Frontline Treatment Considerations in Non-Small Cell Lung Cancer

Grace K. Dy, MD

Although the current standard of care for advanced non-small cell lung cancer (NSCLC) remains platinum doublet chemotherapy for fit patients who do not have a molecular-driven genetic abnormality,¹recent evidence that more than 60% of lung adenocarcinomas harbor one of several known mutations²suggests that most newly diagnosed patients may be candidates for targeted therapy as firstline treatment.

In NSCLC, treatment is evolving rapidly, according to the authors of the American Society of Clinical Oncology’s (ASCO) 2013 Education Book on state-of-the-art therapy in metastatic lung cancer. Today, in addition to clinical factors and histology, many clinicians recommend that molecular features must be considered before treatment is selected.¹

Two new guidelines have addressed these recommendations. The National Comprehensive Cancer Network (NCCN) in 2013 recommended that molecular testing should assess, at the least, for the presence of epidermal growth factor receptor (EGFR) and the anaplastic lymphoma receptor tyrosine kinase (ALK).³In addition, in a joint 2013 statement, the College of American Pathologists, the International Association of the Study of Lung Cancer, and the Association of Molecular Pathology called for clinicians to use testing forEGFRmutations andALKfusions to guide patient selection for therapy with an EGFR or ALK inhibitor, “…in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests.”⁴

Naiyer A. Rizvi, MD, on PD-L1 as a Biomarker for Immunotherapy Agents in Lung Cancer

Rizvi is an associate attending physician at Memorial Sloan Kettering Cancer Center.

Actionable driver mutations were found in 64% of patients with lung adenocarcinomas taking part in the large, ongoing, Lung Cancer Mutation Consortium (LCMC), according to its report of findings at the 2013 ASCO annual meeting²and the 2013 World Conference on Lung Cancer (WCLC).

In just over 1000 patients whose tumors were tested for 10 genes, the most common driver mutation wasKRAS(25%), followed by sensitizing mutations ofEGFR(17%),ALK(8%), and smaller percentages of enrolled patients withMETamplification,BRAF, orPIK3CA,HER2,MEK1,NRAS,orAKT1.²

When these results were used to select targeted therapy, or to enroll patients in trials with targeted therapies, according to LCMC data, those who were treated with a targeted agent had longer median survival than did patients who were not randomized to a targeted therapy.²

Bruce E. Johnson, MD, professor, department of Medicine, Harvard Medical School, and professor of Medicine, Adult Oncology, Dana-Farber Cancer Institute in Boston, presented the data for the LCMC group of 14 participating cancer centers in the United States. He said that of 938 patients for whom clinical follow-up and treatment information were available in the LCMC trial, patients with a driver mutation (n = 260) who were treated with a targeted agent had a median survival of 3.5 years versus a median survival of 2.1 years in patients with a driver mutation who did not receive targeted therapy (n = 360,P< .0001).²

&ldquo;The study shows that one can systematically characterize the majority of patients with adenocarcinoma of the lung for multiple genomic changes,&rdquo; Johnson said of the study&rsquo;s implications for clinical care.

&ldquo;The most encouraging aspect of the study is that the patients with oncogenic drivers who could be treated with targeted therapy lived more than a year longer than those who had an oncogenic driver but did not get targeted therapy and those without an oncogenic driver. This provides evidence to support genomic characterization of NSCLC and administering appropriate targeted treatment,&rdquo; Johnson said.

Dissemination of Molecular Testing

Further prospective studies are still needed to directly address the ability to prolong survival using this approach, he said.Molecular testing for the most common mutations in lung adenocarcinoma is by now widespread in developed countries, according to Grace K. Dy, MD, Associate Professor of Medicine at Roswell Park Cancer Institute in Buffalo, New York.

&ldquo;(Testing) is very routine,&rdquo; Dy said of her practice at Roswell, and appears to be widely practiced in the community setting as well as inferred from patients. Whether for referral patients or for patients who see her for a second opinion or a switch, she said: &ldquo;By the time the patient comes in, at a minimum, theEGFRandALKmutation test results are either already requested or available.&rdquo; Dy continued: &ldquo;Depending on the pathology laboratory they collaborate with, some oncologists may order more comprehensive testing, especially if the patient is a nonsmoker.&rdquo;

Dy added that her institution&rsquo;s laboratory, which is certified by Clinical Laboratory Improvement Amendments (CLIA), &ldquo;will also be implementing, in the ensuing 1 to 2 months, next-generation sequencing technology to characterize relevant mutations, translocations, or copy number variations in 15 genes (AKT1,ALK,BRAF,DDR2,EGFR,ERBB2 (HER2),FGFR1,KRAS,MEK1,MET,NRAS,PIK3CA,PTEN,RET, andROS1)&rdquo; for patients with lung cancer.

