Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer, comprising approximately 80% to 85% of lung cancer cases.

The 3 main types of NSCLC are large cell carcinoma (10%), squamous cell carcinoma (25%), and adenocarcinoma (40%), with numerous less frequent subtypes.

Approximately 70% of patients with NSCLC are diagnosed with locally advanced or metastatic disease (stage IIIB/IV) at the time of diagnosis, with 40% of these newly diagnosed patients with NSCLC having stage IV disease.

The treatment of advanced, recurrent, and metastatic NSCLC is often associated with poor prognosis, and treatment is aimed to extend survival and provide symptom management.

Recent advances in understanding of distinct tumor biology and immunology have allowed for the development of numerous targeted therapies and immune checkpoint inhibitors, which have improved overall survival (OS) in specific NSCLC populations. Molecular characterization has led to the definition of new subgroups of patients with distinct tumor biology who require specific treatments and strategies.

Prior to the introduction of molecular targeted therapy, first-line treatment for advanced-stage NSCLC was limited to systemic cytotoxic chemotherapy and radiation therapy.

Several factors continue to influence systemic anticancer therapy recommendations for patients with advanced NSCLC, including individual tumor histology, patient performance status, molecular and im-munologic tumor characteristics, and driver oncogene biomarker status. These are evaluated to guide decision making among cytotoxic chemotherapy, targeted agents, and immunotherapy. Approximately 83% to 85% of patients with stage IV NSCLC do not have oncogenic driver biomarker status and require first-line therapy recommendations distinct from those of the biomarker-defined populations.

Updated Recommendations for Molecular Testing in NSCLC

Guideline recommendations across several organizations indicate the need for molecular and biomarker testing of tumor samples as part of the routine diagnosis, prior to initiating therapy in the first-line setting, to guide treatment decisions. At minimum, patients must be tested for the 4 oncogenic driversEGFR mutations, ALK rearrangements, ROS-1 gene rearrangements, and

V600E point mutationsas well as PD-L1 tumor expression level.

, Justin F. Gainor, MD, an attending physician in the Thoracic Oncology Group at Massachusetts General Hospital, emphasized the importance of genetic testing in NSCLC for appropriate treatment selection, &ldquo;Over the past 15 years, there have been 2 major new paradigms that have transformed the management of nonsmall cell lung cancer: targeted therapy and immunotherapy. I can say that today, they still have very important roles in the management of our patients. Each has been guided by a different biomarker, and the importance of those biomarkers, I would say, are still very important today. So, patients with newly diagnosed advanced non&ndash;small cell lung cancer should still have comprehensive genetic profiling as well as PD-L1 expression scores.&rdquo;

, Alexander Drilon, MD, the clinical director of the Early Drug Development Service at Memorial Sloan Kettering Cancer Center, described the current landscape of genetic testing, &ldquo;Paying attention to selecting the most appropriate test for profiling patients&rsquo; tumors on a molecular level is critical. [We have] really moved beyond single-gene testing that we used to do in the early 2000s when we knew about fewer genes like

rearrangement. Now we have a whole slew of other potential drivers like ROS-1 and rearranged during transfection (RET) fusions, MET exon 14 alterations,

. [It is] important to choose a test [that is] comprehensive and able to detect all of these alterations in patients who have nonsmall cell lung cancers. My personal preference is [to not] practice single- gene testing anymore and to go for a multiplex comprehensive approach.&rdquo;

In the United States, approximately 20% of all NSCLC adenocarcinomas are characterized by the oncogenic

mutations (10% to 15%), ALK rearrangements (3%- 7%),

mutations (2%-5%), and ROS-1 rearrangements (0.5%-2%) that drive cancer growth.

As described in TABLE 1, these biomarkers can be DNA- or protein-based, requiring detection through sequencing and fluorescence in situ hybridization of immunohistochemistry (IHC), respectively.

Other driver oncogenes can be altered in NSCLC, including

exon 14 alterations, and additional genotypes contribute to 50% of NSCLC diagnoses.

Tyrosine kinase inhibitors (TKIs) are recommended in the first-line and subsequent treatment settings for patients with advanced nonsquamous NSCLC harboring oncogenic driver alterations, including

Patients with metastatic NSCLC with negative or unknown test results for oncogenic biomarkers are recommended to undergo IHC testing for PD-L1 expression prior to first-line treatment.

A positive PD-L1 biomarker expression level of greater than 50% expression is used to direct initial therapy. The FDA-approved checkpoint inhibitor pembrolizumab is indicated in the first-line setting, and nivolumab, atezolizumab, and pembrolizumab are indicated for use in the second-line setting following progression with first-line platinum-based chemotherapy for patients with metastatic, nonsquamous NSCLC with high PD-L1 expression (tumor proportion score [TPS] at least 50%) and without known oncogenic driver mutations.

Importantly, even in tumors with high PD-L1 expression, immunotherapy is not the standard of care for patients with mutations or rearrangements in

molecular genetic abnormalities serve as predictive biomarkers of therapeutic response and are used to guide appropriate TKI treatment choice and subsequent guideline-recommended regimens (TABLE 2).

