Joshua K. Sabari, MD, went through treatment options in the frontline and second-line for patients with non–small cell lung cancer in a 

 case-based peer perspectives live discussion. Sabari, an assistant professor in the Department of Medicine at NYU Langone Health, explained the treatment options in the context of 2 patient cases of lung cancer. 

Do you order molecular testing for patients with squamous cell carcinoma?

I order liquid biopsy and tissue biopsy tests. Liquid biopsy is controversial in this setting, but I order these tests to identify alterations. The key takeaway point here is that in squamous cell carcinoma, the rate for identifying an actionable mutation is a lot lower [rate than in other lung cancers]. There is lots of research going on in the space. [In general], the rate of 

[mutations] in squamous cell carcinoma is low, in the 1% range.

There are mutations that investigators may eventually develop treatments for, and which are undergoing development. There are also some other alterations that we can identify, but these don’t have an FDA-approved therapy available yet; however, I’m an optimist, so I still order a test.

I have a patient now who immigrated from China about 3 years ago. He never smoked but developed squamous cell cancer. He has an 

exon 19 [mutation]. Interestingly, he developed a C797S secondary mutation [while being treated on] Tagrisso [osimertinib] and is now doing quite well in a clinical trial. But the take-home point is that mutations are relatively rare.

What are your treatment options for this patient?

We could go with a combination of chemotherapy and immunotherapy here, or even immunotherapy alone. To address the dyspnea with the back pain, we could also treat with radiation therapy up front, followed by immunotherapy.

What do the National Comprehensive Cancer Network (NCCN) guidelines recommend?

This patient has a PD-L1 expression ˃≥50%. According to the guidelines, the preferred regimens are pembrolizumab [Keytruda] monotherapy, based on KEYNOTE-024 [NCT02220894], which compared pembrolizumab with chemotherapy.

The other option recommended is carboplatin, paclitaxel, or albumin-bound paclitaxel [Abraxane], plus pembrolizumab, based on KEYNOTE-407 [NCT02775435].3 Another option for certain cases is the combination of ipilimumab [Yervoy] and nivolumab [Opdivo], based on CheckMate 227 [NCT02477826].

KEYNOTE-024 evaluated pembrolizumab versus platinum-doublet chemotherapy in the frontline setting in a total of 305 patients who had NSCLC, either squamous cell carcinoma or adenocarcinoma. Patients then received pembrolizumab maintenance therapy. This was the first study that led to the approval of any immunotherapy in the frontline setting for NSCLC.

Median progression-free survival [PFS] in the immunotherapy arm was 10.3 months versus 6 months for the control arm [HR, 0.50; 95% CI, 0.37-0.68; 

 <.001]. The results led to the FDA approval [for pembrolizumab] for patients with metastatic NSCLC whose tumors express PD-L1 as determined by an FDA-approved test in October 2016.

 At that time, the overall survival [OS] benefit had not been reached; but now we have 5-year data coming up, which continue to show the improved OS for pembrolizumab over chemotherapy. We also check PD-L1 expression status in patients because of this clinical trial.

This study demonstrated the role of sequencing, which is a somewhat controversial idea. It demonstrated that giving pembrolizumab first, before chemotherapy, resulted in benefit. 

There was a cure rate of about 25%. Some of the patients never went on to chemotherapy, but about 75% of patients did receive chemotherapy over the course of treatment. As a result, the crossover data continue to accrue. OS still favored the pembrolizumab arm versus the chemotherapy arm in patients who had PD-L1 expression ˃≥50%.

We have more prospective data across multiple studies that suggest immunotherapy can be stopped after 2 years. There have been some relapses, but most patients continue to respond.

Is there a reason to focus on those patients who benefitted from pembrolizumab?

We never talk about cure. We talk about no evidence of disease, but that’s the billion-dollar question, and I just don’t know. I’m sure there’s a biologic or immunologic mechanism,  but we don’t know what that is.

How do the results of the KEYNOTE-407 trial help you when treating a patient such as the one described?

This study specifically focused on patients with squamous NSCLC.

This was a large study that randomized patients 1:1 to pembrolizumab plus chemotherapy versus placebo plus chemotherapy. The investigators allowed for optional crossover, which will have an eff ect on OS results.