The panel includes these genes because there are therapies approved or in clinical trial testing for the corresponding genomic alteration, Dy said. &ldquo;Currently, hot-spot pyrosequencing and fluorescent in-situ hybridization (FISH) assays are used in the pertinent molecular diagnostic tests requested for our lung cancer patients,&rdquo; Dy said.

Mark G. Kris, MD

VEGF

Bevacizumab/Angiogenesis Therapy

EGFR

Cetuximab

Erlotinib

Afatinib

KRAS

ALK

Crizotinib

Lung Cancer Driver Immunosuppressors

At Memorial Sloan Kettering Cancer Center (MSK) in New York City, where theEGFRmutation was first identified, tumor samples from every lung adenocarcinoma patient are tested for as many as a dozen mutations, according to Mark G. Kris, MD, Chief of the Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, at MSK.⁵A genetic marker is found in about two thirds of cases, he said, and the information is used to guide treatment decisions. &ldquo;We can point ourselves to some kind of therapy based on the specific genetic characteristics,&rdquo; said Kris, adding, &ldquo;There is a plan for every sample,&rdquo; if not to guide treatment, then for research efforts.⁵Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, was the first antiangiogenic agent to receive US Food and Drug Administration (FDA) approval for firstline treatment of advanced NSCLC.⁶In a recent meta-analysis, when added to platinum-based chemotherapy, bevacizumab significantly prolonged both overall survival (OS) and progression-free survival (PFS) as firstline treatment in patients with advanced NSCLC. The systematic review included data for 2194 patients (1313 bevacizumab, 881 controls) from four randomized phase II and III trials.⁷A caveat to this evidence is that there is now no predictive marker to guide the choice of angiogenesis treatment.1A meta-analysis of efficacy (n = 2018) and safety (n=1970) data from four randomized trials of cetuximab, anEGFRmonoclonal antibody, plus platinum-based, frontline chemotherapy in advanced NSCLC significantly improved OS, PFS, response, and the overall response rate (ORR), with a manageable safety profile, according to a 2014 published report.⁸However, molecular markers that successfully predict response to EGFR and other tyrosine kinase inhibitors (TKIs) do not appear to predict response to cetuximab.¹Erlotinib, a TKI, was approved in May 2013 for the firstline treatment of patients with metastatic NSCLC whose tumors haveEGFRexon 19 deletions or exon 21 (L858R) substituting mutations, based on a companion mutation test.⁹The FDA approval was based on results from a randomized, multicenter, open-label trial that compared erlotinib to platinum-based doublet chemotherapy. In this study, median PFS was significantly prolonged in erlotinib-treated patients (10.4 months vs 5.2 months,P< .001).⁹Afatinib, a second-generation TKI that irreversibly binds both HER2 andEGFR, was approved in July 2013 for the firstline treatment of patients with metastatic NSCLC whose tumors harborEGFRexon 19 deletions or exon 21 (L858R) substituting mutations, based on a companion mutation test—the therascreen&reg;EGFRRGQ PCR Kit.¹⁰Trials comparing EGFR TKIs with chemotherapy in molecularly unselected patients all demonstrated &ldquo;significantly worse outcomes&rdquo; for patients with wild-typeEGFRtumors who did not receive chemotherapy.¹The role ofKRASmutations in patient selection for chemotherapy and forEGFRtherapy remains controversial, as was described in the post-ASCO 2013 state-of-the-art review in metastatic lung cancer.¹KRASappears to be a weak marker of poor prognosis, based in part on meta-analyses that indicate patients withKRASmutations exhibit lower responses toEGFRTKIs. Overall data show thatKRASmutations do not predict for poorer outcomes from cetuximab in NSCLC. According to the ASCO authors of the 2013 lung cancer summary,KRASmutation is not recommended as a reason to exclude patients from therapy.¹Positive results from phase I and II trials with crizotinib, anALKinhibitor, led to this targeted agent&rsquo;s accelerated approval, along with a companion diagnostic to detectALKrearrangements by FISH.¹¹However, the full role of crizotinib may yet be defined.¹Crizotinib and otherALKinhibitors have been studied only in patients withALKmutations. Until other investigations are completed, it is premature to predict the effects that these drugs will have on patients withALKwild-type tumors, according to the authors of ASCO&rsquo;s 2013 summary report on lung cancer.¹In many NSCLC tumors—almost one half in the LCMC data&mdash;an oncogenic driver is unknown.2 Immunotherapy may yield efficacy, regardless of tumor histology or mutation status, in these patients.

