Strategies for Precision Medicine in NSCLC: A Q&A With Dr. Howard (Jack) West

Howard (Jack) West, MD

Q: How do you form a personalized treatment plan for your patients with non-small cell lung cancer (NSCLC)?

Q: What is the importance of histological subtyping and molecular characterization in deciding to treat with conventional or targeted therapy?

Q: Which first-line conventional and targeted therapies are preferred?

Howard (Jack) West, MD, is the medical director of the Thoracic Oncology Program at Swedish Cancer Institute and president and CEO of Global Resource for Advancing Cancer Education.A:You need to start with the stage of the cancer. Look at the histological subtype of the lung cancer, the bulk of it, the molecular features, and whether there is a specific molecular marker that could change your treatment. Then, examine the characteristics of the patient: his or her health, goals, and ability to tolerate aggressive treatment safely. There are a great many variables that affect and lead to individualization of the treatment path from one patient to another.A:In the setting of advanced-stage disease, there is an early branch point for whether a patient has squamous or nonsquamous histology, with molecular testing being less clearly valuable and indicated for squamous lung cancer. Particularly for nonsquamous disease, especially adenocarcinomas, the presence or absence of an activating mutation, which is most commonly an endothelial growth factor receptor (EGFR) mutation or an anaplastic lymphoma kinase (ALK) rearrangement, is going to lead to an immediate diversion of the treatment plan between recommending first-line chemotherapy-based treatment and recommending a pill-based targeted therapy as the treatment most likely to lead to a beneficial effect for the patient. It is certainly an integral part of the decision-making process. It is no coincidence that the factors of histology and the presence or absence of molecular markers are very high on my list of variables that lead to individualized treatment for the patient.A:There are many different doublet chemotherapy regimens—that is, a 2-drug combination—and they have largely shown an efficacy that is more similar than different. There are subtle differences that would often lead us to favor one doublet regimen over another, depending on the histology. You can have a preferred chemotherapy regimen, but they really come out quite comparably.

Q: How do you treat patients who have progressed after first-line therapy?

In terms of targeted therapies, however, you have EGFR inhibitor-based treatment, such as erlotinib or afatinib, which are US Food and Drug Administration (FDA)- approved and extremely appropriate for first-line treatment of patients with anEGFRmutation. These days, you should look specifically at the subtype of an EGFR mutation. This might lead you to use afatinib for someone with the specificDel19mutation (a deletion in exon 19), but not use it for another commonEGFRmutation, called an L858R mutation (an exon 21 substitution), which seems to not do especially well with afatinib. It is becoming more and more granular all the time: we have gone from finding a single common activating mutation to now having to look at specificEGFRmutations, where you might individualize therapy to one EGFR tyrosine kinase inhibitor over another.A:That is largely based on whether they have a mutation. If not, I would favor docetaxel, or a clinical trial if you have that available. There are only a few agents that have been proven to have a survival benefit in previously treated patients, and that is really limited to erlotinib, docetaxel, and pemetrexed. We have typically favored using pemetrexed in patients with nonsquamous histology; not that it is absolutely the best, but it is certainly a well tolerated option that seems to be among the most effective, for adenocarcinomas at least.

Q: Are there any recent or ongoing clinical trials with emerging therapies that have the potential to greatly impact future treatment of NSCLC?

In the last few years, there have been a couple of trials that directly, head-to-head compared docetaxel to erlotinib in predominantlyEGFRwild-type mutations: one based in Italy¹and one in Japan.²Both indicated that second-line docetaxel was at least modestly superior.A:Yes. At an international meeting in Chicago (the 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology), there was a presentation of second- or third-line nivolumab, which is an immune-checkpoint inhibitor that specifically blocks a target called PD-1.³That was in patients with squamous histology for whom we don’t have nearly enough protective agents. Despite that fact that two-thirds of the patients had received 3 or more lines of therapy and 61% of them had progressed on their last line of therapy, they had a 1-year survival after starting this agent of 42% and a median overall survival of approximately 8 months. The response rate was around 15%, which was not as high as we’d like, certainly, but after patients have received many, many prior lines of therapy, even that is encouraging. It really indicates that a subset of patients are benefiting profoundly from these novel agents. I think it is very likely to lead to an approval; not with this trial specifically, but other phase 3 trials of nivolumab compared with docetaxel in the second-line setting that we expect to see the results from in 2015.

At the same meeting, a randomized phase II trial suggested a survival benefit in squamous patients who received first-line chemotherapy in combination with a PARP inhibitor called veliparib.⁴The study looked at chemotherapy with or without the PARP inhibitor and didn’t see a significant benefit in the broader population, but in the squamous subset of patients, there was a pretty provocative survival difference that is going to lead to a phase III trial in squamous patients. That could certainly lead to a new class of agents being approved in lung cancer and adding to the treatment arm available for squamous disease.

There was also a phase III trial that showed modest benefit from adding ramucirumab, which is a VEGF inhibitor therapy, or an antiangiogenic therapy, combined with docetaxel in the second-line setting.⁵Ramucirumab has already been approved in previously treated gastric cancer.

Q: Do you have any closing advice for community oncologists and their patients?

A larger trial is also being done in adenocarcinoma patients randomizing to docetaxel alone or with an oral antiangiogenic inhibitor called nintedanib (or BIBF 1120), and that trial looks encouraging in the second-line setting.⁶A:One of the important issues is that we have a growing array of treatment options for patients, but they are only available if the patients avail themselves of these options and if their doctors know about them. As the field becomes more complex, it becomes more important for patients to learn what they can about their treatment options and to become active participants in their care. There is a growing disparity in the options available and in the physicians who are aware of these options and those who aren’t as aware and may still recommend a similar treatment option for all of their patients.

References

1. Garassino MC, Martelli O, Broggini M et al. Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial.Lancet Oncol. 2013;14(10):981-988.
2. Kawaguchi T, Ando M, Asami, K, et al. Randomized phase III trial of erlotinib versus docetaxel as second- or third-line therapy in patients with advanced non—small-cell lung cancer: docetaxel and erlotinib lung cancer trial (DELTA).J Clin Oncol. 2014;32(18):1902-1908.
3. Gettinger SN, et al. Long-term survival, clinical activity, and safety of nivolumab (Anti-PD-1; BMS-936558, ONO-4538) in patients (pts) with advanced non-small cell lung cancer (NSCLC) : metastatic non-small cell lung cancer.Int J Radiat Oncol Biol Phys.2014;90(5):S34.
4. Ramalingam S, Blais N, Mazieres J, et al. A randomized, double-blind, phase 2 trial of veliparib (ABT-888) with carboplatin and paclitaxel in previously untreated metastatic or advanced non-small cell lung cancer: metastatic non-small cell lung cancer.Int J Radiat Oncol Biol Phys.2014;90(5):S4-S5.
5. Garon EB, Ciuleanu TE, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial.Lancet. 2014;384(9944):665-673.
6. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.Lancet Oncol. 2014;15(2):143-155.