Administering carboplatin every 3 weeks was a concern because of toxicity, but patients seem to tolerate Abraxane on a weekly basis. My patients with squamous NSCLC tend to be in rougher shape than my patients with adenocarcinoma, so I tend to avoid this. I use this dosage more in the neoadjuvant or adjuvant setting in patients with squamous NSCLC who are potentially curable.

The investigators conducted a second interim analysis, looking at PFS stratified by PD-L1 expression subgroups. The median PFS was 6.4 months versus 4.8 months favoring the pembrolizumab arm [HR, 0.56; 95% CI, 0.45-0.70; 

Patients were stratified by TPS <1%, TPS 1% to 49%, and TPS ≥50%. Patients with a TPS <1% demonstrated a median PFS of 6.3 months versus 5.3 months favoring the pembrolizumab arm [HR, 0.68; 95% CI, 0.47-0.98]. Patients with TPS ≥50% did quite well, however.

My standard of care has been this regimen described in [the] KEYNOTE-407 [trial] in my patients with squamous NSCLC, regardless of PD-L1 expression and depending on the patient’s performance status. If patients have a poor performance status [score], I’m going to administer pembrolizumab alone. If they have good performance status and a high PD-L1 expression, I will offer this regimen because I think the data are better [in this population].

How does the patient’s age and performance status factor into your treatment choice?

Age is just a number. I think what matters is performance status [score]. In the ideal world, you conduct a geriatric assessment, or refer the patient to a geriatrician, but sometimes I just walk the patient to the secretary’s desk to make the appointment. If the patient is able to get up and walk with me and the patient tells me that they are active, that’s my assessment. In an ideal world, we would send them for the assessment.

How does the patient's psoriatic arthritis affect your treatment decision?

This is an underlying autoimmune disease. This condition might give a clinician a reason to pause. But I think the consensus is that unless the patient is on high-dose disease-modifying antirheumatic agents, they tend to tolerate immunotherapy. 

A retrospective study from the Dana-Farber Cancer Institute evaluated patients with different autoimmune diseases with NSCLC who receive PD-L1 monotherapy.

 Eighteen percent of patients had an autoimmune-related disease, and 20% received immunomodulatory agents for their autoimmune disease. The key takeaway is that only a minority of patients experienced an exacerbation of their autoimmune disease.

There’s an ongoing study by Bristol Myers Squibb analyzing therapy that includes nivolumab. The company is enrolling patients who have no autoimmune disease and is looking at the rate of toxicity. Incidence of autoimmune or immune-related adverse events [AEs] was similar to that reported in the clinical trials, which did not include patients with an autoimmune disorder.

Additionally, we now have data in melanoma that has come out of Memorial Sloan Kettering Cancer Center that evaluates patients who experience autoimmune AEs from immunotherapy and then were re-treated. The response rate is right around that 20% to 25% range. The rate of immune-related AEs is a bit higher in patients who have previously experienced AEs.

The investigators found that it was safe to re-treat patients, with the exception of [those who had] pneumonitis. That was the 1 [group] that was potentially not safe. But overall, I think it is safe to treat our patients who have underlying rheumatologic or autoimmune disease, [if they are not currently treated with] disease-modifying agents.

It’s important to be able to seek out a rheumatologist, endocrinologist, or a dermatologist. Having a diverse group of care managers taking care of your patients with you [is beneficial] because patients can run into issues with immunotherapy. We have become more cognizant of that, but I think it’s important to have those consultants available should we need them.

What molecular testing should be ordered? Would you initiate frontline therapy or wait for molecular testing results?

I would order a large panel test. I think in someone who is a never smoker, we have a high pretest probability of having a driver alteration. I would recommend waiting for the results of that test before moving forward. However, if the patient is symptomatic, I don’t think it’s wrong to start chemotherapy alone. It’s hard for me to sit on my hands when I see a sick patient. I will give chemotherapy and hold off on immunotherapy. You can always continue the chemotherapy, depending on the situation.

What would you consider as frontline therapy for this patient?

occurs in about 20% to 25% of patients. About 30% to 35% of my patients have an 

mutation, given my patient population in downtown Manhattan.

In the frontline setting, there is the first-generation EGFR inhibitor Tarceva [erlotinib]. Second- generation inhibitors include gefitinib [Iressa] and afatinib [Gilotrif]. The third-generation inhibitor is osimertinib. All those agents are approved in the frontline setting, and osimertinib is the newest therapy available in the frontline setting.

Is it preferable to use osimertinib up front, or should its use be delayed because of the potential for resistance?

