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ONCAlert | Upfront Therapy for mRCC

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

Published Online: Oct 11,2018
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.1 Non–small cell lung cancer (NSCLC) is the most common type of lung cancer, comprising approximately 80% to 85% of lung cancer cases.2 The 3 main types of NSCLC are large cell carcinoma (10%), squamous cell carcinoma (25%), and adenocarcinoma (40%), with numerous less frequent subtypes.2,3

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.4,5 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.4,5

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.4,5 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.6

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 BRAF V600E point mutations—as well as PD-L1 tumor expression level.5,7

In an interview with Targeted Oncology, 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, “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–small cell lung cancer should still have comprehensive genetic profiling as well as PD-L1 expression scores.”


In an interview with Targeted Oncology, 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, “Paying attention to selecting the most appropriate test for profiling patients’ 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 EGFR, for example...and then later, the ALK rearrangement. Now we have a whole slew of other potential drivers like ROS-1 and rearranged during transfection (RET) fusions, MET exon 14 alterations, BRAF V600E, and HER2. [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.”

In the United States, approximately 20% of all NSCLC adenocarcinomas are characterized by the oncogenic EGFR mutations (10% to 15%), ALK rearrangements (3%- 7%), BRAF mutations (2%-5%), and ROS-1 rearrangements (0.5%-2%) that drive cancer growth.6,8-12 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.5,7,13 Other driver oncogenes can be altered in NSCLC, including KRAS, HER2, RET fusions, and MET exon 14 alterations, and additional genotypes contribute to 50% of NSCLC diagnoses.6,14 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 ROS-1, BRAF V600E, EGFR, and ALK.5

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.5 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.15-17 Importantly, even in tumors with high PD-L1 expression, immunotherapy is not the standard of care for patients with mutations or rearrangements in EGFR, ALK, ROS-1, or BRAF in any line of therapy.


Predictive Biomarkers

ROS-1, BRAF V600E, EGFR, and ALK 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).5,7,13 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.

Activating or sensitizing EGFR 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 EGFR-mutant NSCLC. Despite an initial response to TKIs, most of these patients will become resistant and experience disease progression after first-line TKI therapy.5,14 Sensitizing ALK gene rearrangements are responsive to first-line pharmacological inhibition of ALK by TKIs such as alectinib, crizotinib, and ceritinib.5 While crizotinib is highly active, most patients treated with crizotinib develop resistance.18,19

Patients with ALK-positive NSCLC treated with an ALK inhibitor in the first line can still respond to another ALK inhibitor in the second and third lines. Brigatinib, alectinib, or ceritinib can be used in subsequent lines following progression after crizotinib treatment.18 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%.20 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 ALK-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 ALK-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 ALK 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.22

ROS-1 rearrangements are more common in patients who are negative for EGFR mutations and ALK gene arrangements. ROS-1 confers response with crizotinib treatment in the first line, such as ALK rearrangements. Brigatinib has demonstrated activity against ROS-1 and EGFR TKI-resistant mutations, including T790M resistance mutation.7,23 In the first-line setting, BRAF V600E mutations represent the majority of activating BRAF mutations and are responsive to first-line combination treatment with trametinib and dabrafenib.8,24-29

At this time, no single molecular determinant of response to an immunotherapeutic agent has been identified.4,5,7,13 Notably, PD-L1 is not an optimal biomarker; the level of expression is variable. Despite PD-L1 expression in a subset of EGFR-mutant and ALK-positive NSCLCs, expression has been demonstrated to be highly dynamic, and expression levels change over time and in response to treatments.19 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.30 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.30

Other biomarkers, such as mutational load and smok- ing exposure, may be important potential determinants of response to PD-1 or PD-L1 inhibitors.31 Drilon explained, “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.” NSCLC with higher mutational load was associated with higher rates of durable response, as seen in patients with squamous NSCLC with smoking history.32 As many targetable driver aberrations in adenocarcinomas, such as EGFR mutations and ALK 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.5



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 ALK rearrangements, ROS-1 rearrangements, BRAF V600E mutations, or sensitizing EGFR 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.7 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).33-37 Further analysis in the predictors of efficacy of anti–PD-1 or anti–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

CheckMate 057 Trial

Evidence from the CheckMate 057 trial demonstrated that the subgroup of patients with EGFR-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.7,33 Nivolumab improved survival outcomes in the total population of patients with nonsquamous advanced NSCLC (stage IIIb or IV) compared with docetaxel.33 In the subgroup analysis of the EGFR-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 EGFR-mutated population (HR, 1.46; 95% CI, 0.90-2.37). No data on sur- vival outcomes were reported for the subgroup with ALK 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 EGFR- and ALK- positive patients, may confer diminished sensitivity to immune checkpoint inhibitors.33

KEYNOTE-010 Trial

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).34 Patients with an EGFR-sensitizing mutation (n = 86) or an ALK rearrangement (n = 8) who experienced disease progression following treatment with an appropriate TKI were also enrolled.34 In the EGFR 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 EGFR 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.34

OAK and BIRCH Trials

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 EGFR tumor aberrations, regardless of PD-L1 expression. In the subpopulation of patients with EGFR-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 EGFR 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 ALK-positive disease.36 The disadvantage of atezolizumab in the EGFR-mutated population compared with the wild-type EGFR population added clinical evidence sup- porting the decision to remove all checkpoint inhibitors from the current treatment guidelines for patients with driver-mutated NSCLC.7,17,36,37

In the phase II BIRCH trial, patients with EGFR-mutated (n = 45) and ALK-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.17,35,37 No data were reported for the ALK subpopulation. The ORRs to atezolizumab treatment in the EGFR-mutated cohort compared with the EGFR 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 EGFR-mutated cohort compared with the EGFR 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 EGFR-mutated cohort in the second and third lines.37

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