Targeted Therapies and Immunotherapies Are Transforming Outcomes in Advanced NSCLC

Renato G Martins, MD, MPH

Ten or 15 years ago, a diagnosis of advanced non— small cell lung cancer (NSCLC) led directly to a discussion of chemotherapy. Median survival was around 8 months. Treatment toxicities were significant. Few other options were available.

Today, patients with advanced NSCLC have many more treatment choices and substantially improved outcomes. In some cases, patients can be maintained on new oral therapies for years before seeing progression that requires chemotherapy. Even more exciting, the newest wave of targeted agents and immunotherapies now in clinical testing are extending this responsive period. With each passing month, strategies evolve, survival improves—and medical decision-making becomes more complex. This update highlights recent advances in NSCLC treatment and makes practical recommendations to help oncologists and their patients take full advantage of the latest emerging therapies.

More Targets, Moving Targets

Several therapies target specific molecular pathways that drive tumor growth in advanced NSCLC. Erlotinib, gefitinib, and afatinib are small-molecule EGFR inhibitors, while crizotinib and ceritinib target ALK. These tyrosine kinase inhibitors (TKIs) are approved by the FDA for firstline treatment of patients who are known to have the sensitizing EGFR mutation (about 15% of patients overall) or the ALK gene rearrangement (about 5% of patients). The TKIs are extremely effective in delaying progression. However, only patients with the specific mutation will see a major benefit and resistance is common. That’s why several kinase inhibitors are now being developed to attack additional NSCLC molecular subtypes (eg, HER2, BRAF, RET, and ROS1) or to treat secondary mutations that confer tumor resistance (eg, MET, T790M).¹

• Ceritinib is an example of a second-generation ALK inhibitor that has shown efficacy in both crizotinib- naïve and crizotinib-resistant patients.² The most recent ceritinib data showed an overall response rate of 58.5% in 246 patients.³

Until recently, no second-line therapy has succeeded in treating treatment-resistant EGFR+ tumors. Response rates with afatinib are low4 and combining afatinib with cetuximab causes significant rash.⁵ Two new oral agents that target the T790M mutation, see n in at least half of EGFR-resistant tumors, show promising signs of extended activity in clinical trials.

• AZD 9291, a selective third-generation EGFR-TKI, was well tolerated and produced a 64% response rate in 89 EGFR T790M+ patients.⁶
• CO-1686, another potent inhibitor of EGFR and T790M, showed good efficacy (58% response rate in 40 patients) without the dose-related rash and diarrhea associated with wild-type EGFR inhibition.7 Seattle Cancer Care Alliance (SCCA) is currently enrolling patients with NSCLC and EGFR mutations in two clinical trials of CO-1686 (UW 14031 and UW 14055, www.seattlecca.org/clinicaltrials). Meanwhile, long-awaited results from the RADIANT clinical trial showed no overall survival benefit of adjuvant erlotinib in early NSCLC.⁸ However, in a subset analysis of EGFR+ patients, disease-free survival was 46.4% in 102 patients on erlotinib versus 28.5% in 59 patients on placebo; these statistically nonsignificant yet intriguing results are leading to further testing in this context of early disease.

Given the growing number of clinical trials with targeted agents, oncologists are encouraged to work with specialists at research-based cancer treatment centers such as SCCA to consider enrolling patients in appropriate studies. Although new targeted agents and new indications are being approved faster than ever, helping patients access new drugs a year or two earlier—while they are still in clinical trials—can make a meaningful difference in patients’ lives.

Broad Molecular Profiling—The Key to Tumor Targeting

The growing availability of more effective targeted therapies has forever changed the role of molecular testing in lung cancer. Guidelines already call for up-front testing for EGFR and ALK in nonsquamous cell lung carcinoma, but as additional oncogenic targets have been identified the need for a more comprehensive interrogation of the tumor genome has grown. That’s why the guidelines panel of the NCCN recently stated:

“The NCCN NSCLC Guidelines Panel strongly endorses broader molecular profiling with the goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials. Broad molecular profiling is a key component of the improvement of care of patients with NSCLC.^”9

For oncologists, this recommendation has practical implications for specimen collection and the timing of the test request. In terms of the biopsy, the specimen needs to be of adequate volume and the collection and preparation methodology should aim to preserve high-quality DNA. Regarding the timing of molecular profiling, earlier requests are generally better. Given the 4 to 6 week turnaround required by many multiplex next-generation platforms, most physicians perform the EGFR and ALK mutation testing first and then, if those are negative, conduct the broad profile. As suggested in the new NCCN guidelines, however, broad molecular profiling done as part of an early pathologic workup should now be considered as standard of care.

Immunotherapies Are Improving Survival

Based on insights about how cancer cells hijack T-cell regulatory pathways, several new immunotherapies have been developed to unleash T cells from these inhibitory signals. Most of the new agents target “checkpoint proteins” on the T-cell surface. Ipilimumab, for example, blocks CTLA-4 and has demonstrated a clear survival advantage in melanoma.¹⁰

Over the past 2 years, PD-1 and PD-L1 inhibitors have shown remarkable efficacy in subsets of patients.

• BMS 936559 is an anti-PD-L1 monoclonal antibody that prevents PD-L1 binding to PD-1 and CD80. This agent induces durable tumor regression (objective response rates of 6%-17%) and prolonged disease stabilization (rates of 12%-41% at 24 weeks) in patients with advanced cancers, including NSCLC, melanoma, and renal cell cancer.¹¹ The autoimmune side effects with anti-PD-L1 therapy appear less severe than those with anti-CTLA-4 therapy.

As reported at the 2014 ASCO Annual Meeting, two new agents that block the PD-1/PD-L1 pathway have shown remarkable promise of efficacy in select patients with NSCLC (Figure 1).

• MPDL3280A is a humanized anti-PD-L1 monoclonal antibody that prevents binding to PD-1 and B7.1. In phase I studies, the agent led to an overall response rate of 23% in 53 previously treated patients. Antitumor responses were higher in current or former smokers and in those with higher PD-L1 immunohistochemistry scores.12 Based on these results, MPDL3280A has advanced to a phase II trial in patients with PD-L1-positive tumors and to a global phase III trial for patients with any PD-L1 expression status.

• MK-3475, a humanized IgG4 PD-1 monoclonal antibody, showed robust antitumor activity as first-line therapy in patients with advanced NSCLC that expressed PDL1. Fifty seven of 84 patients tested expressed PD-L1. As reported at ASCO, the preliminary overall response rate in 45 treated patients was 36%, and 55% of patients remained on therapy (duration range, 12-14 weeks).13 Most adverse events were grade 1/2 fatigue, pruritis, dermatitis acneform, diarrhea, and dyspnea.

Conclusion

Here in Seattle, we are testing a growing number of promising targeted therapies and immunotherapies in patients with all stages and types of NSCLC. Because the treatment options are changing so rapidly, and because of the need for molecular profiling to match patients with the best treatment, we encourage oncologists to partner early with an experienced cancer treatment center that offers access to advanced testing and clinical trials.

At SCCA and the University of Washington, we have established a toll-free education and referral service for physicians in the Pacific Northwest. This MEDCON service is an ideal way for referring physicians to check with our oncology specialists to see what new protocols may be available for patients with NSCLC. As new treatment options emerge and as strategies for genomic testing and patient management evolve, early consultation will become critical to ensuring that patients receive the most up-to-date therapy.

References

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