Ipilimumab

Nivolumab

Heather A. Wakelee, MD

MPDL3280A

Biomarker Development in Immunotherapy

Reflecting a widely expressed view among oncologists, Dy said that there is &ldquo;a surge of interest&rdquo; in these forms of treatment. More than other types of targeted agents, antibody drugs that target inhibitory T-cell coreceptor programmed cell death protein 1 (PD-1) and its ligand, PD-L1, may confer new benefits to patients, she said.Ipilimumab was studied in a successful phase II study as firstline treatment of advanced lung cancer using two schedules of ipilimumab versus placebo during platinum-based chemotherapy. The trial methods called for the drugs to be given in a phased manner or concurrent manner (alternating chemotherapy and ipilimumab in different ways). Encouraging results, especially from the phased schedule, have led to a phase III registration trial in squamous NSCLC, with overall survival as an endpoint.^12,13In a recently reported phase I study of 43 chemotherapy-na&iuml;ve patients with locally advanced NSCLC, nivolumab, a PD-1 inhibitor, plus platinum-based doublet chemotherapy showed no evidence of dose-limiting toxicities and a favorable objective response rate of 33%. Maintenance treatment is ongoing.¹⁴The trial found grade 3-4 adverse events of less than 5%. Phase III trials are underway with nivolumab plus chemotherapy as frontline therapy in NSCLC patients.¹⁵A phase II, multicenter, single-arm study of the anti-PD-L1 monoclonal antibody, MPDL3280A, is recruiting patients with PD-L1-positive, locally advanced or metastatic NSCLC.¹⁶Heather A. Wakelee, MD, Associate Professor of Medicine (Oncology) at the Stanford University Medical Center, a panelist at a recent video discussion on checkpoint inhibition in NSCLC, pointed to data from the MPDL3280A phase I trial that included a finding of higher responses among patients with a history of smoking.¹⁷An urgent, but as yet unanswered, question is how best to predict which patients will benefit most from immunotherapy. It appears that the leading contender as a biomarker is PD-L1 expression.

In addition to the smoker versus nonsmoker data, another intriguing finding from a small group of patients in the phase I study with MPDL3280A was that, among patients with evaluable responses and for whom archival samples were available (n = 53), 5 of 6 patients with strong immunohistochemistry (IHC) baseline PD-L1 expression were responders.¹⁶

One expert panelist warned that the study involved &ldquo;very small numbers [and] we don&rsquo;t know if that is going to hold true,&rdquo; but suggested that the study is worthy of follow-up examination, &ldquo;even though there is evidence that the absence of PD-L1 expression does not preclude response.&rdquo;¹⁷

Kris enlarged the discussion by referring to work indicating that targeted agents are much more common with T cells in the tumor and PD-L1 expression. But, Kris said, there are also situations where there are T cells but no PD-L1 in the tumor, and PD-L1 but no T cells—and a finding of neither T cells nor PD-L1.¹⁷

Within variations such as T cells but no PD-L1 in the tumor, or PD-L1 but no T cells, &ldquo;you see very different responses,&rdquo; Kris said, but for these agents to work [best] &ldquo;you need to have PD-L1, and you need to have T cells, and the more you have [the higher the responses].&rdquo;

The next step from the makers of MPDL3280A is to undertake a phase II trial in patients with NSCLC who are PD-L1 positive by the drug maker&rsquo;s proprietary PD-L1 IHC test, a trial that is currently recruiting subjects.¹⁶

