Konduri Reviews the Most Up-to-Date Data Impacting Treatments for 2 Case Studies in NSCLC

Kartik Konduri, MD

Kartik Konduri, MD

During aTargeted Oncologylive case-based peer perspectives presentation, Kartik Konduri, MD, recently discussed the treatment considerations and decisions he makes when treating patients with non—small cell lung cancer (NSCLC). Konduri, the co-medical director of the Lung Cancer Center of Excellence at Charles A. Sammons Cancer Center, Baylor University Medical Center, revealed his treatment decisions to the group based on 2 case scenarios.

Case 1

An 81-year-old man presented with symptoms of coughing, dyspnea, upper back pain, and fatigue requiring frequent rest. His past medical history later revealed hypercholesterolemia, controlled on pravastatin (Pravachol); hypertension, controlled on verapamil (Verelan); and psoriatic arthritis, for which he was not on treatment for 3+ years. The patient was a former smoker but was physically active and played golf weekly. He had an ECOG performance status of 1.

His chest CT revealed a 2.5-cm solid mass in the left upper lobe and lymphadenopathy in the left hilar and bilateral mediastinal nodes and bilateral, small pulmonary nodules (8 mm was the largest). Additionally, PET/CT imaging revealed 18F fluorodeoxyglucose uptake in the lung mass, left hilar and both mediastinal lymph nodes, and thoracic spine (T5/T6).

Bronchoscopy and transbronchial lung biopsy were performed and pathology showed grade 3 squamous cell carcinoma. His PD-L1 expression by immunohistochemistry was 22C3 and his tumor proportion score (TPS) was 65%. The patient was later diagnosed with stage IV squamous non—small cell lung cancer (NCSLC) and it was decided to start him on pembrolizumab (Keytruda).

What are your general impressions of this patient?

This is the most common circumstance of metastatic cancers. This is a case of a patient with metastatic squamous cell NSCLC; however, [the case description] could also apply to metastatic nonsquamous cell NSCLC. The patient is an 81-year-old man who has evidence of multiple medical issues; notably, the psoriatic arthritis. He is physically active. He has disease that has been picked up at 2.5 cm, and a PET scan shows evidence of disease in the lymph nodes and thoracic spine. Therefore, we would say that he has stage IV disease.

Do precautions need to be taken considering his psoriatic arthritis?

The data show that with low-grade autoimmune disorders—psoriatic arthritis, rheumatoid arthritis, and issues of psoriasis without arthritis, among others—that are not causing life-threatening problems, you can get away with treatment; however, you should remain vigilant with your patient. Data from multiple retrospective studies suggest that there is over a 35% response rate for this patient population. Of note, it is a completely different story if patients are getting active treatment for their autoimmune disorder.

For example, I had a patient with stage III disease—before durvalumab (Imfinzi) came into play—and the patient received chemoradiation for left-lung cancer with involvement of the mediastinum. At the same time, she had 1 small contralateral lesion with a separate histology. She was treated and then watched. When she relapsed, she did so in the mediastinum in the chest. At this point, the patient is not in the best of shape to be treated with aggressive chemotherapy; on top of that, she had a PD-L1 of 90%, and she had psoriasis with sheets of skin filled with red sores. I told her to go to a dermatologist and get treatment so that I could reevaluate, but I have had stage IV patients with psoriasis, and I was able to treat them. Currently, I have a patient with rheumatoid arthritis who I give treatment to after talking with her very carefully [regarding the precautions].

Can you explain the rationale of pembrolizumab for this patient with a high PD-L1 expression?

KEYNOTE-024 kicked off the use of immunotherapy.¹In the trial, patients had a TPS of more than 50%, and they were randomized to either chemotherapy or pembrolizumab.

I was impressed with the exploratory endpoint of second progression-free survival [PFS2], which means that the sequencing of the immunotherapy versus the chemotherapy made a difference. If the patients [on the trial] had a high PD-L1 expression and you started off by treating the patient with chemotherapy and then treated them with immunotherapy afterward, the PFS2 is clearly deficient in comparison with those who were treated with immunotherapy first. This tells you that those patients need the immunotherapy drug right up front.