I learned early on in my training to use your best drug up front. I think that osimertinib is a better drug than the first- and second-generation EGFR inhibitors. Now that we have OS data for Tagrisso, I think it makes sense to use Tagrisso in the frontline setting and not to hold it in your back pocket because the patient could develop an 

T790M mutation. Forty percent of patients will not develop T790M. 

The space is getting complicated, but I’m still using Tagrisso as a single agent as the preferred treatment.

 mutation in exon 19 or exon 21, what treatment options do the NCCN guidelines suggest?

The [NCCN] guidelines suggest Tagrisso as a preferred regimen.

 Other recommended agents include erlotinib and ramucirumab. I did not mention dacomitinib [Vizimpro]. That’s also a second-generation EGFR inhibitor available in the frontline setting as well.

Please provide details about the FLAURA trial (NCT02296125).

This study evaluated the fi rst-line use of the third-generation EGFR inhibitor, Tagrisso versus standard of care, which was erlotinib or gefitinib. Interestingly, the investigators excluded afatinib, which is a second-generation EGFR inhibitor that we know is better than these 2 other drugs.

The primary end point was PFS, which was 18.9 months for the Tagrisso arm compared with 10.2 months for the standard-of-care arm [HR, 0.46; 95% CI, 0.37-0.57; 

The investigators reported a 39-month OS for the Tagrisso arm versus 31.8 months for the standard-of-care arm.

One thing to point out was that patients who initially received erlotinib or gefitinib were able to cross over to receive osimertinib. Overall, I think this was a win for patients with an 

mutation. I think we’re getting better at treating these patients with 

Of interest is that patients could cross over, but only if they had T790M [sensitizing mutations]. If patients were in the population who did not have T790M, which was about 40%, there was no benefit giving Tagrisso.

What is the role that sequencing plays in efficacy with these multigenerational tyrosine kinase inhibitors for this patient population?

We still need to better understand sequencing, but we can’t do that comparing across clinical trials. We will need a better biomarker that identifi es who develops T790M and who doesn’t. But we do know that patients who take Tagrisso develop secondary resistance mechanisms like 

or C797S resistance mutations. There are multiple ongoing trials.

There’s a clinical trial that evaluates the bispecific antibody JNJ-372 in which we are seeing responses in the 40% to 45% range in patients who have 

amplification post-EGFR inhibitor [NCT02609776]. I believe there will be potential strategies [in the future] that combine different antibodies with EGFR inhibitors or strategies that combine chemotherapy with EGFR inhibitors.

Why do these mutations tend to develop in Asian populations?

mutation does seem more common in Asian patients, particularly, Asian women. It is not clear why. Examining the subset populations suggests that there is a difference between exon 19 deletion and L858R. The latter seems to have a worse prognosis, which we see in patients of Asian descent versus non-Asian descent. But we don’t have a rationale for this observation.

I’ve examined a small subset of 400 patients at New York University but could not tease out any major difference, including coalteration, driver mutations, or any sort of criteria where patients did better or worse. The only thing that seemed different was smoking status. If a patient was a smoker or if they had a 

, they tend to do worse with osimertinib, but not with first- and second-generation EGFR inhibitors.

Interestingly, pneumonitis and inflammation in the lungs tends to be higher in patients of East Asian descent, but not in Caucasians. But we don’t know why there is a difference. It could be pharmacodynamics because there might be a difference in how subpopulations break down drugs.

The RELAY study evaluated erlotinib with or without ramucirumab [NCT02411448].11 Investigators looked at treatment until progression or unacceptable toxicity. The primary end point was PFS. Patients were stratifi ed by exon 19 versus exon 21 L848R, by sex, region, East Asian descent, and by 

Investigators reported that the PFS primary end point was 19.4 months for patients who received the combination compared with 12.4 months in the control arm [HR, 0.591; 95% CI, 0.461-0.760; 

 <.0001]. The PFS for osimertinib in the RELAY trial was reported as 18.9 months. The PFS rate was 71.9% in the treatment arm versus 50.7% in the control arm.

When toxicity was evaluated, the only treatment-related AEs [TRAEs] that stood out were related to VEGF inhibition. For patients in the combination arm, the grade 1/2 rate for hypertension was 22% compared with 7% in the control arm. For grade 3 hypertension, the combination arm was 24% versus 5% in the control arm.