Patients across each biomarker-defined subpopulation may respond differently to first-line TKI treatment due to tumor heterogeneity. These genetic abnormalities can predict drug sensitivity as well as primary or acquired resistance to TKIs, which can guide selection of optimal second-line and subsequent therapy. For this reason, it is important to highlight the unique differences and heterogeneity in biomarker-defined patient populations.

mutations are predictive of response; the most common mutations are deletions in exon 19 and the L858R point mutation in exon 21, both of which result in activation of the tyrosine kinase domain and are sensitive to the FDA-approved EGFR TKIs (gefitinib, erlotinib, and afatinib) for first-line treatment in patients with advanced

-mutant NSCLC. Despite an initial response to TKIs, most of these patients will become resistant and experience disease progression after first-line TKI therapy.

gene rearrangements are responsive to first-line pharmacological inhibition of

by TKIs such as alectinib, crizotinib, and ceritinib.

While crizotinib is highly active, most patients treated with crizotinib develop resistance.

inhibitor in the first line can still respond to another

inhibitor in the second and third lines. Brigatinib, alectinib, or ceritinib can be used in subsequent lines following progression after crizotinib treatment.

In a phase I study of 42 patients with crizotinib-resistant ALK-positive NSCLC, 31 achieved an objective response (OR) to treatment with brigatinib (objective response rate [ORR], 74%). The 31 patients with an OR had a median progression-free survival (PFS) of 14.5 months and 1-year OS of 83%.

In the phase II, ongoing, open-label, randomized, multicenter, international ALTA (ALK in Lung Cancer Trial of AP26113) trial, investigators studied brigatinib in patients with crizotinib-refractory, advanced, or metastatic

-positive NSCLC (N = 222). Two doses of brigatinib were examined in this study, and treatment with the higher dose of 180 mg daily demonstrated considerable efficacy. Patients treated with 180 mg achieved a confirmed ORR of 54%; their 1-year OS was 80%, and their 1-year PFS was 54%.21 Based on the findings in these trials, the FDA granted brigatinib an accelerated approval in April 2017 for the treatment of patients with metastatic

-positive NSCLC that has progressed on or is intolerant of crizotinib. The optimal sequence of therapy with brigatinib in the first line or after second-generation

inhibitors is being further explored. The phase III ALTA-1L trial is investigating brigatinib efficacy and safety in patients with ALK-positive metastatic NSCLC as a first-line treatment compared with crizotinib.

ROS-1 rearrangements are more common in patients who are negative for

gene arrangements. ROS-1 confers response with crizotinib treatment in the first line, such as

rearrangements. Brigatinib has demonstrated activity against

TKI-resistant mutations, including T790M resistance mutation.

V600E mutations represent the majority of activating BRAF mutations and are responsive to first-line combination treatment with trametinib and dabrafenib.

At this time, no single molecular determinant of response to an immunotherapeutic agent has been identified.

Notably, PD-L1 is not an optimal biomarker; the level of expression is variable. Despite PD-L1 expression in a subset of

-positive NSCLCs, expression has been demonstrated to be highly dynamic, and expression levels change over time and in response to treatments.

The diagnostic PD-L1 IHC companion as- says are different with each agent, and some agents consider PD-L1 expression on both tumor cells and tumor- infiltrating immune cells when defining PD-L1 positivity.

Furthermore, the expression level of PD-L1 is subjective across clinical trials, and developments are still needed to better understand how levels of PD-L1 expression correlate with response.

Other biomarkers, such as mutational load and smok- ing exposure, may be important potential determinants of response to PD-1 or PD-L1 inhibitors.

Drilon explained, &ldquo;Tumor mutational burden [TMB], on a very simplistic level, is a measure of how complex a cancer is, [or] the number of mutations that occur within [a] tumor. We found that depending on the assay that [is used], you can measure tumor mutational burden by counting the number of non-synonymous mutations. If you have many more mutations, that counts as a high score versus if you have much fewer, that would be an intermediate or a lower score.&rdquo; NSCLC with higher mutational load was associated with higher rates of durable response, as seen in patients with squamous NSCLC with smoking history.

As many targetable driver aberrations in adenocarcinomas, such as

rearrangements, are not associated with smoking, these tumors are less likely to have DNA heterogeneity and subsequently, less neoantigen presentation conferring lack of response to immunotherapy.

Guideline-Recommended Treatment Selection

A continuously evolving area of therapeutic development and recommendation is in the biomarker-defined population. For patients who experience disease progres- sion after second-line therapy, there is a need for widely applicable treatment approaches to extend survival,

minimize toxicity, and improve quality of life. Immunotherapy has expanded the range of treatment options for a distinct population of patients with advanced NSCLC who have disease progression following cytotoxic therapy. It has demonstrated consistent durable responses and long-term improvements in OS in comparison with single-agent docetaxel delivered in the second-line setting. Currently, treatment guidelines have removed recommendations supporting the use of any immune checkpoint inhibitors in NSCLC populations with

mutations in those who have progressed on available TKIs who are candidates for subsequent treat- ment.7 NSCLC treatment guidelines recommend TKIs for these patient populations with progressive disease.

