Barbara L. Jones

More than two dozen abstracts at the December 2013 meeting of the American Society of Hematology (ASH) focused on the detection, measurement, or monitoring of minimal residual disease (MRD) in patients with multiple myeloma (MM). This emphasis is &ldquo;very exciting,&rdquo; according to Brian G. M. Durie, MD, founder and chair of the International Myeloma Foundation (IMF) and Hematologist/Oncologist at Cedars-Sinai Medical Center in Los Angeles, California. According to Durie the focus on MRD reflects real progress in what the IMF recently declared as the goal of its Black Swan Research Initiative (BSRI): MRD-Zero.

MRD-Zero will be achieved when tools are available to physicians to successfully determine when patients arrive at, and are able to sustain, the status of MRD. One study reported at ASH showed that it can be done. Ola Landgren, MD, PhD, and colleagues showed in a small pilot study that 11 of 12 patients with high-risk smoldering MM (HR-SSM) achieved and sustained MRD-Zero.

Several other abstracts from ASH examined the expanded possibilities in MRD testing and monitoring with the use of alternative sophisticated models.

In a Spanish study, researchers undertook a first-time characterization of the MRD clone at the biological level, as what they described as a &ldquo;unique model for understanding chemoresistance.&rdquo; This is important work, Durie commented, because there is a need to better understand the nature of resistant subclones in order to achieve MRD-Zero.

There are no black swansuntil there is a black swan.

There is no cure for multiple myeloma. Until there is a cure. Thus, the Black Swan Research Initiative (BSRI) of the International Myeloma Foundation is well-named for what is described as a breakthrough approach to finding a cure for myeloma.

The BSRI is unique as an &ldquo;actual research project aimed at finding a functional cure for myeloma, not an open-access platform to support external research,&rdquo; explained Brian G. M. Durie, MD, in one of his regular online postings, &ldquo;Dr. Durie&rsquo;s Blog.&rdquo;

&ldquo;A core tenet of BSRI is that many patients might be cured [already] and don&rsquo;t know it because previously we have lacked the sophisticated tests necessary to determine that zero minimal residual disease (MRD-Zero) has been achieved.&rdquo;

The most recent ASH meeting featured testing methods for MRD with great near-term potential.

&ldquo;Using the latest procedures involving flow cytometry and full DNA sequencing, we will be able to detect down to less than 1 cell per million of myeloma. Thus, we can identify who has been cured, and what combinations of therapies led to that cure.&rdquo;

Black Swan Research Initiative&rsquo;s distinctly different pathway to a cure.

http://myeloma.org/MtEntryPage. action?source=/imf_blogs/myeloma_voices/

2013/09/black-swan-research-initiativesdistinctively- different-pathway-to-a-cure.html

Complete eradication of all subclones in MM is required to prolong patient survival. Members of the same group from the Universidad de Salamanca, Spain, conducted a sophisticated analysis of subclones with different genetic profiles, clonogenic profiles, and differing drug sensitivities. They found that distinct phenotypic subclones translate into different cytogenetic profiles and clonogenic potential. As the balance between different subclones changes over the course of treatment, so does the extent of specific cytogenetic abnormalities, as well as patient risk. &ldquo;Careful monitoring of specific subclones may have implications toward an adapted therapy to overcome chemoresistant cells,&rdquo; the investigators concluded.

Regarding the clinical implications of this work, Durie said that an understanding of subclones, which persist or emerge despite current novel therapy, &ldquo;is key to developing more successful treatment and achieving MRD-Zero.&rdquo;

A number of abstracts at the ASH meeting compared molecular testing and flow cytometry to assess MRD.

One was a &ldquo;deep sequencing approach&rdquo; to an analysis of bone marrow samples from 133 patients who were treated similarly within the Spanish Myeloma Group trials.

The investigators compared the prognostic value of traditional response criteria to assess MRD with a sequencing-based platform (LymphoSIGHT), multiparameter flow cytometry (MFC), and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) of Ig genes. Their findings established a near equivalence between the MRD studies, at 91%, and the flow cytometry, at 96%. The investigators also found a high correlation between MRD levels by sequencing, by ASO-PCR, and by MFC. Based on these results, &ldquo;MRD assessment by sequencing is a useful method for patient risk stratification and can be used to determine molecular complete response (CR) in MM,&rdquo; the group concluded.