Most clinicians who treat with VEGF inhibitors are used to managing hypertension, but the investigators noted that grade 1 bleeding and hemorrhaging was higher in the ramucirumab group [53%] versus 24% in the control arm. Overall, grade 3/4 TRAEs were not too severe. This is another regimen to consider when discussing treatment options with your patients.

I think we need to consider combination strategies and that’s why I think these studies are important.

What are the potential treatments in the next-line setting?

We have data evaluating carboplatin and pemetrexed [Alimta], but we don’t have data for pembrolizumab in the second-line setting. I would, however, mention that I would avoid pembrolizumab in the second-line setting because it can prevent your patient from receiving other targeted therapies [in the future].

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. Version 3.2020. Published February 11, 2020. Accessed April 6, 2020. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

2. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. 

 2016;375(19):1823-1833. doi:10.1056/NEJMoa1606774

3. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. 

2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865

4. Reck M, Schenker M, Lee KH, et al. Nivolumab plus ipilimumab versus chemotherapy as first-line treatment in advanced non-small-cell lung cancer with high tumour mutational burden: patient-reported outcomes results from the randomised, open-label, phase III CheckMate 227 trial. 

 2019;116:137-147. doi:10.1016/j.ejca.2019.05.008

5. Pembrolizumab (KEYTRUDA) checkpoint inhibitor. News release. FDA Office of Media Affairs; October 24, 2016. Accessed April 6, 2020.www.fda.gov/drugs/resources-information-approved-drugs/pembrolizumab-keytruda-checkpoint-inhibitor

6. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. 

 2018;379(21):2040-2051. doi:10.1056/NEJMoa1810865

7. Leonardi GC, Gainor JF, Altan M, et al. Safety of programmed death-1 pathway inhibitors among patients with non-small-cell lung cancer and preexisting autoimmune disorders. 

 2018;36(19):1905-1912. doi:10.1200/JCO.2017.77.0305

8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer (version 3.2020). Published February 11, 2020. Accessed March 30, 2020. nccn.org/professionals/physician_gls/pdf/nscl.pdf

9. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. 

2018;378(2):113-125. doi:10.1056/NEJMoa1713137

10. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. 

 2020;382(1):41-50. doi:10.1056/NEJMoa1913662

11. Nakagawa K, Garon EB, Seto T, et al. Ramucirumab plus erlotinib in patients with untreated, EGFR-mutated, advanced non-small-cell lung cancer (RELAY): a randomised, double-blind, placebo-controlled, phase 3 trial. 

 2019;20(12):1655-1669. doi:10.1016/S1470-2045(19)30634-5

Articles

Joshua K. Sabari, MD, goes through treatment options in the frontline and second-line for patients with non–small cell lung cancer in a Targeted Oncology case-based peer perspectives live discussion.

Sabari Examines Frontline and Second-Line Treatment Options in NSCLC

A high percentage of pathologic complete responses (pCRs) were observed with atezolizumab (Tecentriq) in combination with carboplatin and nab-paclitaxel (Abraxane) chemotherapy as neoadjuvant treatment of patients with resectable non–small cell lung cancer (NSCLC), meeting the primary end point of a phase 2 study, which is the only known study of its kind.

“The results showed that a high proportion of patients had a complete pathological response or a major pathological response, even in the high-risk population of patients included in our study, in which more than 75% of patients presented with stage IIIA disease,” wrote the study authors, led by Catherine A. Shu, MD, of the Division of Hematology/Oncology, Department of Medicine, Herbert Irving Comprehensive Cancer Center at Columbia University.

 were from 30 evaluable patients with resectable NSCLC. After enrollment, one patient was found to have colon cancer and therefore was non-evaluable and replaced by another patient. In terms of cancer types, 57% of patients had adenocarcinoma (n = 17), 40% had squamous cell carcinoma (n = 12), and 3% had a large-cell neuroendocrine tumor (n = 1). Baseline screening showed that in 55% of patients (n = 16) had tumor PD-L1 expression of 1% or higher, and 27% of them (n = 8) had tumor PD-L1 expression of 50% or higher. AJCC 7th edition–defined stage IIIA disease was observed in 77% of patients (n = 23). Resection was carried out in 26 patients; however, 4 patients did not have a R0 resection due to unresectable disease in 3 and brain metastases in 1.