This change in recommendation was based on the emerging understanding of the role of checkpoint inhibitors and the growing body of clinical evidence that demonstrates that the subgroups of patients with classic oncogenic driving mutations do not achieve survival benefit or high rate of response in the second-line and subsequent settings with PD-1 or PD-L1 agents after progression on prior TKI therapy (TABLE 3).

Further analysis in the predictors of efficacy of antiPD-1 or anti&ndash;PD-L1 immunotherapy treatment in subgroups of patients with driver mutations is needed.

Emerging Clinical Evidence of PD-1/PD-L1 Treatment in Patients With Driver-Oncogenic NSCLC

Pivotal Immunotherapy Trials With Driver-Mutated Subgroup Analyses

Evidence from the CheckMate 057 trial demonstrated that the subgroup of patients with

-mutated NSCLC who had disease progression and had received prior TKI or were re- ceiving an additional line of TKI are unlikely to benefit from nivolumab in the second-line or third-line setting, which con- tributed to the removal of immunotherapy from the guidelines in this population.

Nivolumab improved survival outcomes in the total population of patients with nonsquamous advanced NSCLC (stage IIIb or IV) compared with docetaxel.

-mutated population (n = 82) in the CheckMate 057 trial, OS favored docetaxel compared with nivolumab (HR, 1.18; 95% CI, 0.69-2.00). PFS also favored docetaxel treatment in the

-mutated population (HR, 1.46; 95% CI, 0.90-2.37). No data on sur- vival outcomes were reported for the subgroup with

rearrangements (n = 21). A similar lack of benefit was observed for the subgroup of patients who never smoked. As discussed previously in this article, low levels of mutational load in neversmokers, as seen in

- positive patients, may confer diminished sensitivity to immune checkpoint inhibitors.

The phase II/III KEYNOTE-010 trial compared the efficacy and safety of pembrolizumab with docetaxel in patients with at least 1% PD-L1expressing advanced NSCLC in the second-line setting and beyond (N = 1034).

rearrangement (n = 8) who experienced disease progression following treatment with an appropriate TKI were also enrolled.

status subgroup analysis of the KEYNOTE-010 trial, docetaxel treatment was associated with favorable survival benefits compared with pembrolizumab, as evidenced by superior OS (HR, 0.88; 95% CI, 0.45-1.70) and PFS (HR, 1.79; 95% CI, 0.94-3.42). In contrast, pembrolizumab treatment reduced the risk of death and extended survival in the wild-type

subgroups for both OS (HR, 0.66; 95% CI, 0.55-0.80) and PFS (HR, 0.83; 95% CI, 0.71- 0.98) compared with docetaxel, which was consistent with results in the overall treatment population.

Similar to previous trials with the immune checkpoint inhibitors nivolumab and pembrolizumab, the subgroup analyses of the OAK clinical trial demonstrated that atezolizumab did not exhibit favorable survival benefits as monotherapy in the second-line setting and beyond (progression with previous TKI) compared with docetaxel among patients with locally advanced or metastatic NSCLC with

tumor aberrations, regardless of PD-L1 expression. In the subpopulation of patients with

-mutated NSCLC (n = 85), docetaxel treatment improved median OS compared with atezolizumab (16.2 months vs 10.5 months; HR, 1.24; 95% CI, 0.71-2.18). However, atezolizumab increased median OS compared with docetaxel in the

wild-type population (15.3 months vs 9.5 months; HR 0.69; 95% CI, 0.57-0.83). No data were reported for the 2 patients enrolled with

-mutated population compared with the wild-type

population added clinical evidence sup- porting the decision to remove all checkpoint inhibitors from the current treatment guidelines for patients with driver-mutated NSCLC.

In the phase II BIRCH trial, patients with

-positive disease (n = 9) with PD-L1 expression in tumors and tumor-infiltrating lymphocytes had minimal responses to atezolizumab across the first-line and subsequent lines of therapy.

subpopulation. The ORRs to atezolizumab treatment in the

wild-type cohort were 23% and 19%, respectively, in the first-line setting (no prior chemotherapy for advanced NSCLC); 0% vs 21%, respectively, in the second line (progression during or following no more than 1 prior platinum-based regimen); and 7% vs 18%, respectively, in the third-line (progression during or following at least 2 prior chemotherapy regimens for advanced disease). Notably, median OS was substantially shorter in the

wild-type cohort treated with atezolizumab in the second line (6.8 months vs 16.3 months) and in the third line or beyond (3.4 months vs 14.7 months). Median PFS in the EGFR wild-type cohort was ap- proximately 2-fold greater than that observed in the

-mutated cohort in the second and third lines.

Response to Immune Checkpoint Inhibitors in EGFR-Mutant and ALK-Positive NSCLC

A retrospective analysis evaluated patients with EGFR mutations (n = 22) and ALK rearrangements (n = 6) and a matched comparator population (n = 30) of

-negative patients treated with PD-1 or PD-L1 inhibitors at a single institution between 2011 to 2016. The majority of patients (82%) had disease progression following treatment with TKIs; 11% of patients were TKI-resistant and treated with a TKI in combination with a PD-1 inhibitor. Significantly more patients with wild-type disease achieved an OR compared with patients with

rearrangements treated with PD-1 or PD-L1 inhibitors (23.3% vs 3.6%; P = .053). Only 1 patient with

rearrangements achieved an objective response (OR) to pembrolizumab, which was not confirmed, but all ORs were confirmed in the wild-type population. Additionally, the median PFS in patients treated with PD-1 or PD-L1 inhibitors was significantly shorter in

-positive disease compared with nononcogenic driver-mutated disease (2.07 months vs 2.58 months; HR, 0.52; P = .018).