A group from the National Cancer Institute, led by Landgren, compared serum heavy-light chains (HLC) with free light-chains (FLC) as predictors of early CR in newly diagnosed patients with myeloma who were treated with carfilzomib, lenalidomide, and dexamethasone in an ongoing, prospective, clinical trial for patients with MM and HR-SMM.

Early monitoring (after 2 cycles) of HLC patterns, the group found, was an independent predictor of rapid response.

The International Myeloma Foundation. The International Myeloma Foundation launches the Black Swan Research Initiative to develop the very first definitive cure for multiple myeloma.

http://myeloma. org/BSRI/IMF_BlackSwanLaunch_031113_F3.pdf

Landgren O, Mailankody S, Kwok M, et al. Clinical and correlative pilot study of carfilzomab, lenalidomide, and dexamethasone followed by lenalidomide extended dosing (CRdR) in high-risk smoldering multiple myeloma. American Society of Hematology, 2013. Abstract 1939.

Paiva B, Corchete LA, Gutierrez N, et al. Phenotypic and genomic analysis of multiple myeloma (MM): minimal residual disease (MRD) clonal plasma cells. American Society of Hematology, 2013. Abstract 402.

Paino T, Paiva B, Sayagues JM, et al. Phenotypic identification of subclones in multiple myeloma with different genomic profile, clonogenic potential and drug sensitivity. American Society of Hematology, 2013. Abstract 531.

Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing approach for minimal residual disease (MRD) detection in multiple myeloma patients. American Society of Hematology, 2013. Abstract 1848.

Bhutani M, Costello R, Korde N, et al. Serum heavy-light chains (HLC) and free light chains (FLC) as predictors for early CR in newly diagnosed myeloma patients treated with carfilzomib, lenalidomide, and dexamethasone (CRd). American Society of Hematology, 2013. Abstract 762.

Articles

More than two dozen abstracts at the December 2013 meeting of the American Society of Hematology (ASH) focused on the detection, measurement, or monitoring of MRD in patients with multiple myeloma.

Minimal Residual Disease (MRD) Marches to Front Line of Myeloma Research

Table. Smoldering Multiple Myeloma: A Case Study

Asymptomatic, active, 53-year-old woman was found to have an elevated erythrocyte sedimentation rate (ESR) with elevated serum proteins (90 g/L) in routine examination

Complementary studies revealed normal hemoglobin, creatinine, and serum beta-2-microglobulin

M component: 35 g/L; plasma cells (PCs) in bone marrow (BM): 33%

No lytic lesions were detected; magnetic resonance imaging (MRI) showed osteoporosis with 1-2 focal lesions

(The full-panel discussion can be accessed at:

http://www.youtube.com/watch?v=FNw7bctXqfg

The panel was sponsored jointly by the International Myeloma Foundation, the Annenberg Center for Health Sciences, and Clinical Care Options) Before the presentations, audience members voted on whether or not to recommend starting systemic myeloma therapy for the following patient. The result: 61% no, 39% yes. At the conclusion of the presentations and discussion, the vote was essentially unchanged.

Thus, before the opening of the official 55th Annual American Society of Hematology (ASH) meeting in December 2013, two members of an international panel of myeloma experts, one from Spain and one from the United States, presented opposing arguments for the treat versus watch-and-wait approaches for a sample patient case of HR-SMM (

). The panel, which featured three other presentations on current research regarding myeloma, was moderated by Brian G.M. Durie, MD, founder and chair of the International Myeloma Foundation and hematologist/oncologist at Cedars-Sinai Medical Center in Los Angeles, California.

Yes: Initiate Therapy Based on Risk of Progression

A consensus emerged from both sides that while patients with &ldquo;early myeloma or ultra-high-risk SMM require treatment,&rdquo; a better definition of HR-SMM is needed, along with clinical trials that may answer the critical question of whether or not early intervention changes the natural history of the disease.