At a median follow up of 12.9 months (Interquartile range [IQR], 6.2-22.9) major pathological responses were observed in 57% (95% CI, 37%-75%) of 30 patients. In addition, pCRs were achieved in 33% of patients (95% CI, 17%-53%), and 6 of those patients were in the stage IIIA disease group. Of the responders in the study, 63% had a partial response as their best response per RECIST criteria. Stable disease was observed in 30% of those patients (n = 9), and progressive disease was observed in 7% of patients (n = 2).

An investigation of the potential correlation between PD-L1 expression and responses, no significant association was found (

 = .67). A significant association was observed between the achievement of major pathological response and RECIST criteria response categories (

 = .0022), which was noticed in a post hoc analysis. Objective responses regardless of PD-L1 expression were also observed through a post hoc analysis showing a median best percentage change in tumor size of –34% (range, –41 to –9) in patients with less than 1% PD-L1 expression and –40% (range, –52 to –21) in those with PD-L1 expression of 1% or higher (

Twenty-three patients received at least day 1 of treatment of all 4 cycles with atezolizumab in combination with carboplatin and nab-paclitaxel. Of those patients, 97% completed at least 3 cycles of combination therapy. Chemotherapy dose reductions were required in 67% of patients (n = 20). As a result of treatment-related toxicities, 17% of participants (n = 5) underwent surgery early. Ninety percent of patients developed thrombocytopenia or neutropenia, which led to missing at least one dose of nab-paclitaxel.

In the overall safety analysis, treatment-related adverse events (TRAEs) were seen in most patients. The most common any-grade TRAE was neutropenia, which was observed in 87% of patients (n = 26). Other common any-grade TRAEs included anemia (77%), thrombocytopenia (63%), fatigue (57%), alopecia (47%), and nausea (43%). Frequent grade 3/4 adverse events (AEs) included neutropenia (50%), alanine aminotransferase concentration increase (7%), aspartate aminotransferase concentration increase (7%), and thrombocytopenia (7%).

Arthralgia/myalgia, diarrhea, increased alanine aminotransferase concentrations, increased aspartate aminotransferase concentrations, hypothyroidism, and hyperglycemia were among possible immune-related events observed in the trial. Also, serious TRAEs occurred in 3% of patients and included grade 3 febrile neutropenia, grade 4 hyperglycemia, and grade 2 bronchopulmonary hemorrhage. No deaths occurred due to treatment. There were also no treatment-related surgical delays.

Other post hoc analyses looked into disease-free survival (DFS) according to pathological responses. Patients who did not have a major pathological response had a median DFS of 14.3 months (95% CI, 9.9 to not reached [NR]) versus 34.5 months (95% CI, 10.7-NR) in those who had a major pathological response (HR, 0.7; 95% CI, 0.1-4.3; 

 = .71). Among subjects with a pCR, the median DFS was 34.5 months but was not reached in those who did not have a pCR (HR, 0.4; 95% CI, 0.04-3.70; 

Responses were evaluated by tumor histology as well and showed that more patients had a major pathological response and pCR in the adenocarcinoma group (53% and 33%, respectively) than in the squamous cell carcinoma group (80% and 50%). According to molecular tumor tests, 15% of patients in the adenocarcinoma group had 

 mutations. These mutations did not impact responses.

“Pathological response as an early surrogate endpoint for survival is encouraging, and if validated as a biomarker, could shorten the time between trials and approval of therapy by pharmaceutical regulatory authorities, thereby allowing more patients faster access to better therapies,” wrote Shu et al about the implication of this research.

This was an open-label, multicenter, single-arm trial conducted at 2 sites in the United States. Patients who were enrolled had stage IB-IIIA NSCLC that was considered to be surgically resectable by a thoracic surgeon. All patients in the study had an ECOG performance status of 0 or 1, adequate organ function, adequate pulmonary function, and measurable disease, as was required per the study criteria.

Intravenous atezolizumab 1200 mg was administered on day 1 in combination withnab-paclitaxel (100 mg/m²) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1 of each 21-day cycle. This treatment continued for 4 cycles before patients were considered ready for surgery.

The trial’s primary end point was major pathological response, and the secondary end points were objective response, DFS, and overall survival.

“Our trial, together with ongoing randomized trials, provides more evidence on the risks and benefits of immunotherapy as a neoadjuvant treatment, and could help to answer questions regarding the optimal duration, best surrogate endpoint, and best predictive biomarkers for treatment,” the authors added.