Notably, the ORRs observed in this single center study were similar to those across

subgroups in clinical trials (CheckMate 057 and KEYNOTE-010). In both studies, the PD-1 inhibitors produced response and survival benefits compared with docetaxel in the overall intention-to-treat populations, but in

-mutant subgroup analyses, no survival benefit was observed.

The phase II ATLANTIC trial was the first prospective evaluation of an immune checkpoint inhibitor in a dedicated cohort of patients with

-mutated and ALK-translocated disease (n = 111). Durvalumab was evaluated in the third- line setting in patients with locally advanced or metastatic NSCLC, and patients were stratified based on tumor cell PD-L1 expression (high PD-L1 expression [&ge;25% or &ge;90%] or low [<25%]).38 The ATLANTIC trial revealed valuable insights into the activity of durvalumab in driver-mutated NSCLC; EGFR-mutated and ALK-translocated molecular subpopulations have not only distinct tumor biology but also immunobiology.

PD-L1 expression alone was not predictive of efficacy in patients with mutated disease. Importantly, all ORs achieved in the mutated population were in EGFR-mutated patients, and no ORs were achieved by the ALK-positive subpopulation.

wild-type tumors had greater response to durvalumab, consistent with other PD-1 and PD-L1 inhibitors, than did mutated tumors. The ORR increased with the level of PD-L1 expression: the ORR was 12.2% in

-positive NSCLC and high PD-L1 expression, and the ORR was 16.4% and 30.9% in the wild-type cohort with high PD-L1 expression of &ge;25% and &ge;90%, respectively.

-mutated NSCLC cohort, the ORR in patients with a high PD-L1 expression was 12.2% compared with 3.6% in patients with low PD-L1 expression. Only 1 EGFR-positive patient with low PD-L1 expression achieved an OR. These results suggest that immune checkpoint inhibitors are unlikely to induce respons- es in heavily pretreated EGFR-mutated patients. Additionally, regardless of PD-L1 positivity, this population has lower re- sponse to immunotherapy than wild-type populations.

Gainor commented on the ATLANTIC trial, "I think the best prospective data with single-agent checkpoint inhibitors came from the ATLANTIC study. Notably, even when that study tried to enrich for responders by focusing on PD-L1 expressionin here, it was 25% or greater&mdash;the response rate among

patients with that degree of PD-L1 expression was only 12%. And there were no responses observed in the

subgroup, despite having high PD-L1 expression. And I think this speaks to a point that PD-L1 expression is a less reliable predictive biomarker in patients with

-positive disease. This is for several reasons, [the] first [being] that these tend to be low mutation tumors.

tend to occur in never- or light-smokers, and so we would expect them to have a low TMB."

Pooled Survival Outcomes From Key Immunotherapy Clinical Trials

Notably, patients with oncogenic driver mutations were frequently excluded from key clinical studies of PD-1 and PD-L1 agents. In this way, several meta-analyses have pooled subgroup analyses of patients with previously treated

-mutant advanced NSCLC across key clinical trials. These meta-analyses demonstrated that while the PD-1/PD-L1 inhibitors nivolumab, pembrolizumab, and atezolizumab improved OS and PFS in the wild-type EGFR population compared with docetaxel, no response or survival benefits were achieved in the

New Frontiers: Combination Chemotherapy Checkpoint Inhibitor Treatment in Driver-Oncogenic NSCLC

The role of checkpoint inhibitors in EGFR-mutated advanced NSCLC was investigated in a meta-analysis across 3 randomized clinical trials (CheckMate 057, KEYNOTE-010, POPLAR). Treatment with immune checkpoint inhibitors, including nivolumab (n = 292), pembrolizumab (n = 691), and atezolizumab (n = 144), was compared with docetaxel (n = 776) in the second-line or subsequent therapy setting (N = 1903). The intention-to-treat population achieved a 32% reduction in risk of death with immune checkpoint inhibitor therapy compared with docetaxel treatment (HR, 0.68; 95% CI, 0.61-0.77; P <.0001). Mirroring the OS benefit observed in the total treatment population, the wild-type

NSCLC subpopulation (n = 1362) achieved a 34% reduction in risk of death with treatment with immune checkpoint inhibitors (HR, 0.66; 95% CI, 0.58-0.76; P <.0001). Importantly, there was no reported OS advantage in the

-mutated subpopulation (n = 186); immune checkpoint inhibitors were not superior to docetaxel for OS (HR, 1.05; 95% CI, 0.70-1.55; P = .81).39 A similar finding for OS in the

-mutated NSCLC subpopulation was demonstrated in a second meta-analysis that expanded the data set to include the OAK trial. There was no OS benefit of PD-1 or PD-L1 inhibitor treatment compared with docetaxel in the