Results from clinical trials in SMM have been mostly consistent in finding no benefit from early treatment.

In studies of bisphosphonates versus observation, the bisphosphonates have been found to delay the time to skeletal events, but not the time to progression (TTP). More recently, studies with thalidomide plus zoledronic acid (ZOL) versus no ZOL for early versus delayed intervention found no benefit in TTP, in symptomatic disease, or in overall survival (OS).

However, the risk of progressive disease to active disease is &ldquo;heterogeneous,&rdquo; said Jes&uacute;s F. San Miguel, MD, PhD, from Universidad de Navarra, Spain. &ldquo;None of these trials discriminates between low-risk patients who are not likely to benefit from intervention (and) highrisk patients who may well benefit from therapy,&rdquo; San Miguel stated.

One recent trial is an exception. The randomized, phase III trial from the Spanish myeloma group produced the first evidence of an improvement in OS in a group of patients with SMM whose disease met either the Mayo or the Spanish classification criteria for HR-SMM, defined as 50% risk of progression within 2 years. These criteria require 10% or more PCs in the BM plus &ge;3 g/dL of MC

or most of the PCs (>95%) being clonal plus immunoparesis.

In this study, 119 patients were randomized to receive either lenalidomide plus dexamethasone or no treatment for nine cycles, followed by lenalidomide maintenance. Patients who progressed on lenalidomide maintenance could receive low-dose dexamethasone based on biologic progression alone (not clinical progression).

At a median of 40 months, the response rate (RR), TTP, and OS favored the experimental treatment arm. &ldquo;Over 80% of patients (in the lenalidomideplus- dexamethasone arm) responded, with over 15% [experiencing] complete responses,&rdquo; San Miguel said. &ldquo;During the maintenance phase, the sCR plus CR rate increased to 26%.&rdquo;

This RR was clearly different from what has been previously reported for thalidomide, and very similar to the RR that the Spanish group observed with lenalidomide/dexamethasone in symptomatic patients.

&ldquo;The simplest explanation for me is that we are dealing with different populations of patients,&rdquo; said San Miguel.

The primary endpoint of the Spanish study was TTP. Median TTP was significantly longer in the treatment group than in the observation group (the median was not reached at 21 months; hazard ratio [HR] for progression .18; 95% confidence interval [CI] .09-32;

<.001). A total of 76% of patients had already progressed in the observation arm, indicating a veryhigh- risk population, versus only 23% clinical progression in the experimental arm.&rdquo;

What was most striking to myeloma experts was the OS data in the Spanish trial. With a median follow up of 47 months, there was a clear OS advantage for the lenalidomide/dexamethasone arm. &ldquo;At 5 years, 95% of the patients are alive versus 78% of patients in the no treatment arm.&rdquo;

Side effects were primarily grade 2 or lower and less than 10% of grade 3 side effects were seen.

To many, these data provide compelling evidence that early intervention could be beneficial for patients with HRSMM.

SanMiguel conceded that some physicians would argue that a proportion of patients even in the high-risk population will never progress, and, based on this, they would require that better criteria be used to define high risk.

No: Improve Knowledge and Seek Consensus Regarding Definition of High Risk

But, he asked: &ldquo;Can (the risk of) 30% of patient (overtreatment) justify the risk of undertreating the 70% who would benefit from treatment?&rdquo;

Two significant problems persist in the care of patients with MM. The first is that a correct definition of MM is lacking, according to S. Vincent Rajkumar, MD, professor of medicine at the Mayo Clinic, Rochester, Minnesota, speaking on behalf of the &rsquo;no treatment&lsquo; choice of SMM. The second, he said, is that, &ldquo;We are talking about multiple diseases but we are considering them as one disease.&rdquo;

The disease definition of MM is currently based on end-organ damage, and according to Rajkumar and some colleagues, this needs to change.

