Update on Next-Generation Therapies for NSCLC

July 31, 2014
Jane de Lartigue, PhD

Special Reports, NSCLC (Issue 3), Volume 3, Issue 1

Treatment for non-small cell lung cancer (NSCLC)—which includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma—has traditionally consisted of surgery, chemotherapy, and radiation therapy.

Corey J. Langer, MD

Next-Generation EGFR inhibitors

Lecia V. Sequist, MD, Discusses Adverse Events Associated With CO-1686

Sequist is a medical oncologist at Massachusetts General Hospital.

Treatment for non-small cell lung cancer (NSCLC)—which includes adenocarcinoma, squamous cell carcinoma, and large cell carcinoma—has traditionally consisted of surgery, chemotherapy, and radiation therapy. The identification of genomic aberrations that drive NSCLC has created a paradigm shift toward therapies that target molecular drivers, leading to remarkable improvements in patient outcomes. However, 5-year survival rates remain poor, and there is continued need for newer options.Targeted therapies in NSCLC have mostly focused on the epidermalgrowth factor receptor (EGFR), a tyrosine kinase receptor that regulates important growth factor signaling and is expressed on more than 60% of NSCLCs.1Inhibition of EGFR has become an accepted treatment strategy for advanced NSCLC, but most patients eventually relapse because of the development of acquired resistance.

“Typically, advanced-stage patients whose tumors harbor EGFR mutations are treated with EGFR inhibitors such as gefitinib or erlotinib,” said Benjamin P. Levy, MD, director of thoracic oncology at Mount Sinai Beth Israel in New York. “What to do with these patients once their tumors grow on these drugs remains unknown and thus an unmet need.”

Numerous molecular mechanisms of resistance have been uncovered, including the gatekeeper mutation T790M. Observed in about 50% of patients, it disrupts the ability of the EGFR inhibitor to bind to its target and increases the kinase activity of mutant EGFR, making inhibition less effective.2,3

To overcome T790M resistance, newer inhibitors have been developed that specifically target this form of the EGFR. CO-1686 (Clovis Oncology) and AZD9291 (AstraZeneca), are two agents being evaluated in phase II and III trials (NCT02186301, NCT02147990, NCT02151981).

“These drugs have demonstrated unprecedented outcomes in advanced-stage patients who have progressed on first-generation tyrosine kinase inhibitors (TKIs) with response rates of close to 60% for both drugs and a favorable adverse event (AE) profile,” Levy said.

Corey J. Langer, MD, director of thoracic oncology at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia, is also enthusiastic about these compounds.

“They have generated high response rates that often prove quite durable, thus avoiding, or, at least, delaying, the need for cytotoxics,” he said.4,5CO-1686 was recently granted Breakthrough Therapy designation by the Food and Drug Administration (FDA) based on these findings.

Overcoming Resistance to ALK-Targeted Therapies

“The Clovis compound is even more remarkable in that it does not generally induce the stereotypic side effects seen with erlotinib or afatinib. Because it does not target EGFR wild type, the incidence of unpleasant side effects such as diarrhea and rash is much lower," Langer said.Another significant driver of NSCLC is the formation of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion genes, which results in constitutive activation of ALK kinase activity. The multitargeted kinase inhibitor crizotinib (Xalkori; Pfizer) was approved in 2011 and has proven successful in the treatment of patients with NSCLC with ALK gene rearrangements.6

As with EGFR inhibitors, resistance to crizotinib almost always occurs, and a number of second-generation ALK inhibitors are under development to address the need to overcome crizotinib resistance. The lead agent, ceritinib (Zykadia; Novartis), recently received FDA approval, based on a single-arm trial of patients with ALK-positive NSCLC who failed crizotinib therapy. Response rates were more than 50% and median duration of response was more than 7 months.7

Close behind are alectinib (Roche) and AP26113 (Ariad Pharmaceuticals). In a phase I trial of AP26113 in patients with NSCLC, the objective response rate (ORR) was 67% in patients not previously treated with a TKI and 73% among patients previously treated with crizotinib. It was generally well tolerated; most AEs were grade 1/2 in severity and the most common grade 3/4 treatment-related AE was diarrhea (4%).

The FDA has also granted Breakthrough Therapy designation to alectinib. In a phase I study of patients with NSCLC who were crizotinib-refractory, alectinib demonstrated an ORR of 59%, and 80% of patients remained on the study for more than 6½ months without progression. It was also well tolerated.9Langer is intrigued by these agents, which he said are “quite active in the ALK resistance setting and potentially less toxic than ceritinib.”

Immune Checkpoint Inhibitors

“Although these agents do not necessarily expand the therapeutic portfolio compared with ceritinib, they may enhance quality of life,” Langer said.A novel treatment paradigm has emerged recently from the understanding that tumorigenesis depends on more than just the properties of the cancer cell. The importance of the interaction between the tumor and the host immune system has become increasingly appreciated.