-mutated NSCLC population (HR, 1.09; 95% CI, 0.84-1.41; P = .51). Furthermore, the PFS was significantly shorter in the

-mutant subpopulation treated with PD-1 or PD-L1 inhibitors compared with docetaxel (HR, 1.44; 95% CI, 1.05-1.98; P = .02). In contrast, treatment with PD-1 or PD-L1 inhibitors compared with docetaxel in the wild-type

population demonstrated benefits in OS (HR, 0.67; 95% CI, 0.61-0.76; P <.001) and had significantly longer PFS (HR, 0.86; 95% CI, 0.77-0.95; P = .004).40 The most recent me- ta-analysis included 5 key clinical trials (CheckMate 057, CheckMate 017, KEYNOTE-010, POPLAR, and OAK) and demonstrated that antiPD-1/PD-L1 treatment in previously treated, advanced NSCLC patients (N = 2752) was associated with a lower risk of death compared with docetaxel in EGFR wild-type tumors (HR, 0.67; 95% CI, 0.60-0.76), but not in EGFR-mutated tumors (HR, 1.12; 95% CI, 0.80-1.56).41

The Addition of Atezolizumab to Bevacizumab Plus Chemotherapy: IMpower150

The role of immune checkpoint inhibitor monotherapy in highly select patients with oncogene-driven tumors warrants additional studies to better define the patients who may derive benefit from the development of novel immune-based combinations. Combining different treat- ment modalities may potentially increase the clinical benefit of immunotherapy by increasing the immunogenicity of the tumor, bypassing immunological escape mechanisms at different levels of cellular benefit, and ad- dressing tumor heterogeneity. The potential benefits of im- munotherapy in ALK- or EGFR-positive NSCLC among patients with advanced refractory disease is currently being further explored in clinical trials evaluating combination immunotherapy and chemotherapy. The goal of these ongoing trials is to better understand immune-based treatment approaches and to better define and modulate the immune landscape of

Despite the available data that show poor efficacy of immune checkpoint inhibitor monotherapy in the treatment of advanced NSCLC patients with

translocation, recent data from the IMpower 150 study indicate a potential role for the addition of a checkpoint inhibitor to combination platinum-doublet chemotherapy plus bevacizumab in these subgroups refractory to TKI treatment. Bevacizumab, an anti-

agent, combined with chemotherapy is currently an approved frontline systemic treatment of metastatic non-squamous NSCLC.

In the phase III IMpower150 trial, combination treatment with atezolizumab in addition to bevacizumab-plus-chemotherapy (carboplatin and paclitaxel) resulted in a significant improvement in PFS and OS over bevacizumab-plus-chemotherapy alone, regardless of PD-L1 expres- sion and

genetic alteration status. A total of 1202 patients with metastatic nonsquamous NSCLC were enrolled, including patients with

genetic alterations (n = 108). These 108 patients had received treatment with at least 1 approved TKI, which had resulted in subsequent disease progression or unacceptable adverse events.

wild-type population, PFS was significantly longer with the addition of atezolizumab to bevacizumab-plus-chemotherapy compared with bevacizumab-plus-chemotherapy alone (8.3 months vs 6.8 months; HR, 0.62; 95% CI, 0.52-0.74; P <.0001). Notably, this PFS benefit was also observed in the 14% of enrolled patients who had

-positive NSCLC (9.7 months vs 6.1 months; HR, 0.59; 95% CI, 0.37-0.94). The PFS benefit of atezolizumab combined with bevacizumab- plus-chemotherapy compared with bevacizumab-plus-chemotherapy alone was even more pronounced in those with actionable

The IMpower150 results are notable, as this chemotherapy-plus-immunotherapy combination was beneficial in the subgroups who have no phase III evidence supporting any benefit of PD-1 and PD-L1 inhibitor treatment as monotherapy or in combination with platinum-based regimens (that is, subgroups with

-mutated NSCLC who have failed TKI treatments).

Gainor described the notable results of this trial, &ldquo;It was a bit surprising to all of us to see that the benefits to adding atezolizumab to carboplatin/paclitaxel/bevacizumab even extended to the

-positive subgroups compared with the control arm. The reason this was surprising is because in earli- er studies of just using single-agent checkpoint inhibitors, the benefits among

-positive patients were quite minimal with just single-agent checkpoint inhibitors. We saw response rates among

patients were 10% or less, and in meta-analyses, there was no improvement in survival compared with single-agent docetaxel. And among

-positive patients, really the response rates have been 0 in the limited studies to date.&rdquo;

Drilon commented on the future of combination treatment give the results from the IMpower150 trial, &ldquo;The hope is that for [patients with] stage IV advanced nonsmall cell lung cancer [nonsquamous], the combination of chemo and immune therapy with bevacizumab might result in [a] response not just in tumors [that are] much more sensitive to immune therapy, but also in cancers that maybe fall below that cutoff like PD-L1.&rdquo;