Rajkumar, along with San Miguel and other myeloma colleagues, identified these subgroups of patients with SMM who have ultra-high-risk disease:

Patients with more than 60% PCs in the BM. Even without end-organ damage, these patients may be considered to have MM because they progress very rapidly

Patients with high free light-chain (FLC) ratio (&ge;100), who progress very rapidly; 80% or more within the first 2 years

Patients with more than 1 focal lesion on MRI; who also progress very rapidly: 80% within the first 2 years

Rajkumar explained: &ldquo;We need to recognize that the various cytogenetic subtypes of SMM progress to MM at different rates, and each subtype may actually represent a distinct disease entity.&rdquo;

Rajkumar described three subgroups of SMM:

Patients with ultra-high-risk features (&ge;80% risk of progression within 2 years). These patients are best treated as patients with MM regardless of the presence or absence of end-organ damage

Patients with high-risk features (~50% risk of progression within 2 years), a population for which clinicians are now debating the value of early therapy

Patients without any high-risk features, about whom there is consensus favoring a watch-and-wait strategy

&ldquo;What we have right now,&rdquo; said Rajkumar, &ldquo;is a small cohort of patients with myeloma who are ultra-high risk. Then we have patients with HR-SMM who have about a 25% high risk per year of progression.&rdquo;

The real debate, according to Rajkumar, is not about the management of ultra-high-risk or low-risk SMM, but rather whether or not clinicians should treat patients in the middle, with HRSMM, who, according to most studies, have shown evidence of progressionfree survival but no survival advantage. Showing an improvement in OS, the Spanish myeloma trial poses the question of whether or not there should still be a debate about treatment of HR-SMM.

Figure. Low-risk, high-risk, and ultra-high-risk smoldering multiple myeloma.

BMPC, bone marrow plasma cells; FLC, free light-chain ratio; PC, plasma cells; SMM, smoldering multiple myeloma.

In other words, the key clinical question is: should not all patients with HRSMM be treated?

Perhaps not, Rajkumar suggested. &ldquo;The first problem with the Spanish trial that we need to address is that it is not generalizable to a large proportion of the (patient population). One-half of the patients in the Spanish trial1 were enrolled based on the results of a flow cytometrybased assay that is not generally available.&rdquo;

The second problem, according to Rajkumar, is that the actual event rate in the Spanish trial is small. &ldquo;The entire survival difference is based on a death rate of 4 deaths (of 57 patients) in the treatment group versus 13 deaths (of 62 patients) in the observation group. Even minor imbalances in the cytogenetics of the patients, such as deletion 17p and t(4;14) at baseline could have skewed the OS difference (between treatment groups).&rdquo;

Another question is whether or not the survival benefit in the Spanish trial could have been conferred by the dexamethasone. This question will be investigated in a study under recruitment, led by Sagar Lonial, comparing lenalidomide versus observation in asymptomatic patients with HR-SMM.

For patients whose disease bears ultra- high-risk features (&ge;60% PCs in BM, FLC ratio &ge;100, and >1 focal lesion on MRI), Rajkumar urged: don&rsquo;t wait, because these patients will progress rapidly or get renal failure very quickly.&rdquo;

&ldquo;This is not (the patient) we are speaking about,&rdquo; he said. &ldquo;We are speaking about the high-risk patients: abnormal immunophenotype, abnormal FLC ratio; &ge;3 g M protein, and &ge;10% plasma cells.&rdquo; For this patient group, &ldquo;We still need to do clinical trials if we are to make this a reality for patients,&rdquo; he said (Figure).

A discussion led by moderator Durie established the contours of a consensus among panel members.

Although the typical clinical manifestations of MM are summarized by the CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone lesions), a significant proportion of patients with MM present with a variety of other clinical manifestations.

among patients with symptomatic MM, 74% presented with CRAB symptoms, 20% presented with non-CRAB manifestations, and 6% had both clinical features.

&ldquo;For patients who already have high risk of progression within 2 years (&ge;80%), there is no reason to wait for the other shoe to drop&hellip;and have some catastrophic problems before we initiate therapy. We basically have to take the 15% to 20% or so of patients who we currently call smoldering and treat them as early as possible, at pre-CRAB myeloma. The remaining 80% should be enrolled in clinical trials that will seek to answer the question whether early intervention changes the natural history of the disease,&rdquo; Durie stated.