The 2-year overall survival (OS) data were clearly in favor of immunotherapy; for pembrolizumab, the median OS was 30.2 months versus 14.2 months with chemotherapy. The response rates were 44.8% versus 27.8%, respectively.

What if the patient had a low PD-L1 expression—would that change your treatment choice?

The KEYNOTE-042 trial randomized patients 1:1 to pembrolizumab versus chemotherapy with a PD-L1 score greater than 1%, and it gave us some insight.²Of note, there were no US patients in this trial. For this patient population, the [2-year] OS was 39.3% with pembrolizumab versus 28.0% with chemotherapy. The median OS after evaluation was 16.7 months versus 12.1 months, respectively.

The problem with this scenario is that for patients who were getting chemotherapy from the opposite side of the spectrum, not many ended up getting immunotherapy. Another problem is that 453 patients in this study had 1% to 49% PD-L1 expression. This study has approximately 800 patients. If you have 800 patients who are more than 1% but just 453 who were 1% to 49%, you can assume the rest of the patients are greater than 50%. The population with a PD-L1 expression greater than 50% is driving the [survival] curve.

In the exploratory analysis of patients with PD-L1 expression between 1% to 49%, it is not statistically significant. We were hoping that we would find some answer for this population of patients [with low PD-L1 expression], and there is some activity, but the OS is not statistically significant in the exploratory analysis. That became an issue for discussion.

Would you consider adding chemotherapy with pembrolizumab for this patient?

The KEYNOTE-407 trial was the hidden gem for squamous NSCLC, which was posted at the American Society of Clinical Oncology Annual Meeting last year.³Patients had stage IV disease with a good performance status. Their tumors were checked for PD-L1, and the patients were randomized 1:1 to chemotherapy with immunotherapy versus chemotherapy alone. After 4 cycles, they received placebo or continued with immunotherapy for a total period of 2 years. This is generally how long patients have been going [with their treatment]. Two years is generally considered the standard at this point in time. We do not know if we should go beyond it, but we do know that we should not go less than 2. There was a trial called CheckMate 153, which suggested that the 1-year PFS rate is lower if you give the treatment for more than 1 year.⁴If it should be more than 2 years is a matter of debate, but most of us will stop at 2 years. You can make an argument to continue, as well.

The KEYNOTE-407 trial showed a second interim trial with a median OS of 15.9 months for pembrolizumab plus chemotherapy versus 11.3 months with placebo plus chemotherapy. Chemotherapy with immunotherapy is now considered the standard of care for patients with squamous NSCLC.

The problem here is that that as the TPS increases, so does the outcome for those patients. If you look at the data so far, the maturity of the data do not suggest that giving chemotherapy with immunotherapy clearly makes a big difference in terms of patients’ OS. We do not know the data yet, but they will mature over time, and we will be able to get a better understanding. In the less than 1% and the 1% to 49%, we do not have any information regarding the benefits of immunotherapy on its own. There is clear evidence of benefit for survival when you combine chemotherapy and immunotherapy; however, our biggest issue is the OS data. This is now considered the standard of care; however, if the patient has a PD-L1 more than 50%, you can get away with just giving the patient immunotherapy alone. This is an iffy discussion, and it is somewhat of a subjective prognosis. We don’t know that adding chemotherapy makes the biggest difference in the world, but data do show that response rates will increase. The depth of their response is still unclear.

Would you consider additional testing for this patient to make your treatment decision?

We are not doing next-generation sequencing testing at our practice because we do not have enough targets to fully use it. The only circumstance where I will test is for patients with squamous NSCLC who are nonsmokers. This is also a part of the National Comprehensive Cancer Network guidelines.⁵In this case, my worry is that the patient’s tumor was not properly assessed. There are components where you have other considerations.

There are people who firmly believe in liquid biopsy, and the specificity for liquid biopsies is nearing 100%. If you are positive on the liquid biopsy, you can be sure that it is the right answer. However, if you have a negative report, the sensitivity is in the range of just 70%. It also depends upon what platform you are using. It is not a perfect test. I had a patient who was anALK-mutant progressor and I recommended that she get another biopsy; however, she did not want one. We decided on getting a blood test instead to see if I could pick up a mutation that I could then use when choosing a targeted agent. Sometimes, patients will resensitize or build a mutation that will not allow for 1 drug but will allow for another. I will do it in that scenario, but in general, I like to take tissue. That is my approach, but it is not necessarily the right approach, because there isn’t one currently. In general, most of us believe the standard is to do a tissue biopsy if the tissue has adequate cellularity.