Gainor described the potential mechanism of the benefit of this combination regimen in the driver positive subgroup in the IMpower150, &ldquo;One potential explanation is that chemotherapy may have led to tumor antigen release, and this may have spurred or resulted in increased sensitivity to the checkpoint inhibition. An alternative hypothesis is that there may have been an interplay between the

inhibition with bevacizumab and PD-L1 inhibition with atezolizumab. That interplay may have been particularly important in patients with

-positive lung cancer. Still, a third hypothesis is that there may have been something unusual about this particular subgroup of patients...It did seem like a disproportionate number of patients in had both [

-positive lung cancer], which calls into question the molecular testing that was performed and the quality of testing. [This] raises the question [whether] all of these patients [were] truly

-positive. Perhaps that may have explained some of the benefit.&rdquo;

Articles

Clinical Articles

Lung and bronchus cancer are the leading causes of cancer-related deaths in the United States and will be responsible for an estimated 154,050 American deaths in 2018. An estimated 234,030 new cases of lung and bronchus cancer will be diagnosed in 2018, which represents 13.5% of all new cancer diagnoses in the United States.

Role of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Oncogenic Driver Mutations

Can you provide a brief overview of the incidence and classification of lung cancer?

: Lung cancer can be broken down into nonsmall cell lung cancer [NSCLC] and small cell lung cancer. Non&ndash;small cell lung cancers are the most common type of lung cancer and occur in about 4 out of 5 patients, and the most common histology for non&ndash;small cell lung cancers is adenocarcinoma. In general, in the United States, about 200,000 cases are diagnosed a year, and so it makes it a very substantial population of patients with this burden of disease.

Can you discuss the importance of molecular testing in patients with stage IV NSCLC and the pros and cons of panel versus single-gene testing?

: Paying attention to selecting the most appropriate test for profiling patients&rsquo; tumors on a molecular level is critical in this day and age, and that&rsquo;s because we&rsquo;ve really moved beyond single-gene testing that we used to do in the early 2000s, when we knew about fewer genes like

for example, in 2003 and 2004&mdash;and then later, the

rearrangement. Now we have a whole slew of other potential drivers like

. And so, it&rsquo;s important to choose a test that&rsquo;s comprehensive and that&rsquo;s able to detect all of these alterations in patients who have nonsmall cell lung cancers. My personal preference is not to practice single-gene testing anymore and to go for a multiplex comprehensive approach.

At our center, we use DNA-based next-generation sequencing [NGS], recognizing that not all NGS assays are the same. And, of course, the caveats are that because it&rsquo;s a big test that looks for hundreds of genes, it can sometimes take a few weeks to come back. And for patients who are sick, it&rsquo;s critical to find out early on, maybe within the first week, whether or not those cancers have a driver. And so, a strategy that we&rsquo;ve adopted at our center is to do rapid-phase testing, where we look for

using mutation-specific immunohistochemical antibodies, and that way you might get an answer within the first 1 to 2 days and be able to institute targeted therapy early. And then the rest of the sample we send for comprehensive NGS. So, I think NGS is the way to go in this day and age.

Can you describe the emerging role of tumor mutational burden as a biomarker in clinical practice and how it may be used alone or in conjunction with programmed death-ligand 1 (PD-L1) testing?

: Tumor mutational burden [TMB] on a very simplistic level is a measure of how complex a cancer is, meaning the number of mutations that occur within the tumor. And we found that depending on the assay that you use, you can measure tumor mutational burden, by counting the number of what we call nonsynonymous mutationsmeaning if you have many more mutations that count as a high score versus if you have much fewer, that would be an intermediate or a lower score. The TMB-high patients, those have been associated with benefit from immune checkpoint inhibition, and, again, this cutoff varies depending on the test that you use. But it seems like there is an association between cancers that are TMB high that have a greater proclivity for response either to single-agent immune checkpoint blockade or to combination immune checkpoint blockade. And so, it&rsquo;s one of the potential biomarkers that we&rsquo;re looking at in the immuno-oncology space.

Now, TMB doesn&rsquo;t always completely coincide with the level of PD-L1 expression on cancers, and so I think the approach that&rsquo;s favored now is to treat these as overlapping but independent biomarkers. And so, if I have a patient who, for example, may have a PD-L1negative tumor but really has a high TMB score, I would think very carefully about whether or not I might get immunotherapy to that patient, even though the PD-L1 status is negative.

How have the results of the FLAURA trial changed the sequencing of EGFR- targeted agents in clinical practice?

: The FLAURA trial is a landmark trial that randomized

-mutant lung cancer patients to osimertinib, which is a third-generation EGFR TKI [tyrosine kinase inhibitor], versus first-generation agents erlotinib or gefitinib, recognizing that osimertinib has several advantages. It&rsquo;s able to target the most common mechanism of resistance with the first-generation agents, vis-à-vis a gate-keeper

mutation. In addition to that, it also has excellent CNS [central nervous system] coverage, especially for patients who have brain metastases. And we know that patients who don&rsquo;t have brain metastases, given that they have lung cancer, also have a proclivity or a tendency to develop brain metastases in certain situations.