Shu CA, Gainor JF, Awad MM, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. 

 Published online May 7, 2020. doi:10.1016/ S1470-2045(20)30140-6

"Our trial, together with ongoing randomized trials, provides more evidence on the risks and benefits of immunotherapy as a neoadjuvant treatment, and could help to answer questions regarding the optimal duration, best surrogate endpoint, and best predictive biomarkers for treatment."

Neoadjuvant Atezolizumab With Chemotherapy Feasible in Advanced NSCLC

 case-based peer perspectives live discussion, David Gerber, MD, a professor of internal medicine and associate director of clinical research at The University of Texas Southwestern Medical Center in Dallas, addressed the role of biomarkers in guiding treatment decisions for patients with non–small cell lung cancer based on a patient scenario. 

: Why do you think they did a biopsy on the patient’s metastases instead of the primary site?

You can tap the pleural effusion to improve symptoms. The challenge of pleural fluid is that it might be harder to do molecular analysis because there may be fewer cells. You may have a bony metastatic site where it’s also hard to do molecular analysis because you have to decalcify the tissue and it’s not as viable.

It may be that biopsying the liver is safer than biopsying a lung lesion. You still have issues of bleeding and pain and infection, but usually you don’t have a risk of pneumothorax. They biopsied the liver lesion and it showed adenocarcinoma, so now we have pathologically proven stage IV adenocarcinoma in a former smoker.

: What kind of molecular testing would you order for this patient?

[I would order] next-generation sequencing [NGS] plus PD-L1 testing.

You don’t get PD-L1 status from a blood test. We get [plasma for molecular biomarkers testing]; we’re looking at DNA. We’re looking at the genes in the cancer, so you can detect a mutation. PD-L1 is a protein on the cancer cell surface.

If you have a patient with stage IV cancer, maybe 0.5% or 0.3% of the DNA in the blood is from the cancer. We [have tests that can] pull that out, so that’s another option.

These tests don’t necessarily [look for] circulating tumor cells; this is just the [circulating tumor] DNA. Circulating tumor cells have a diff erent assay. We’re not sure what to do with that information right now in a lot of cancers. There are some cancers, like breast, prostate, and maybe colon cancer, where it’s prognostic [for] response to therapy.

: Which mutations do you usually test for in these patients?

If we’re sending [tissue for] NGS, [the number of genes] depends on the panel. It might be about 200 genes through [the] Caris Life Sciences [assay]. At The University of Texas Southwestern, we have a panel that’s CLIA [Clinical Laboratory Improvement Amendments] certified, and it’s 1415 genes. It pairs germline, or the patient’s DNA, with the tumor’s DNA.

In lung cancer, the National Comprehensive Cancer Network [NCCN] recommends, at a minimum, testing for 

mutations.¹ Those are 4 subsets of lung cancer. If you think about nonsquamous, non–small cell lung cancer [NSCLC], what is [the rate of] 

mutations are around 1% of cases. [As you go down the list] they start to get rare; but if you don’t look for it, you don’t find it.

If you have a nonsquamous case, it can’t hurt to look for an 

mutation also because there are TRK inhibitors that are FDA approved regardless of the type of cancer.

 It doesn’t matter anatomically what it is. There are 

mutations in lung cancers. I’m not talking about 

-amplified or HER2-expressing tumors, like you would look for in breast cancer; it’s a different biomarker. [We would] look for a mutation in 

exon 20 that predicts response to HER2 inhibitors.

This patient is a former smoker; does smoking history or other factors affect the patient’s mutation status?

mutations will probably be in less than 5% of those cases. If your patient is a never smoker and you’re looking for 

, depending on the histology and the patient, [it will be about] 60%.

I do have patients who are African American men who smoked a lot and have 

mutations. But there are times where you may go to greater efforts to genotype. In general, the [treatable] mutations are going to be in the patients who have smoked less.

There are a couple of exceptions. I’m not sure that 

mutations are necessarily more common in never smokers or former smokers. 

mutations have long been considered [untreatable] in oncology. It is the second most common mutation in human cancer. The most common mutation in human cancer is 

Why do you never hear about inhibitors of 

They don’t exist. All these other mutations are proto-oncogenes, so when they are mutated, they function more. 

is a tumor suppressor; its job is to prevent cancer. When it’s mutated, it stops doing its job or doesn’t do it as much. You’re not trying to inhibit mutant 

; you’re trying to increase its function. It’s a lot harder to increase the function of a molecule in medicine than it is to inhibit it or slow it down.