Can you discuss the most current data for patients with nonsquamous NSCLC?

The IMpower150 trial discussed the use of a 4-drug regimen.⁶The study randomized patients with squamous NSCLC 1:1:1 to atezolizumab (Tecentriq) and carboplatin plus paclitaxel (arm A); atezolizumab, carboplatin, and paclitaxel plus bevacizumab (Avastin; arm B); or carboplatin, paclitaxel, and bevacizumab (arm C). It was [focused on the] arm B versus arm C comparison.

For the intent-to-treat (ITT) wild-type population—those who did not have anEGFRorALKmutation—there was clear evidence in OS, which was 19.2 months for arm B versus 14.7 months for arm C. If you add all the patients, including those withEGFRandALKmutation, the median OS was 19.8 months for arm B and 14.9 months for arm C. There is still benefit with this 4-drug regimen.

If you look at the subgroup analysis, this is where it gets interesting. TheEGFR-positive patients seem to have an OS benefit of not estimable for arm B versus 17.5 months for arm C, but the hazard ratio (HR) crosses 1. This was not an ITT analysis, and the FDA did not approve this group of patients to be treated with the 4-drug regimen. The label for atezolizumab in combination with carboplatin, paclitaxel, and bevacizumab is for patients who areEGFRandALKwild-type. However, there has been discussion that this is the only study suggesting that there is a possible benefit in terms of PFS and maybe even OS for these patients after progression. Many people believe that this is the regimen we should choose, whereas others don’t believe that there are adequate data for it. It depends upon how much of an early adopter you are as to how much you want to push it. In general, I will have a discussion [about it] with my patients.

The IMpower130 study looked at chemotherapy with carboplatin and nab-paclitaxel (Abraxane) plus atezolizumab versus carboplatin and nab-paclitaxel alone for patients with metastatic nonsquamous NSCLC.⁷Normally, we do not use a paclitaxel regimen, but that is what was done in this study. The 3-drug regimen suggests an improvement in PFS and OS. This application is sitting with the FDA right now. The problem, however, is the choice of chemotherapy. Normally, we use carboplatin-pemetrexed chemotherapy, but this is not what was done here. It may be that there is a benefit, but how much should we make out of it?

Case 2

A 63-year-old man presented to his primary care physician with intermittent cough and difficulty breathing on exertion and his past medical history later reveaeld hyperlipidemia, well managed on simvastatin (Zocor); hypothyroidism, managed on levothyroxine (Synthroid); chronic obstructive pulmonary disease, managed on inhalers. The patient had recently quit smoking but had a history of 40 packs per year. On physician exam, he was noted for intermittent wheezing and his ECOG performance status was 1.

His Creatinine clearance were within normal limits, but his chest CT revealed a 3.1-cm spiculated mass in the right upper lobe and 2 enlarged right mediastinal lymph nodes, 1 measuring 1.5 cm and 1 measuring 1.7 cm; moderate emphysema was also noted. His PET scan confirmed the lung lesion and mediastinal lymphadenopathy without evidence of distant metastases and his brain MRI was negative.

The patient underwent a pulmonary function test, which revealed forced expiratory volume in first second of expiration, 1.2; diffusing capacity of the lungs for carbon monoxide, 52%. Additionally, a bronchoscopy with transbronchial lung biopsy and lymph node sampling revealed adenocarcinoma with positive nodes in stations 4R and 7; level 4L was negative. His was staging T2aN2M0, stage IIIa. Based on the extent of mediastinal disease and emphysema, the patient’s cancer was deemed inoperable, and he was referred for consideration of concurrent chemotherapy and radiation.

What are your general impressions of this patient?

This is a 63-year-old man who has the usual problems that you would see with lung cancer. He has good functional status, as well as good kidney function. He has a 3.1-cm spiculated mass in the right upper lung and mediastinal lymph nodes that are positive. He has further evaluation for his brain function, and his brain MRI is good. Additionally, the pulmonary functions are somewhat adequate.

