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Immunotherapy and Chemotherapy Combos Are the New Standard of Care for NSCLC, Says Konduri

Publication: Targeted Oncology

Kartik Konduri, MD, recently spoke on the treatment considerations and decisions he makes when treating patients with non–small cell lung cancer (NSCLC). Konduri, medical director of the Chest Cancer Research and Treatment Center, Baylor University Medical Center, explained his treatment decisions based on 2 case scenarios during a Targeted Oncology live case-based peer perspectives presentation.

Case 1

A 63-year-old man presented to his primary care physician with intermittent cough and difficulty breathing on exertion. His past medical history showed hyperlipidemia, well-managed on simvastatin (Zocor); hypothyroidism, managed on levothyroxine (Synthroid); chronic obstructive pulmonary disease, managed on inhalers. He had a 40-pack-year smoking history, but recently quit. A physical exam was performed and showed intermittent wheezing, but he had an ECOG performance status of 1. His creatinine clearance levels were within normal limits.

A chest x-ray revealed opacity in the lung right upper lobe and a chest CT showed a 3.1-cm spiculated mass in the right upper lobe and 2 enlarged right mediastinal lymph nodes measuring 1.5 cm and 1.7 cm; moderate emphysema noted. A PET confirmed lung lesion and mediastinal lymphadenopathy without evidence of distant metastases. His brain MRI was negative.

A bronchoscopy with transbronchial lung biopsy and lymph node sampling revealed adenocarcinoma with positive nodes in stations 4R and 7; level 4L was negative. Genetic testing was negative for known driver mutations. He was staged with T2aN2M0, stage IIIa.

What are your general impressions of this patient?

This is a 63-year-old patient who has a mass in the lung and a few lymph nodes in the mediastinum. This is not uncommon; we see this quite a bit. Most of these patients have a long-term history of smoking. The patient is in good functional status, which allows us to be able to treat this type of patient with the most aggressive measure possible. So this is a patient that fits with what we see in the general population, and I see it very often.

What are the options for treatment?

Until recently, treatment of stage III lung cancer has been challenging in terms of different treatments based upon small pieces of data. Not many large randomized trials have been done. In the past, stage III patients were treated with induction chemotherapy followed by surgery based upon some smaller trials.

Then a larger intergroup trial suggested that there could be benefit with chemotherapy and radiation concurrently followed by surgery. That benefit seemed to be somewhat restricted to a small subset of patients who were evaluated in an unplanned exploratory analysis to show that a lobectomy could improve outcomes after chemoradiation. However, the standard of care for a patient with stage III lung cancer and large volume mediastinal disease has been chemotherapy and radiation given concurrently with definitive intent. In some institutions a [patient with] small-volume mediastinal disease is treated with chemotherapy and radiation up front followed by surgery.

With the advent of the data from the PACIFIC trial, this has changed.1 Many institutions now routinely use chemotherapy and radiation followed by consolidation immunotherapy for a patient like this.

The PACIFIC trial was well-conducted. They allowed for patients with stage III disease who had gotten chemotherapy with radiation, at least 2 cycles of platinum-based chemotherapy. The trial allowed different types of treatment realizing that not one particular type of chemotherapy regimen is given for everyone in stage III NSCLC. Within 1 to 6 weeks after finishing the chemoradiation, patients were randomized to durvalumab (Imfinzi) versus placebo in a 2:1 fashion.

The patients were treated for a total of 12 months. These patients should have had stability of disease or improvement after completion of chemoradiation. Of course, they also collected optional tissue to look for biomarkers, including PD-L1 status.  This study also included a small portion of patients with EGFRmutations.

The co–primary endpoints were progression-free survival (PFS) and overall survival (OS). They reported the PFS and published it, but the OS data has not yet been reported. Although there was some release of information recently, stating that the OS endpoint has also been met. We are waiting to hear the specific details about the magnitude of OS benefit. It is always good to see a confirmation of OS benefit in such trials and it validates our change of practice.

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 radiotherapy. He underwent therapy with cisplatin/etoposide and concurrent thoracic radiotherapy.

Follow-up imaging showed a partial response with shrinkage of the primary and nodal lesions.

What are your general impressions of this patient after he was treated with chemotherapy and radiation?

It looks like the patient was evaluated, and they found a couple of lymph nodes in the mediastinum. The patient underwent what is considered a standard therapy, with cisplatin/etoposide, along with concurrent radiation. He had somewhat of a partial response and shrinkage of the primary disease and the lymph nodes. This is what we hope and expect, that the patient does not have progressive disease after starting the induction chemotherapy and radiation regimen. 

Currently, this is where we would try additional therapy. As I mentioned before, some institutions, based on the volume of mediastinal disease, would have or might still be doing surgery afterward. But that is sort of the minority, especially if one has large-volume mediastinal disease. If the patient has a good response and has had resolution of adverse effects (AEs) from the chemotherapy/radiation, many of us would now give maintenance immunotherapy for a period of 1 year.

At this point in time, there is only 1 choice of immunotherapy, durvalumab, based upon FDA approval. None of the other immunotherapies have been studied in a large-trial setting.

Case 2

A 59-year-old Caucasian man presented with symptoms of chest pain, cough, and dyspnea. His past medical history revealed hypertension, managed on a calcium channel blocker; and osteoarthritis. He was a former smoker with a 10-pack-year history.