What other mutations or issues should physicians keep in mind when testing?

mutations in lung cancer for a long time, and it came down to which MET cases matter. We were looking at 

amplification, such as with FISH [fluorescence in situ hybridization]; we were counting the number of genes or chromosomes. We were looking at 

expression, so that’s the protein [detected by] immunohistochemistry, and those trials were negative. It’s the 

exon 14 mutation [that should be targeted, and this mutation] tends to respond well to MET inhibitors.

When you do a blood test looking for the DNA of cancer, there are times that the test will be negative but the tumor is positive [for a mutation]. Maybe the tumor didn’t shed enough DNA [for the test] to pick it up. There are also cases where there is negative testing in the tissue, and the patient is positive for a mutation with a blood test. Is that a false-positive blood test? It’s not; it could have to do with tumor heterogeneity. When you stick a needle in the tumor, you’re [sequencing] just 1 site, whether it’s a lymph node or a primary or metastatic tumor. That area might not have that particular mutation that you could detect.

Have you had cases where the first and/or second biopsy didn’t have enough tissue and you still needed to get a third biopsy?

I have. This is going back to 2009, when we first learned about 

fusion-positive lung cancer. I had a patient who was a never smoker with lung cancer, and she had been on an EGFR inhibitor, hadn’t had any testing, and hadn’t responded at all [to therapy]. She received some chemotherapy; she was on hospice in a wheelchair, getting supplemental oxygen, and she came for a second opinion.

I told her I had just heard about a new subtype of lung cancer called 

-positive lung cancer, and I thought we should look to see if she had it. Even though just 3% of lung adenocarcinoma is 

 positive, for a never smoker with adenocarcinoma, the chance of having an 

mutation is about 50%. I did a biopsy on her liver and there was insufficient tissue. I asked if we could do 1 more, and it came back 

positive. Our pathologist had never heard of the test, so I had to get them to order it, and it was positive. She went on to live another 5 years. These are hard decisions.

How does PD-L1 factor in when deciding on treatment, and is it considered a biomarker?

If you test for PD-L1, we consider negative as 1% or less expression, ntermediate as 1% to 49%, and high or positive as 50% or greater. PD-L1 is the biomarker that helps us determine the efficacy of immune checkpoint inhibitors that target PD-L1 or PD-1. It is not a perfect biomarker.

mutations if you suspect a patient has them?

We were spoiled in thoracic oncology with biomarkers like 

mutation and I’m giving an EGFR inhibitor, my response rate is over 90% with a third-generation EGFR inhibitor. If I don’t have an 

mutation and I give an EGFR inhibitor, my response rate is below 1%. I can only give an EGFR inhibitor if the biomarker is positive. With greater than 90% versus less than 1%, it’s a clear decision. You know what to do.

What makes mutation biomarkers positive in this setting?

For the most part, when we’re looking for mutations, we tend to take any evidence of a mutation as the tumor being positive [for that aberration]. It tends not to come back measured by cells because we’re looking at the DNA and not a cell surface marker. At the cellular level, that’s difficult to interpret. With 

, when we’re doing FISH testing, there is a cutoff saying it should be that 15% of cells or more have that rearrangement. What do you do if it’s 14%? Is that different from 16%? You can do another test looking for the protein. If that’s there, that’s not to be functionally meaningful—especially when we’re testing the blood—because the denominator of DNA is not cancer DNA, it’s all the DNA in the blood. The total cancer DNA may be 0.5%. We don’t know that, but when you get 0.2% coming back with a mutation, that’s a positive result, and you’re going to act on it.

How would you handle this patient, considering the results by IHC?

The relationship between mutations of a cancer and the likelihood of immunotherapy working is antigenicity. The more mutations the cancer has, the more foreign it appears to

the patient’s immune system and the more likely immunotherapy will work.

[This patient has] 14 mutations per megabase; is that a high level or a low level? It depends on the company and the clinical trial. Bristol Myers Squibb uses 10 mutations per megabase [as a threshold for high expression], and AstraZeneca uses 16 mutations per megabase in their durvalumab [Imfinzi] with or without tremelimumab studies, so it depends. It’s something that’s hard to agree upon.

What are the treatment choices, and which factors influence your recommendations for this patient?