The patient has evidence of stage III disease, and the extent of the mediastinal cancer is deemed inoperable. In terms of treatment options, many people have strayed away from doing induction chemotherapy or chemoradiation for patients with stage III disease. However, with the advent of immunotherapy, that has changed.

Do you typically order genetic testing for locally advanced lung cancer?

The problem with ordering genetic testing is that you do not always know what to do with it. Additionally, the data we have are not sound, and we have to make decisions for patients where it makes a big difference for them, whether they take a pill for a year or more on immunotherapy. Additionally, these drugs obviously come with their own adverse events (AEs) and other problems.

If you choose to do genetic testing, genetic targets generally do not change even after the patient has been treated with chemotherapy or radiation. That may be different with PD-L1 status, because it is considered somewhat of a dynamic biomarker. In my practice, genetic testing is reflexed. If it goes out for testing and we have that data, we can keep it in hand. There is no way we would be losing out if we do the testing.

What are the options for treatment?

What happens in clinical trials does not necessarily translate into what happens in the community. That is one of the reasons why community-based stage III lung cancer trials are so hard to do—because the practice patterns are so varied. There is no standardized way of care.

He underwent therapy with cisplatin/etoposide and concurrent thoracic radiotherapy and follow-up imaging showed a partial response with shrinkage of the primary and nodal lesions.

Does the patient require further treatment after the patient achieves a partial response (PR)?

This patient receives cisplatin/etoposide and goes through radiation. He goes on to have a PR. That leads us to what we are doing at this point in time, which was the basis of the PACIFIC study.⁸The phase III trial consisted of stage III patients with advanced, unresectable disease with good functional status. They were randomized 2:1 within 6 weeks after chemoradiation to durvalumab or placebo. The primary endpoints were PFS and overall survival.

For patients treated with durvalumab, the median PFS was 17.2 months compared with 5.6 months with placebo. I do not understand why the median PFS is 5.6 months on the arm that is just getting chemoradiation. These patients are underperforming in terms of what we usually see, and we do not know why that is. Nonetheless, the patients were stratified and randomized well.

The important part of this trial is the 24-month OS rate, which was 66.3% in the durvalumab arm and 55.6% in the placebo arm.⁹The HR is 0.88, with a Pvalue of .005. The curves clearly separate and make a distinct impression in terms of OS benefit.

In the PACIFIC study, are there subgroups who benefited more or benefited less with durvalumab?

For patients with a PD-L1 status of 1% prior to chemoradiation, the PFS and OS HR crosses 1. That is why I believe this patient population should not receive durvalumab, but that is a matter of debate in this scenario, because the study was not statistically powered to look at that. Nevertheless, most of the HRs favor the use of intervention with immunotherapy.

Another interesting thing that this trial looked at was the patients who received chemoradiation within 14 days versus more than 14 days prior to the trial. The trial allowed up to 6 weeks before the administration of immunotherapy. The HR plots suggest that those patients who were treated with chemoradiation followed by immunotherapy on the clinical trial within 2 weeks seemed to do better. I’m not sure if there is value there, but this is something to discuss. If you can give a patient the immunotherapy sooner, this trial suggests it may translate to a better outcome. I give my patient the immunotherapy as soon as possible; however, it can be difficult after chemoradiation. Some people can do it, but they are not the majority.

References:

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2. Gilberto L, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS)>1%: open-label, phase 3 KEYNOTE-042 study.J Clin Oncol.2018;36(suppl; abstr LBA4). ascopubs.org/doi/abs/10.1200/JCO.2018.36.18_suppl.LBA4.
3. Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (chemo) with or without pembrolizumab (pembro) for patients (pts) with metastatic squamous (sq) non-small cell lung cancer (NSCLC).J Clin Oncol. 2018;36(suppl; abstr 105). meetinglibrary.asco/org/record/161684/abstract.
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7. Cappuzzo F, McCleod M, Hussein M, et al. Impower 130: progression-free survival (PFS) and safety analysis from a randomised phase 3 study of carboplatin + nab-paclitaxel (CnP) with or without atezolizumab (atezo) as first-line (1L) therapy in advanced non-squamous NSCLC. Presented at: 2018 ESMO; October 19-23; Munich, Germany. Abstract LBA_53.
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