It's not a surprise the results of the FLAURA trial were positive for an improved benefit in terms of survival with osimertinib versus erlotinib and gefitinib, and that&rsquo;s with progression-free survival. It really changed the standard of care. And now there&rsquo;s FDA approval for osimertinib as the first-line therapy of choice for EGFR-mutant lung cancer cases. And I think this really underscores the paradigm of using your best drug first, knowing that osimertinib was previously approved for patients who have progression on a first-generation or second-generation TKI that then develop a

mutation. Now we&rsquo;re moving that to the frontline setting and using it for everybody.

: What is the best approach for the treatment of patients with brain metastases?

: Fortunately, many of the tyrosine kinase inhibitors that are available for ALK-rearranged lung cancers have good CNS coverage. And I&rsquo;m speaking specifically about alectinib, ceritinib, and brigatinib, which are next-generation agents, compared with crizotinib, which was the former standard of care and is a first-generation ALK TKI. Now, similar to the EGFR space, where the FLAURA trial was positive for osimertinib in terms of progression-free survival over earlier-generation TKIs, there&rsquo;s the ALEX trial that randomized patients to alectinib versus crizotinib. Those are patients with

-rearranged disease. And no surprise, because alectinib targets potential mechanisms of resistance to earlier generation therapy with crizotinib and has better CNS penetration, alectinib won in terms of progression-free survival and is now the new standard of care for

-rearranged lung cancers also have a proclivity for metastases to the brain, although there are reports of the

-rearranged population potentially having a lower level of brain metastases. Crizotinib is FDA approved for this population, and it can have activity in the CNS. However, there are other drugs that are currently being developed that may have better CNS penetration. An example of 1 drug that&rsquo;s currently in clinic trials is entrectinib, which has been looked at in ROS1-rearranged lung cancer patients, and that drug is known to effectively cross the blood-brain barrier and address CNS disease.

: What were the key findings of the phase II ALTA trial leading to the FDA approval of brigatinib in relapsed/refractory

: The phase II ALTA trial looked at the utility of brigatinib in

-directed TKI therapy. Brigatinib is a later-generation TKI that targets many mechanisms of acquired resistance to earlier generation therapy with crizotinib, meaning on-target mutations that might emerge with treatment. It&rsquo;s no surprise that this drug was active in this trial, with a response rate that exceeded 40% and really good progression-free survival compared with some of the other TKIs. And so, because of this, brigatinib is cur- rently approved by the FDA as a second-line therapy for patients with

-rearranged lung cancers who previously received crizotinib.

What is your approach to treatment sequencing in

: Alectinib is currently the standard of care for

-rearranged [nonsmall cell] lung cancers. Because [we have] moved one of our better drugs into the first-line setting, the question becomes what [drug should be used] after that. I think there are 2 potential options in terms of TKI therapy, like brigatinib and lorlatinib, that do have very broad coverage against possible on-target resistance mechanisms. [It is] still not very clear what the response rate is going to be like when we treat more patients. Although, with the lorlatinib data, we have seen that patients have responded after several prior TKIs. It&rsquo;s encouraging. Until we have definite FDA approval for another TKI after alectinib beyond exploring one of [the] TKIs on clinical trials or [prescribing] it for patients, a very viable option is [to] consider giving patients chemotherapy plus/minus immunotherapy [after alectinib].

-mutant lung cancers include a proportion of patients that have

V600E mutations in their tumors, and this has been well known to be a target in the melanoma world. We found that these mutations can occur in nonsmall cell lung cancers, up to a frequency of about 2%, depending on the series that you look at. We know that these are highly actionable, and if you give a single-agent

nhibitor like vemurafenib or dabrafenib, you might achieve response rates of approximately 30%. However, following the lead again of what we&rsquo;ve seen in the melanoma world, when you give a combination of a

inhibitorspecifically, dabrafenib and trametinib&mdash;we know that the response rate more than doubles to 63% with that combination in the phase II setting. And so, that&rsquo;s currently approved by the FDA for the treatment of

V600Emutant lung cancer patients and would be my first choice for someone that&rsquo;s stage IV and treatment naïve, knowing that the outcomes we&rsquo;re seeing with the combination paralleled the outcomes that we&rsquo;ve seen with tyrosine kinase inhibitor therapy for the

What is the rationale for combining PD-1/PD-L1targeted agents with chemotherapy?

: The rationale for adding chemotherapy to immune therapy is complex but can basically be broken down to the fact that chemotherapy drugs can, in a way, modulate the immune system. And so, the purpose of adding chemotherapy to immune therapy is to hopefully boost the likelihood of immune therapy acting to augment the immune system, making tumors visible to the immune system and the immune system attacking these cancers and getting rid of them.

What is the rationale for combining a PD-L1targeted antibody and chemotherapy with a VEGF-targeted antibody?

: The purpose behind adding bevacizumab, which is an antiangiogenic agent, to immune therapy is in the same way that chemotherapy may modulate the immune system. There are data for antiangiogenic therapy with a monoclonal antibody added to VEGF for also modulating immune effec- tor cells, which may then help the immune therapeutic do its job, so to speak, when administered in combination.

What are the implications of using the effector T-cellshigh population as a predictive biomarker, like within the IMpower150 trial, to predict efficacy of the atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) regimen?