References

1. Shepherd FA, Bunn PA, Paz-Ares. Lung Cancer in 2013: State of the Art Therapy for Metastatic Disease. Available at: http://meetinglibrary.asco.org/conent/288-132
2. Johnson BE, Kris MG, Berry LD, et al. A multicenter effort to identify driver mutations and employ targeted therapy in patients with lung adenocarcinomas: The Lung Cancer Mutation Consortium (LCMC).J Clin Oncol. 2013;31(suppl). Abstract 8019.
3. NCCN Guidelines for Patients: Non-Small Cell Lung Cancer. Flash version, pages 38-39. Available at: http://www.nccn.org/patients/guidelines/nscl/index.html#38
4. Lindeman NI, Cagle PT, Beasley MB, et al. Molecular testing guideline of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors: guidelines from the College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology.J Mol Diagn. 2013;15:415-453. Available at: http://www.ncbi.nlm.gov/pubmed/23562183
5. Tailoring therapy to the genetic characteristics of each tumor. A panel discussion with Mark Kris, MD. May 2013. Available at CancerSmart: http://www.mskcc.org/videos/tailoring-therapy-genetic-characteristics-each-tumor
6. Schmid-Bindert G. Update on antiangiogenic treatment of advanced non-small cell lung cancer (NSCLC).Target Oncol. 2013;8:15-26.
7. Soria JC, Mauguen A, Rock M, et al. Systematic review and meta-analysis of randomised, phase II/III trials adding bevacizumab to platinum-based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer.Ann Oncol. 2013;24(1):20-30. Available at: http://www.ncbi.nlm.gov/pubmed/23180113
8. Pujol JL, Pirker R, Lynch TJ, et al. Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer. 2014;83:211-218. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24332319
9. Genentech (a member of the Roche group). FDA approved Tarceva&reg; (Erlotinib) and Cobas EGFR Mutation Test for Specific Type of Lung Cancer. May 2013. Available at: http://www.gene.com/media/press-releases/14407/2013-05-14/fda-approves-tarceva-erlotinib-tablets-a
10. US Food and Drug Administration (FDA). Afatinib. July 2013. Available at: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm
11. Xalkori [package insert]. New York, New York: Pfizer; 2013. Available at: http://www.pfizerpro.com/hcp/xalkori?source=google&HBX_PK=s_crizotinib&o=69985681|245244793|0&skwid=43700003265045638
12. Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small cell lung cancer: results from a randomized, double-blind, multicenter phase II study.J Clin Oncol. 2012;30:2046-2054. Available at: http://www.ncbi.nlm.gov/pubmed/22858559
13. ClinicalTrials.gov. Randomized, multicenter, double-blind, phase 3 trial comparing the efficacy of ipilimumab in addition to paclitaxel and carboplatin versus placebo in addition to paclitaxel and carboplatin in subjects with stage IV/recurrent non-small cell lung cancer (NSCLC). Available at: http://clinicaltrials.gov/ct2/show/NCT01285609?term=NCT01285609&rank=1
14. Rizvi NA, Antonia SJ, Chow LQM, et al. A phase I study of nivolumab (anti-PD-1; BMS-936558, ONO-4538) plus platinum-based doublet chemotherapy (PT-doublet) in chemotherapy-na&iuml;ve non-small cell lung cancer (NSCLC) patients.J Clin Oncol. 2013;13(suppl). Abstract 8072. Available at: http://meetinglibrary.asco.org/print/1167107
15. ClinicalTrials.gov. An open-label, randomized, phase 3 trial of nivolumab versus investigator&rsquo;s choice chemotherapy as first-line therapy for stage IV or recurrent PD-LI+ non-small cell lung cancer. CheckMate 026. Available at: http://clinicaltrials.gov/ct2/show/NCT02041533?term=nivolumab+and+lung+cancer+first-line&rank=1
16. ClinicalTrials.gov. A study of MPDL3280A in patients with PD-LI-positive, locally advanced or metastatic non-small cell lung cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT01846416?term=MPDL3280A&rank=5
17. Checkpoint Inhibition in Non-Small Cell Lung Cancer. Peer Exchange Panel: Corey Langer, Mark Kris, Benjamin Levy, Mark Socinski, Heather Wakelee on Checkpoint Inhibition in NSCLC. Feb 7, 2014. Available at: http://www.onclive.com/peer-exchange/nsclc-outcomes/Introduction-Improving-Clinical-Outcomes-in-NSCLC