You don’t want to give checkpoint inhibitor monotherapy. You want to give chemotherapy alone [or in a combination]. We have platinum [therapy] plus pemetrexed [Alimta] and pembrolizumab [Keytruda]. We also have platinum- and taxane-based therapy plus atezolizumab [Tecentriq] with or without bevacizumab [Avastin].

There was a time when I could look at the NCCN guidelines and they told me what to do for patients with lung cancer. That is no longer the case, and I’m sad to say they’ve lost some of their usefulness. 

In this case, the patient has NSCLC and PD-L1 expression status of 2%. About 70% of cases fall into that category. About 30% are going to be PD-L1 negative, so I’m talking about the 70% [that are positive].

[The NCCN recommends] platinum chemotherapy, pemetrexed [Alimta], and the immune checkpoint inhibitor pembrolizumab as category 1. [You may also use] the platinum/taxane combination with the antiangiogenic [agent] bevacizumab plus anti–PD-L1 atezolizumab. We also have platinum nanoparticle albumin-bound paclitaxel [Abraxane] as an option. There’s no FDA indication for this, but combination immunotherapy [is also suggested].

Do you feel that there’s a difference between the approved drugs for this setting (pembrolizumab, nivolumab [Opdivo], atezolizumab, and durvalumab) in toxicity or efficacy?

Some are PD-1 versus PD-L1, some are humanized antibody versus fully human antibody, and some are immunoglobin G1 [IgG1] versus IgG4. I’m not sure there is a meaningful difference in efficacy or toxicity between PD-1 and PD-L1. IgG1 versus IgG4 would tell you how [the] complement interacts with the antibody; I don’t think that’s relevant to the mechanism. And a fully humanized versus a human antibody would tell you the likelihood of an infusion reaction.

With a humanized antibody—that’s atezolizumab or pembrolizumab—the chance of an infusion reaction is probably 1% to 2%. With a fully human antibody like durvalumab or nivolumab, the risk of an infusion reaction is less than 1%. The single time in my practice I have changed from one checkpoint inhibitor to another was when a patient had pembrolizumab and they had an infusion reaction; not autoimmune toxicity, not pneumonitis, not nephritis, not colitis—they had an allergic infusion reaction. I said, “I’m going to switch to a fully human antibody.”

What are the design and efficacy of relevant trials in this setting?

The KEYNOTE-042 [NCT02220894] study [involves] patients that had PD-L1 status of less than 1%, and they’re receiving immunotherapy [of pembrolizumab] or chemotherapy.

Looking at the progression-free survival [PFS] of the group whose status is at least 50%, there was the greatest benefit in PFS, with a hazard ratio of 0.81 [95% CI, 0.67-0.99; 

 = .017]. For patients with less than 20% PD-L1 status, there was a hazard ratio of 0.94 [95% CI, 0.80-1.11]; it’s not significant. When you look at patients with PD-L1 expression greater than 1%, that’s also not significant [HR, 1.07; 95% CI, 0.94-1.21]. But it’s never worse than chemotherapy.

What’s interesting to me is that the OS is better with immunotherapy than it is with chemotherapy regardless of the PD-L1 cutoff.

There was an exploratory analysis, and [it showed that] no difference in OS whether you give immunotherapy first or chemotherapy first. We don’t know about chemotherapy plus immunotherapy; that has not been formally asked.

Please discuss the important aspects of the IMpower150 study.

IMpower150 [NCT02366143] was a 3-arm study; patients received chemotherapy plus bevacizumab, an antiangiogenic drug; chemotherapy plus the immune checkpoint inhibitor atezolizumab; or both immunotherapy and antiangiogenic therapy.

I want to point out that this trial suggests that immunotherapy works better if the patient has liver metastases. I don’t know why that was looked at [as a stratification factor]. There is another trial that looks at liver metastases, and those patients did worse. I don’t know why this question is being asked. However, if you ask enough questions, you’ll eventually find something.

The other trials that I [mentioned], which added chemotherapy or immunotherapy to chemotherapy, excluded patients with 

positive. Those patients were [about 13% of the entire cohort] were included in this trial, and they benefited. We didn’t know whether they would benefit from the addition of immunotherapy to platinum [therapy and] pemetrexed; that question hadn’t been asked in that study.

How does the CheckMate 227 [NCT02477826] trial compare to these other therapies?

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