A CT of the chest and abdomen showed a 9-cm spiculated mass in the left lower lobe, a loculated pleural effusion in the left hemithorax, diffuse liver nodules, and right adrenal metastases. His PET/CT showed 18F-FDG uptake in the left lung mass, pleura, liver, and right adrenal gland. His brain MRI was negative for intracranial metastases.

His physical exam was notable for decreased breath sounds in the left lung base; no hepatomegaly and he had an ECOG performance status of 1. Cytopathologic examination of pleural fluid was positive for malignancy. Image-guided biopsy of the liver lesion showed a poorly differentiated adenocarcinoma of the lung.

With regards to molecular testing, next-generation sequencing (NGS) was negative for EGFRROS1BRAFALK gene rearrangement, METand HER2. His immunohistochemistry showed PD-L1 expression in 2% of cells.

What are your general impressions of this case?

This patient has a large mass in the lung and has had work-up done to confirm metastatic disease.  Findings of metastases including in the pleura, the liver, and the right adrenal gland are noted. These are common sites of metastases for lung cancer. We routinely do PET scans and MRIs on the brain for staging work-up. To see this type of presentation is fairly common.

What type of molecular testing would you do for a patient such as this?

The question is whether there is a chance that one can treat the patient with an effective targeted therapy. In this evaluation, next-generation sequencing for targeted therapy was conducted. Many newer targets are also now being evaluated by NGS testing; some of them include TRK, RET fusions andmutations, etc. Additionally, evaluation for PD-L1 expression, as was done in this case, is what I would consider standard of care. This patient scenario is what we would see in a real-life setting.

What are the goals of therapy for this patient?

Even though we have exciting new therapies, including molecular and immunotherapy treatments, unfortunately the goal of a cure for all is yet to be achieved. Currently, our goal is to try to make this disease more of a chronic situation, where we can help improve survival, quality of life, and functionality of the patient by selecting an appropriately directed therapy.

What are the treatment options for this patient?

The molecular markers for this patient were found to be negative; the ones that significantly stand out are EGFRROS1BRAF, and ALK gene rearrangements. Molecular therapy is unfortunately not beneficial for a person when testing does not show a target. 

This patient has 2% PD-L1 tumor proportion score. This expression is considered low. Anything over 1% for PD-L1 is considered to be positive but not strongly positive (which is greater than 50%).

In this scenario, we need to consider some form of therapy that utilizes chemotherapy with immunotherapy, given the latest data that has been published and presented recently.

What are some of the data that support this decision?

KEYNOTE-189 was a very well-done trial.2 It is a phase III trial that utilized patients who had metastatic nonsquamous NSCLC cancer stage IV disease. They did not allow EGFR- or ALK-positive patients. This was a frontline trial.

One of the standard chemotherapies for good functional status patients with metastatic nonsquamous NSCLC is a pemetrexed/platinum-based doublet. This was what they utilized, either carboplatin or cisplatin, along with pemetrexed. They then combined the chemotherapy with pembrolizumab (Keytruda) for the study arm versus placebo for the observational arm. 

Patients were allowed to continue on pemetrexed maintenance. For the study arm, pemetrexed was combined with pembrolizumab. The observation arm just had pemetrexed and placebo. There was crossover allowed for pembrolizumab to be utilized for patients who had taken pemetrexed only, on the observation arm.

The primary endpoints were robust with OS and PFS. They stratified for patients who had PD-L1 expression less than 1% or more than 1%.

The study was designed based on a prior phase II trial, which had shown promise, KEYNOTE-021. In this trial, there was no comparative arm, and it was a much smaller study. So the phase III trial provided proof and confirmation to the findings of the smaller phase II study.

What would your choice of second-line therapy be if this patient progressed?

That is the challenge for many of us at this time. After utilization of all our effective lines of therapies up front, we do have concerns [about] what one could use afterwards. Many times, we would have to resort to standard chemotherapies, probably a taxane- or gemcitabine-based treatment. A clinical trial would have high utility in this setting.  As we know more about our targets and immunotherapies, many other exciting clinical trials are becoming available.  Finding such a treatment could be the best fit for many of our patients.

Are there any additional data that you are excited about regarding immunotherapy in NSCLC?

Immunotherapy in combination with chemotherapy has now become a standard of care, not just for metastatic nonsquamous NSCLC but also for squamous cell NSCLC.  This is based on recent data from the KEYNOTE-407 that was presented at the 2018 ASCO Annual meeting.

I think this is an exciting time where we have newer and better options for our patients who can potentially get significant benefit, even if their tumor PD-L1 expression is not strong. We knew that strong PD-L1 was a marker for a good benefit from these drugs. There is some data from KEYNOTE-042 suggesting that there may be benefit for patients with low PDL1 expression, with single-agent pembrolizumab.3 There are some caveats from this trial, nearly 50% of the patients on that trial had higher than or equal to 50% expression of PD-L1, which may have skewed the overall results.

The take home point is that many more patients with metastatic NSCLC whose PD-L1 expression is not strong enough, can qualify for immunotherapy treatment when combined with chemotherapy.  Stage III patients may benefit from immunotherapy after chemoradiation. This may result in an improvement in outcomes for patients with NSCLC.

Read the full story at Targeted Oncology.

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