: I think we should be very careful when we look at new potential biomarkers. IMpower150 was a randomized trial that looked at patients in the first-line setting with stage IV advanced NSCLC. Patients were randomized to carbopla- tin/paclitaxel and bevacizumab, a well-recognized regimen based on previous testing, with or without atezolizumab, an immune checkpoint inhibitor. In this trial, the investigators looked at the T-effector signature, which seemed like there may be a signal for increased benefit in those that fell into the highT-effector category. However, we know that even PD- L1 and TMB, which one can argue are much more vetted in terms of biomarkers, aren&rsquo;t perfect in their ability to predict the likelihood of response to immune therapy. I think that looking at this T-effector signature is much more in its infan- cy compared [with] other biomarkers. So, it&rsquo;s something that I think we should continue to look at on an investigational level. But on a clinical level, I wouldn&rsquo;t yet jump to rely on this as a potential signature for giving this combination until we see further data come out.

In your opinion, which NSCLC population would benefit most from the ABCP regimen?

: The combination of ABCP parallels the combina- tion of carboplatin/pemetrexed and pembrolizumab. The hope is that for [patients with] stage IV advanced nonsmall- cell lung cancer...(nonsquamous), the combination of chemo and immune therapy with bevacizumab might result in [a] response not just in tumors [that are] much more sensitive to immune therapy, but also in cancers that maybe fall below that cutoff like PD-L1.

How would you characterize the utility of dual checkpoint inhibition in patients with metastatic NSCLC?

: Recently there has been a trial examining the utility of giving the combina- tion of antiPD-1 and cytotoxic T-lymphocyte&ndash;associated antigen 4 [CTLA4] therapy specifically with nivolumab and ipilimumab. This was [administered] in patients that, in a certain subpopulation, had higher levels of TMB. [The] take-home point is [that] the combination does seem to work, and [it is] something that we can look forward to as a potential strategy for treating NSCLC, knowing that activity has also been demonstrated for [patients with] small cell lung cancer.

As clinicians, whenever we give several drugs in combination, one thing that we need to be cognizant about is the additional toxicity of adding a second agent. CTLA4-directed therapy on its own can have a higher [adverse] effect profile compared [with] PD-L1 monoclonal antibody administration. When you give both drugs together, clini- cians need to be very careful to watch for potential immune-related adverse events that might emerge with treatment.

Given the fact that this therapy is a combination and that there is the possibility for increased adverse events, if this treatment does eventually get approved, l think I would personally consider it for patients who are more fit and have less comorbidities, certainly patients who do not have a substantial history of a prior autoimmune disease. Based on the trial design, this would be for the first-line setting for patients with NSCLC.

In what treatment setting and NSCLC subpopulations is the use of immune combination therapy beneficial to patients with NSCLC?

: The question as to whether or not to use immune therapy for patients whose cancer is harboring an actionable driver is really a question of when to use immune therapy. So, it boils down to sequencing, essentially. We know that for patients with

mutations; recurrent gene rearrangements involving

mutations that there are targeted therapies in development, several of which have very high response rates and good progression-free survival. So, when choosing therapies for patients, it&rsquo;s all about the odds of responding to treatment. And you could argue that because for certain subsets of these driver-positive patients, like

, for example, where there are FDA-approved therapies and

, that you should start with a targeted therapeutic because you&rsquo;re seeing response rates in excess of 60% and very good progression-free survival.

Now, what do we know about immune therapy for these driver-positive lung cancers? Well, there have been several reports now, both retrospective and subset analyses of prospective trials, showing that the likelihood of response with single-agent immune checkpoint inhibition is much lower in these populations. So, one example is a retrospective study out of Boston, with

, where the likelihood of response was 3% for

positive lung cancers compared with an historic response rate of 20% in unselected cases.

So, when you see numbers like that and compare them with a response rate of 60% to 80%, you know that you should save these therapies potentially in your back pocket for the future and not use them up front. There are much more recent data, some from our institution on the likelihood of response in

exon 14altered lung cancers and a separate series in

-mutant lung cancers. Again, we&rsquo;re seeing response rates that are less than 15%. And so, I think that if you were to think about a single-agent immune checkpoint inhibitor, this would be given relatively late in the course of therapy. And I would argue that after targeted therapy, if you&rsquo;re going to use chemotherapy alone, then you might use chemotherapy before going to single-agent immune checkpoint inhibitor.

Things are changing now because of the addition of immune therapy to chemotherapy. And beyond platinum/ pemetrexed/pembrolizumab, there were recent data from the IMpower150 study, which randomized patients to carboplatin/paclitaxel/bevacizumab plus or minus atezoli- zumab, showing that there was a signal for benefit in the driver-positive subsets that included

Alexander Drilon, MD, clinical director of Early Drug Development Service at Memorial Sloan Kettering Cancer Center, discusses the evolving role of immune-checkpoint blockade in NSCLC.

Role of Immunotherapy in NSCLC

Role of Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer Oncogenic Driver Mutations

Clinical Perspectives in the Evolving Role of Immune-Checkpoint Blockade in Distinct NSCLC Populations

Expert Insights in the Treatment Landscape of Oncogenic Driver-Positive NSCLC