&ldquo;The major issue is to update CRAB criteria (taking into account) the new criteria and new technology available to define early myeloma, and to better (discriminate) the benign tumor from the malignant tumor that is myeloma, taking out the gray zone that is the mix of the malignant and the benign,&rdquo; Durie said.

Mateos MV, Hernandez MT, Giraldo P, et al. Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma.

Perez-Persona E, Vidriales MB, Mateo G, et al. New criteria to identify risk of progression in monocloncal gammopathy of uncertain significance and smoldering multiple myeloma based on multiparameter cytometry analysis of bone marrow plasma cells.

Rajkumar SJ, Merlini G, San Miguel JF. Hematologic cancer: redefining myeloma.

ClinicalTrials.gov. Lenalidomide or observation in treating patients with asymptomatic high-risk smoldering multiple myeloma. http://clinicaltrials. gov/ct2/show/NCT01169337.

Talamo G, Farooq U, Zangari M, et al: Beyond the CRAB symptoms: a study of presenting clinical manifestations of multiple myeloma.

In most malignancies, early detection and intervention are prerequisites for a possible cure. Consequently, why is the standard of care for myeloma a watch-and-wait approach, with no treatment until progression?

Debate Continues on Initiating Therapy for High-Risk Smoldering Myeloma

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,

recent evidence that more than 60% of lung adenocarcinomas harbor one of several known mutations

suggests 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&rsquo;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.

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).

In 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 for

fusions to guide patient selection for therapy with an EGFR or ALK inhibitor, &ldquo;&hellip;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.&rdquo;

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 meeting

and 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 was

(25%), followed by sensitizing mutations of

(8%), and smaller percentages of enrolled patients with

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.

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,

&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.

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, the

mutation 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 (

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.

At Memorial Sloan Kettering Cancer Center (MSK) in New York City, where the

mutation 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.

A 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.

Bevacizumab, 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.

In 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.

A caveat to this evidence is that there is now no predictive marker to guide the choice of angiogenesis treatment.1

A meta-analysis of efficacy (n = 2018) and safety (n=1970) data from four randomized trials of cetuximab, an

monoclonal 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.

However, molecular markers that successfully predict response to EGFR and other tyrosine kinase inhibitors (TKIs) do not appear to predict response to cetuximab.

Erlotinib, a TKI, was approved in May 2013 for the firstline treatment of patients with metastatic NSCLC whose tumors have

exon 19 deletions or exon 21 (L858R) substituting mutations, based on a companion mutation test.

The 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,

Afatinib, a second-generation TKI that irreversibly binds both HER2 and

, was approved in July 2013 for the firstline treatment of patients with metastatic NSCLC whose tumors harbor

exon 19 deletions or exon 21 (L858R) substituting mutations, based on a companion mutation testthe therascreen&reg;

Trials comparing EGFR TKIs with chemotherapy in molecularly unselected patients all demonstrated &ldquo;significantly worse outcomes&rdquo; for patients with wild-type

mutations in patient selection for chemotherapy and for

therapy remains controversial, as was described in the post-ASCO 2013 state-of-the-art review in metastatic lung cancer.

appears to be a weak marker of poor prognosis, based in part on meta-analyses that indicate patients with

mutations do not predict for poorer outcomes from cetuximab in NSCLC. According to the ASCO authors of the 2013 lung cancer summary,

mutation is not recommended as a reason to exclude patients from therapy.

Positive results from phase I and II trials with crizotinib, an

inhibitor, led to this targeted agent&rsquo;s accelerated approval, along with a companion diagnostic to detect

However, the full role of crizotinib may yet be defined.

inhibitors have been studied only in patients with

mutations. Until other investigations are completed, it is premature to predict the effects that these drugs will have on patients with

wild-type tumors, according to the authors of ASCO&rsquo;s 2013 summary report on lung cancer.

In 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.

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.

In 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.

The 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.

A 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.

Heather 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.

An 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.

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;

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.

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.

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

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).

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

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.

. 2013;15:415-453. Available at: http://www.ncbi.nlm.gov/pubmed/23562183

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

Schmid-Bindert G. Update on antiangiogenic treatment of advanced non-small cell lung cancer (NSCLC).

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.

