Treatment Paradigm Evolving in Early-Stage Lung Cancer

Gina Columbus

Dan J. Raz, MD
Dan J. Raz, MD
While systemic therapies have steadily moved through the pipeline for patients with non–small cell lung cancer that is more advanced or metastatic, the same cannot be said for those with early-stage disease—even though approximately 50% of this patient population will relapse following surgery and standard chemotherapy. However, the ongoing Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST) are looking to change this.

ALCHEMIST is a group of 3 randomized clinical trials seeking to determine whether adding adjuvant targeted therapy based on identified molecular abnormalities will improve outcomes and lower risk of recurrence. For example, the first phase, ALCHEMIST - Screening Trial (A151216), will test patients’ tumors for EGFR mutations and ALK translocations. If positive for EGFR, they will be referred to the ALCHEMIST - EGFR Treatment Trial [A081105] where they will be randomized to receive adjuvant erlotinib (Tarceva) or placebo. If positive for ALK, patients will be referred to the ALCHEMIST - ALK Treatment Trial (E4512) and will be randomized to receive crizotinib (Xalkori) or placebo as adjuvant treatment.

If a tumor does not test positive for either EGFR or ALK, they are then put on the ALCHEMIST – Immunotherapy Treatment Trial [ANVIL; EA5142] where they will receive adjuvant nivolumab (Opdivo) or observation.

“The ALCHEMIST trial is a really important trial and I hope that people refer patients to centers where they are doing the [study] because it’s important and the more patients that get put on the trial, the quicker it gets done,” said Dan J. Raz, MD. “While there are not a lot of biomarkers right now that are useful for early-stage lung cancer to assign whether patients get therapy, there is a lot of very interesting research.”

Raz, co-director, Lung Cancer and Thoracic Oncology Program, assistant professor, Division of Thoracic Surgery, Department of Surgery, and thoracic surgeon at City of Hope, shared his insight on the ongoing ALCHEMIST trial and some novel techniques, such as tissue slice culture, that are propelling the field of lung cancer forward in an interview during the 2017 OncLive® State of the Science SummitTM on Advanced Non–Small Cell Lung Cancer.

OncLive: You spoke on surgical resection in an era of biomarker-driven therapy in lung cancer. What has changed here?

Raz: A lot has changed in lung cancer in general, in terms of personalized medicine and using a patient's own tumor to come up with more specific treatments. I spoke about how it relates to patients with earlier-stage disease who are having surgery. Currently, there is not a whole lot of personalized medicine we do for patients who are undergoing surgery, but there are a lot of advances we are making. There are new clinical trials and some research ideas that I spoke about to try to introduce the topic. 

You mentioned the ALCHEMIST trial in your lecture. Can you discuss that a little bit and the potential impact of this trial’s findings?

That is a very important trial for patients with lung cancer, but especially for those who have earlier-stage disease. What this trial does is it looks at the mutational profile of patients with lung cancer who have undergone surgical resection and earlier stage disease—so stage Ib to IIIa. It allows them to receive standard therapy, but then based on their mutational profile, they get additional therapies if they have certain changes.

There are 3 separate trials within this trial. One is for patients with sensitizing EGFR mutations who get erlotinib or observation. The other one is for patients who have an EML4-ALK translocation who receive crizotinib or placebo. They get randomized. The third trial is for patients who don’t have any of these mutational changes; they are eligible to get immunotherapy for 1 year. Recruiting is probably going to be a while until all the results are ready. 

What other trials in this space are showing interest?

There are a few different biomarkers that have tried to evaluate which patents are sensitive to standard chemotherapy. Unfortunately, most of those have not really panned out, but there are a few clinical trials that are still evaluating certain DNA-repair enzyme changes that might be promising. We'll have to see what the results of those are.

One thing I spoke about is using a patient's tissue—to culture the tissue and treat with different agents and see how those respond. That is something that has been around for a long time, but there have been advances, techniques, and a renewed interest because of personalized medicine in those types of techniques. 

This is what we refer to as ex vivo testing. [It involves] taking tissue out either through a biopsy or through surgery and then doing something to it; you can test whether those cancers are sensitive to different types of treatments. There are a lot of different ways of doing that. The simplest way is to culture it—to plate it in a Petri dish—but that changes the tumor a lot. That was the older way this was done. 

The most labor-intensive way is putting it into mice; the mice grow and you treat them with medication, but it takes a long time and it’s very expensive. There is something in between called a tissue slice culture, which takes little pieces of tissue, sections them, and preserves all the architecture of the cancer. However, it allows us to treat with many different medications and get an answer within just a few days about what the tumor is sensitive to. That is still a research procedure, so we don’t know exactly how that correlates with what happens in people. However, from everything that we’re learning about it, it seems like a very good tool that has a lot of potential. 

What do you hope to see in the next 5 to 10 years in this setting?

I would love to see all of the advances that we are making in the lab get translated to patients. The bottom line is that there are a lot of promising medications and new treatment ideas that take so long to get to patients who desperately need them. I would love to see more techniques like the tissue slice culture that can allow patients to match with more personalized therapies and experimental therapies and, if that facilitates development of new drugs, that would be wonderful. 

I would also love to see more early-stage patients being involved in clinical trials that test newer drugs. It is hard to test what we call first-in-human drugs in early-stage patients with lung cancer. However, there are a lot of drugs approved for other indications that could be helpful in these patients. For patients like these who are going to have their cancer removed, it’s a great opportunity to treat them with new drugs to see how the tumor changes and reacts to those medications. Unfortunately, we just don’t do a lot of those trials, but it’s a good opportunity. 
National Cancer Institute. The ALCHEMIST lung cancer trials. Updated July 24, 2017. Accessed December 15, 2017.
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