Initially, the efficacy of immunotherapeutics, designed to boost the anticancer immune response, was limited in solid tumors because they are poorly immunogenic. More recently, an improved understanding of the immune system and of mechanisms of tumor-induced immunosuppression has led to the development of targeted immunotherapies that are achieving some success in solid tumors, including NSCLC.

Checkpoint proteins are the immune system’s fail-safe mechanism, preventing damage to normal tissue by ensuring the cytotoxic T cells are only switched on at the appropriate time and are switched off when no longer needed. They include the programmed death-1 (PD-1) receptor and its ligands, PD-L1 and PD-L2.10Cancer cells exploit this system by manipulating the expression of the immune checkpoint proteins to suppress T-cell activity and down-regulate the antitumor immune response. This realization led to the development of checkpoint inhibitors that could augment the tumor-specific T-cell response.

Among the checkpoint agents being evaluated in NSCLC are nivolumab (Bristol-Myers Squibb) and MK-3475 (Merck), both anti-PD-1 monoclonal antibodies, as well as MPDL3280A (Roche) and BMS-936559 (Bristol-Myers Squibb), which target the ligand PD-L1. Nivolumab demonstrated durable responses in a phase I trial of patients with previously treated NSCLC, with an ORR of 24% over a median duration of response of 74 weeks and median overall survival (OS) of 14.9 months. This agent is being evaluated in 2 phase III trials (NCT01642004 and NCT01673867) in NSCLC.10,11

MK-3475 and MPDL3280A have both shown ORRs of more than 20% in phase I trials of patients with NSCLC.12,13Phase III trials are ongoing, comparing various chemotherapeutic regimens in patients with NSCLC (NCT0905657, NCT02142738, and NCT02008227). In many cases, increased expression of PD-L1 correlates with improved drug efficacy and, as such, PD-L1 expression is being evaluated as a potential biomarker of response.

Further highlighting the significance of these findings, Levy explained that, “These outcomes need to be put in context of traditional chemotherapeutic strategies that generally yield response rates of only 5% and survival times of less than 3 to 6 months in the third-line setting.” Another advantage of these agents is that they have significant efficacy in the squamous subtype of NSCLC, for which there are currently no FDA-approved targeted therapies; for example, the ORR of nivolumab was 33% among patients with squamous cell histology compared with 12% in nonsquamous cell patients.11

Langer concluded, “The advent of the PD-1 and PD-L1 inhibitors promises to have a major impact on a much larger swath of patients, although these agents are not targeting a specific oncogenic driver.”


  1. Pastorino U, Andreola S, Tagliabue E, et al. Immunocytochemical markers in stage I lung cancer: relevance to prognosis.J Clin Oncol. 1997;15:2858-2865.
  2. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib.N Engl J Med. 2005;352(8):786-792.
  3. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.PLoS Med. 2005;2(3):e73.
  4. Wakelee H. Phase 1 evaluation of CO-1686, an irreversible, mutant-selective inhibitor of EGFR mutations (activating and T790M). Presented at European Lung Cancer Conference. 26-29 March 2014; Geneva, Switzerland.
  5. Janne PA, Ramalingam SS, Yang JC, et al: Clinical activity of the mutant selective EGFR inhibitor AZD9291 in patients with EGFR inhibitor—resistant non-small cell lung cancer (NSCLC). ASCO Annual Meeting. Presented May 31, 2014. Abstract 8009.
  6. United States Food and Drug Administration. Crizotinib. FDA web site. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm376058.htm. Accessed July 20, 2014.
  7. United States Food and Drug Administration. Ceritinib. FDA web site. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm395386.htm. Accessed July 20, 2014.
  8. Ou S, Gadgeel S, Chiappori A, et al. Safety and efficacy analysis of RO5424802/CH5424802 in anaplastic lymphoma kinase (ALK)-kinase positive non-small cell lung cancer (NSCLC) patients who have failed crizotinib in a dose-finding phase I study. Presented at the European Cancer Congress 2013. Amsterdam. Abstract 44.
  9. Camidge DR, Bazhenova L, Salgia R, et al. Updated results of a first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. Presented at the European Cancer Congress, 2013. Amsterdam. Abstract 3401.
  10. Sundar R, Soong R, Cho B, et al. Immunotherapy in the treatment of non-small cell lung cancer.Lung Cancer. 2014;85:101-109.
  11. Brahmer JR, Horn L, Antonia SJ, et al. Nivolumab in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial. Presented at the 15th World Conference on Lung Cancer. October 27-October 31, 2013. Sydney, Australia. Abstract MO18.03.
  12. Garon EB, Balmanoukian A, Hamid O, et al. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC).. Presented at the 15th World Conference on Lung Cancer. October 27-October 31, 2013. Sydney, Australia. Abstract MO18.02.
  13. Spigel DR, Gettinger SN, Horn L, et al. Clinical activity, safety and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer.J Clin Oncol. 2013;31(suppl): Abstract 8008.