Targeted Therapies Convey Survival Benefit in Patients With Lung Cancer, Regardless of Smoking History

Dara L. Aisner, MD, PhD

Dara L. Aisner, MD, PhD

Regardless of smoking history, patients with cancer of the lung harboring specific genetic alterations who were treated with targeted therapies experienced longer survival than those patients who did not receive targeted treatment, according to results of a multi-institutional extension study to identify and treat oncogenic driver events. Sixty patients with a history of smoking and withEGFR/ALK/ROS1alterations derived similar benefit from targeted therapy, when compared with 75 patients with no history and with similar alterations. Dara L. Aisner, MD, PhD, and colleagues demonstrated a survival benefit of 1.5 years for patients who received targeted therapy. The researchers concluded that molecular testing should be performed on all individuals with lung cancer irrespective of clinical characteristics.

“Lung cancer patients with a smoking history should undergo the exact same genetic testing as patients with no history of smoking,” said Aisner, associate professor in the department of pathology at the University of Colorado School of Medicine. She cautioned clinicians not to succumb to testing fatigue, however, in which an oncologist might test a majority of lung cancer patients in his or her practice and yet never identify an actionable finding, and decides not to conduct genetic testing in all patients moving forward.

Although guidelines recommend genetic testing regardless of a patient’s smoking history, testing fatigue may bias oncologists against offering genetic testing in patients with lung cancer who have a previous history of smoking. “What this study argues is that even though these actionable findings are not very common, they are very treatable,” Aisner said.

In 2010, the Lung Cancer Mutation Consortium (LCMC) was established to determine the frequency of different oncogenic drivers in lung cancer, facilitate clinical protocol enrollment, especially for rare subsets, and enable the exchange of information and protocols among the institutions. A second cohort of patients (LCMC 2) were enrolled because additional oncogenic drivers were identified that could be targeted with novel genotype-specific agents.

In LCMC 2, 16 institutions across the United States enrolled 1367 lung cancer patients to study their tumors to identify whether a targeted therapy could be utilized. After applying eligibility criteria, there were 904 histologically confirmed cases with sufficient tissue for testing for at least 1 of 14 cancer related genes. Of the 904 patients, 63% were former smokers and 25% were never smokers.

“The primary goal of the study was to look at outcomes relative to targeted therapies in the setting of a known molecular alteration that could be targeted,” said Aisner. “The smoking question was a post hoc addition, which we thought was important to address. For patients with a history of smoking, finding the biomarker and treating it has as much probability of benefit for that patient as you would see in a never smoker,” said Aisner. But she does point out that not every patient—smoking or non-smoking—will see this benefit from targeted treatments. Regardless of smoking status, some patients will see little benefit, although others may see much more benefit than the average 1.5 years increase over patients who do not receive targeted therapies.

Survival was longer in 162 patients with mutations in any targetable driver gene includingsEGFR(n = 95),ERBB2(n = 6),veBRAF(n = 9),ALKr(n = 28),ROS1r(n = 8),RETr(n = 8),METamp(n = 2), or multiple drivers (n = 6) who received targeted therapy compared with patients with such mutations who did not receive targeted therapy, and compared with those patients without an identified driver (P<.001).

Previous reports have suggested thatTP53mutation might adversely affect the survival of patients treated with targeted therapy for oncogenic driver mutations in lung cancers. In this study, patients withsEGFRwho weretreated with targeted therapy and harbored aTP53mutation displayed a trend toward shorter survival compared with those without aTP53mutation (2.9 years vs not reached,P= .06). The researchers said that this is the first study to demonstrate the adverse prognostic impact ofTP53mutations on patients treated with targeted therapy directed againstsEGFR,ALKr, orROS1ralterations. &ldquo;This association was enhanced when disruptiveTP53mutations only were considered in comparison to subjects with noTP53mutation (P= .009),&rdquo; she said. The study used published approaches to determine if aTP53mutation should be considered &lsquo;disruptive.&rsquo;

&ldquo;This study strengthens the evidence that smoking status might be a predictor of the probability of having a targetable alteration, but if you do have a targetable alteration, it&rsquo;s equally treatable,&rdquo; said Aisner. &ldquo;The findings reinforce the message that people should not be biasing against testing for patients with a history of smoking.&rdquo;

Reference:

Aisner DL, Sholl LM, Berry L, et al. The impact of smoking and TP53 mutations in lung adenocarcinoma patients with targetable mutations—the Lung Cancer Mutation Consortium (LCMC 2).Clin Cancer Res.2017. pii: clincanres.2289.2017. doi: 10.1158/1078-0432.CCR-17-2289.