Adapting to the Brave New World of Lung Cancer Treatment

Paradigm shift seems an inadequate, though often-used, description of what has happened in lung cancer therapy in the past decade. In this issue of ONCOLOGY, Dr. Carrizosa and colleagues lead us on a comprehensive tour of the molecular targets and therapies that have shaped this new framework for evaluating and treating patients with lung cancer. They review in detail the discovery of epidermal growth factor receptor (EGFR) gene mutations and ALK translocations, and the development of therapies that successfully target these molecular abnormalities. They discuss acquired resistance to EGFR- and ALK-directed therapies, with an eye towards future platforms for combating resistance. They outline other recent developments in lung cancer treatment, including an overview of potential KRAS-directed therapies and a discussion of developments in immunotherapy. The authors also provide a clear and useful algorithm for personalized lung cancer treatment (see Figure 4 in their article).

While the future of lung cancer treatment as outlined by the authors is promising, the present holds considerable challenges for clinicians and researchers. The BATTLE trial[1] has demonstrated the feasibility of obtaining larger patient specimens, and the authors’ diagnostic and treatment algorithm (and any sensible algorithm one can imagine) hinges on obtaining a diagnostic biopsy with adequate tissue for biomarker testing. Nevertheless, our ability to obtain sufficient tissue to make treatment decisions lags behind our understanding of the importance of selecting therapy based on molecular markers. Evaluation of patients with a suspected diagnosis of advanced lung cancer has long focused on acquiring tissue in the most rapid and safe manner possible, often resulting in small cytologic specimens. Even in the controlled setting of clinical trials with tissue acquisition as a goal, obtaining sufficient tissue for molecular studies remains a challenge, with recovery rates of viable tumor samples typically less than 50% across multiple clinical trials.[2-7] In a typical outpatient setting, care may be fragmented and biopsies performed without the input of a medical oncologist. Obtaining sufficient tissue on a first biopsy in the majority of patients is unlikely without a major change in our approach. This change will require, at a minimum, education of colleagues across multiple disciplines and earlier involvement of the medical oncologist in the care of a patient with suspected lung cancer.

The approach outlined by Dr. Carrizosa and colleagues, if successful, will ultimately result in the division of lung cancer patients into smaller and more descriptive subsets. In this future, each of these subsets is akin to a rare malignancy, and the hope of an immediately available personalized treatment option for each patient remains distant without a rapid increase in the accrual of patients to clinical trials. Participation of adult cancer patients in clinical trials is dismal at 2% to 4%,[8] with even lower participation rates for minorities and the elderly (who comprise most of our lung cancer patients). We would advocate for an algorithm where “refer for clinical trial participation” appears first at each decision point. The Lung Cancer Mutation Consortium study, a touchstone for those advocating molecular testing, would not have been possible without large-scale participation of patients and the cooperation of multiple institutions from the very outset of the therapeutic decision-making process. The success story of crizotinib (Xalkori) for patients with ALK translocations also illustrates how rapid identification and accrual of patients to molecularly targeted clinical trials leads to better access to appropriate therapy for patients, not just for patients participating in the clinical trial but also for those who subsequently benefited from the relatively rapid approval of this agent by the US Food and Drug Administration (FDA).

Accrual of patients to clinical trials in the era of molecular testing will require a high level of sophistication on the part of clinicians and patients and a strong partnership between the patient, family, and physician. In an ideal world, patients would participate in tissue-acquisition trials at initial diagnosis and upon progression. Those with druggable mutations would be offered first-line targeted-therapy trials or combinations of targeted therapies. At progression, based on biopsy results revealing the mechanism of acquired resistance, patients would be directed again to the most appropriate trials. Negative perceptions surrounding early-phase clinical trials will need to change.

While the title of the article is “New Targets and Mechanisms in Lung Cancer,” Dr. Carrizosa and colleagues, by necessity, focus on non–small-cell lung cancer (NSCLC). Identification of molecular drivers and the development of targeted therapies for small-cell lung cancer (SCLC) lag far behind NSCLC. While different disease biology may account for some of this discrepancy, the same challenges we face in achieving progress in NSCLC are, at least in part, to blame for the lack of progress in SCLC. Comprehensive tissue-acquisition protocols, whole-exome sequencing in large numbers of patients, and increasing clinical trial participation in patients with SCLC are vital to change. Similarly, if we are to provide new options for the large numbers of NSCLC patients with no actionable mutation, we must focus on identifying new mutations through tissue acquisition. In the meantime, these patients are ideal candidates for the large number of available immunotherapy trials.

Achieving the goal of personalized lung cancer therapy will require abandoning or adapting long-held practices. However, as Dr. Carrizosa and his colleagues point out, change is good…and necessary.

Financial Disclosure:Dr. Pinder-Schenck receives research support from Pfizer. Dr. Antonia has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1:44-53.

2. Reck M, Hermes A, Tan EH, et al. Tissue sampling in lung cancer: a review in light of the MERIT experience. Lung Cancer. 2011;74:1-6.

3. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372:1809-18.

4. Hirsch FR, Varella-Garcia M, Bunn PA, et al. Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non–small-cell lung cancer. J Clin Oncol. 2006;24:5034-42.

5. Mok TS, Wu Y-L, Thongprasert S, et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-57.

6. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non–small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900-9.

7. Zhu C-Q, da Cunha Santos G, Ding K, et al. Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group study BR.21. J Clin Oncol. 2008;26:4268-75.

8. Lara PN, Higdon R, Lim N, et al. prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment. J Clin Oncol. 2001;19:1728-33.