2017, a further 22 patients have been added to the ongoing phase I pilot trial in heavily pretreated relapsed/refractory multiple myeloma. Data were presented from the dose escalation cohort evaluating doses of 150, 450 or 800 million cells; 94% of patients achieved overall response, of which 16 patients had very good partial responses, with 10 complete responses. The therapy added almost one year of PFS (11.8 months). Among evaluable patients receiving >150 million cells, 95.5% responded, with 50% achieving complete response. Importantly, there was no difference in response rates between patients with low or high levels of BCMA expression which could be crucial to an earlier regulatory filing.
Celgene presented six-month data from the TRANSCEND trial for JCAR-017 (anti-CD19 T cells) in patients with relapsed/refractory B-cell non-Hodgkin’s lymphoma. The data included 114 treated patients, 51 of whom were given the pivotal dose of 100 million cells. Of 37 patients with diffuse large B-cell lymphoma (DLBCL) receiving this dose, 49% remained in remission with 46% maintaining a complete response at six months. Toxicity remained manageable at all doses tested. If the ongoing pivotal trial is successful, JCAR-017 would join Yescarta and Kymriah in what is becoming a quickly crowded market in poor-prognosis DLBCL.
Longer term follow-up data were also presented for Gilead/Kite’s ZUMA-1 trial for Yescarta (anti-CD19 T cells), which led to approval in third-line large B-cell lymphoma. At a median follow-up of 15.1 months (n = 101) the ORR was consistent with the previously reported 8.7 month follow-up (83% and 82%, respectively). However, the complete responses increased to 58% from 54%, and in patients who had initially only achieved partial response at one month (n = 34), 32% achieved complete responses.
2018 is on track to see a record number of new blockbuster drugs scheduled to launch across a wide range of therapeutic areas, including cancer, according to the Drugs to Watch 2018 report. Compiled from data within the Cortellis database, from Clarivate Analytics, the report features profiles of 12 new game-changing drugs that are predicted to achieve annual sales of >$1 billion by 2022.