. 2013;24(1):20-30. Available at: http://www.ncbi.nlm.gov/pubmed/23180113

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

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

US Food and Drug Administration (FDA). Afatinib. July 2013. Available at: http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm

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

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.

. 2012;30:2046-2054. Available at: http://www.ncbi.nlm.gov/pubmed/22858559

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

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.

. 2013;13(suppl). Abstract 8072. Available at: http://meetinglibrary.asco.org/print/1167107

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

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

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Although the current standard of care for advanced NSCLC remains platinum doublet chemotherapy, recent evidence suggests that most newly diagnosed patients may be candidates for targeted therapy as firstline treatment.

Frontline Treatment Considerations in Non-Small Cell Lung Cancer

Between 2007 and 2011, a collaboration among clinical oncologists, pathologists, and industry scientists led to the identification of a new molecularly defined subset of non-small cell lung cancer (NSCLC), followed by the finding that crizotinib, then under development as a MET inhibitor, was an inhibitor of anaplastic lymphoma kinase (ALK). Clinical testing rapidly established the efficacy of crizotinib in patients with

-rearranged NSCLC, and FDA approval of crizotinib followed for this indication in August 2011.

That less than 5 years had elapsed between discovery of a newly defined subtype of NSCLC and the development, testing, and FDA approval of an effective targeted therapy (along with a diagnostic test) may serve as a model for successful next-generation development of targeted therapies, according to Alice T. Shaw, MD, PhD, from Harvard Medical School and Massachusetts General Hospital, in Boston. Shaw traced events that mark this example of contemporary bench-tobedside science at the 11th International Congress on Targeted Therapies in Cancer, held mid-August in Washington, DC by Physicians&rsquo; Education Resource (PER).

rearrangements were first discovered in anaplastic large cell lymphoma about 20 years ago, and &ldquo;rediscovered&rdquo; in 2007 by Hiroyuki Mano, MD, PhD, and colleagues from Japan. Mano led a research team that found a fusion gene with portions of the echinoderm microtubule-associated protein-like 4 (

) gene and ALK in a small subset of Japanese patients with NSCLC.

fusion activates ALK, which is normally not expressed in the lung.

Mano&rsquo;s research also found that, not only was the

fusion gene a potent oncogenic driver in nude mice models, but blocking the kinase activity of

&ldquo;completely abrogated&rdquo; the oncogenic activity.

Gene translocations that activate tyrosine kinases may represent excellent drug targets for many cancers, especially with NSCLC, according to Shaw.

rearrangements occur in 3% to 7% of patients with NSCLC who share a few key characteristics. Specifically,

rearrangements are enriched in patients who are never- or light smokers and tend to be found in patients who are 10 to 15 years younger than the average patient with NSCLC. They occur primarily in the adenocarcinoma type of NSCLC.

When the expansion phase of the phase I clinical study of crizotinib commenced at approximately the same time as the

-rearranged NSCLC subtype was identifiedearly results showed that the majority of patients had responded.

In the phase II follow- up, single-arm study in patients with advanced

-positive lung cancer, the drug produced a similarly high response rate of about 60%. In both studies, median progression-free survival (PFS) was about 8 to 10 months. Crizotinib approval was based on the response rate seen in these trials.

The role of crizotinib in the treatment of

-positive lung cancer was confirmed by a head-to-head comparison of crizotinib to standard chemotherapy in patients with advanced

In this phase III trial, all patients were

-positive by the standard fluorescence in situ hybridization (FISH) assay, and all had failed first-line platinum-based chemotherapy. The primary endpoint was PFS. Secondary endpoints were response rate, overall survival, safety, and patient-reported outcomes.

Patients were randomized 1:1 to receive either crizotinib or a standard second-line agent, such as pemetrexed or docetaxel. No crossover was designed. However, once patients progressed on the chemotherapy arm, they came off study and received crizotinib in a separate ongoing phase II study, according to Shaw.

Between 2007 and 2011, a collaboration among clinical oncologists, pathologists, and industry scientists led to the identification of a new molecularly defined subset of NSCLC, followed by the finding that crizotinib, then under development as a MET inhibitor, was an inhibitor of ALK.

Barbara L. Jones | Authors

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