8:45 PM
Apr 12, 2018
 |  BC Innovations  |  Targets & Mechanisms

Meeting the burden

New developments in TMB, synthetic lethality, oncolytic viruses & more at AACR18

A major theme at this year’s AACR is the abundance of preclinical discovery driven by molecular signatures in patient samples, suggesting the research community is heeding the call for studies better grounded in human data, and for new ways to develop the right treatments for the right patients.

That’s one of the key findings of BioCentury’s third annual analysis of the meeting abstracts, which records 87 new and emerging targets, 39 new synthetic lethal interactions, and expanded interest in oncolytic viruses, cell therapies and other new modalities.

Moreover, this year sees not only a near-quadrupling of abstracts on tumor mutation burden (TMB) compared with last year, but contains studies identifying differences in TMB between Chinese and Western patients that could indicate checkpoint inhibitors will have higher rates of efficacy in Chinese populations.

BioCentury surveyed 5,584 abstracts published ahead of this year’s meeting of the American Association for Cancer Research (AACR), which will take place April 13-18 in Chicago, Ill. The analysis includes a combination of machine learning and manual verification, and counts abstracts with mentions of preclinical targets, indications, cell types, modalities or other designated search terms. Abstracts were vetted for translational context.

Patient relevance permeates multiple lines of research presented at this year’s AACR meeting.

TMB features in 45 abstracts, up from 12 in 2017 and two in 2016, reflecting the attention TMB is gaining as a predictor of response to checkpoint inhibitors following a series of retrospective biomarker studies. In addition, Bristol-Myers Squibb Co. announced in February data from its Phase III CheckMate -227 trial in first-line non-small cell lung cancer (NSCLC) showing that in TMB-high patients, Opdivo nivolumab plus Yervoy ipilimumab met the progression-free survival (PFS) endpoint vs chemotherapy.

Patient relevance permeates multiple lines of research presented at this year’s AACR meeting.

In addition to 33 emerging targets -- defined as those that jumped from zero or one abstract in 2017 to four or more in 2018 -- 54 new targets are described, one-third of which derive from patient samples (see “Hello RNA”).

Synthetic lethality features in 50 abstracts, an area that utilizes molecular profiles of patient tumors to discover mutations that make tumors vulnerable to druggable targets. Synthetic lethal pairings can guide selection of drug combinations or development of new therapies.

Cellular senescence is referenced in 72 abstracts; this field likewise relies on studies of patient samples to illuminate both wanted and unwanted consequences of cellular senescence induced by disease or treatment regimens.

And 19 abstracts document the relationship between patient microbiomes and disease biology, progression or treatment response. That focus sits at the intersection of immuno-oncology and microbiome research, and holds potential for helping companies identify patients likely to respond to checkpoint inhibitors or other immunotherapies.

Breaking down the abstract

Breast cancer continues to be the most highly studied indication, in line with data from the last two years showing research in this indication far outstripping even other highly active areas like lung cancer, colorectal cancer and prostate cancer.

Breast cancer is a focus of about 22% of the total number of abstracts mentioning an indication, although only about one quarter focus on triple-negative breast cancer (TNBC) -- the most aggressive and underserved indication (see “Top Indications at AACR 2018”).

Figure: Top indications at AACR 2018

Breast cancer, mentioned in over 1,100 abstracts at the 2018 American Association for Cancer Research (AACR) annual meeting, continues to be the biggest focus in preclinical cancer research, with lung, colorectal and prostate cancer again trailing behind, mimicking the pattern of the last two years. Abstracts mentioning leukemia increased from 2017, as did head and neck cancer, which did not make it into the top indications last year, while brain cancer, ovarian cancer and sarcoma saw markedly fewer mentions than last year. Lymphoma includes both Hodgkin’s disease and non-Hodgkin’s lymphoma (NHL). T cell lymphoma, B cell lymphoma, follicular lymphoma and mantle cell lymphoma (MCL) are categorized as NHL subtypes, and cutaneous T cell lymphoma (CTCL) is categorized as a subtype of T cell lymphoma. The chart depicts 14 cancer types mentioned in 100 abstracts or more, broken down by cancer subtype. “Unspecified subtype” includes the number of abstracts that did not fall into the selected cancer subtypes. Source: AACR abstracts as of March 14

Lung, colorectal and prostate cancer together represent about one-third of the activity.

Liver cancer has moved up the leaderboard, going from 12th place in 2017 to 10th, and head and neck cancer has moved for the first time into the picture, featuring in 132 abstracts. That could be a response to the 2016 approvals of Opdivo and Merck & Co. Inc.’s Keytruda pembrolizumab in head and neck cancer, which most likely spurred additional investigation of immunotherapies and biomarkers in the indication.

Interest in research on immune cells continues to grow in cancer, with increased mentions of almost all cell types searched. The trend crosses both adaptive and innate immunity, and the data show a growing focus on cells that shape the tumor microenvironment, such as dendritic...

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