Sanborn Covers Recently Presented Trials Supporting Immunotherapy in Frontline NSCLC


Rachel Sanborn, MD, recently discussed the treatment options and considerations she makes when treating patients with non&mdash;small cell lung cancer. Sanborn, director of Thoracic Oncology, Providence Cancer Center, explained her treatment decisions based on 2 case scenarios during a <em>Targeted Oncology </em>live case-based peer perspectives presentation.

Rachel Sanborn, MD

Rachel Sanborn, MD

Rachel Sanborn, MD, recently discussed the treatment options and considerations she makes when treating patients with non—small cell lung cancer (NSCLC). Sanborn, director of Thoracic Oncology, Providence Cancer Center, explained her treatment decisions based on 2 case scenarios during aTargeted Oncologylive 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 recently quit smoking but had 40-pack-year history. A physician exam showed intermittent wheezing and his ECOG performance status was 1. His creatinine clearance levels were within normal limits

A chest CT revealed 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 later confirmed the lung lesion and mediastinal lymphadenopathy without evidence of distant metastases. His brain MRI was negative.

A pulmonary function test was performed and revealed a forced expiratory volume in 1 second, 1.2; diffusing capacity of the lung for carbon monoxide, 52%. A bronchoscopy with transbronchial lung biopsy and lymph node sampling revealed adenocarcinoma with positive nodes in stations 4R and 7; level 4L was negative. He was later staged at T2aN2M0, stage IIIa. Genetic testing was negative for known driver mutations.

Based on the extent of mediastinal disease and emphysema, the patient&rsquo;s cancer was deemed inoperable, and he was referred for consideration of concurrent chemotherapy and radiation.

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

Previously I ordered genetic testing for these patients with locally advanced lung cancer. The primary goal is screening patients who would have been eligible for the RTOG clinical trial, which assigned patients to targeted therapies based upon EGFR/ALK rearrangements. It then looked at induction targeted therapy, followed by definitive chemotherapy radiation. I was previously ordering genetic testing for that reason. But, outside of looking for a clinical trial, and that study is now closed, I don't order genetic testing because it is not actionable per standard of care for these patients. It doesn't factor into the upfront treatment for stage III lung cancer.

What are the options for treatment?

In this patient situation, where there are multiple stations of lymph nodes involved, with good performance status, who is not a candidate for surgical resection, concurrent radiation would be considered the upfront standard of care. This would be followed by consolidation durvalumab as immunotherapy.

For a different patient than what we present in this slide, say a patient with a single mediastinal lymph node or a patient who otherwise has resectable disease, then one can think of either neoadjuvant chemotherapy or neoadjuvant chemoradiation. The data out there is a lot more controversial about that. And that would be followed by surgical resection. What is presented here is the cleaner, straight-forward case of a nonresectable patient in which concurrent chemoradiation has been shown to have superior survival outcomes to the sequential chemoradiation approach. That would then be followed by the consolidation immunotherapy.

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

Does the patient require further treatment?

The patient tolerated treatment well and was given one of the gold-standard regimens. He did have some response, and it actually wasn't mandated with the PACIFIC trial.1It was basically lack of disease progression. That early scan that was done was making sure the patient didn't progress through or have an early pneumonitis-type toxicity. The patient had a good start but, because of the PACIFIC study, he does require further treatment. He would then move next to consolidation immunotherapy with durvalumab (Imfinzi). As in the PACIFIC study, one year of durvalumab 10 mg every 2 weeks. And then, after that, they would go to monitoring.

Can you further explain the rationale for further treatment based on the PACIFIC study?

The PACIFIC study was a randomized phase III trial that was evaluating patients with unresectable stage III lung cancer who did not have progression after they finished their standard of care upfront treatment and still had a good performance status. The study then randomized those patients to either consolidation durvalumab for 12 months versus placebo. This is because the standard of care outside of a clinical trial is not further treatment, only monitoring. It was a 2:1 randomization in that phase III study.

The findings demonstrated improvement in progression-free survival (PFS) for patients who received consolidation immunotherapy with durvalumab. Median PFS was 16.8 month with durvalumab compared with 5.6 months with the placebo. It was a significant improvement, which also led to improvements in 12 and 18-month PFS. Even at the 18-month mark, PFS was 44% for patients who had gotten consolidation immunotherapy. That was only 27% for patients who had received placebo. This looks like an ongoing and durable improvement.&nbsp;

The overall survival (OS) data was not yet presented, but is expected to be presented fairly soon based upon a recent release saying that their OS endpoint was met. We will have to see what those numbers look like, but certainly the improvement in PFS is a promising thing. That change in the PFS is what led to the approval of durvalumab in the consolidation setting, and changed standard of care when this was presented last year.

Are there any other data supporting immunotherapy in the consolidation setting?

This was a nonrandomized phase II trial that was performed by the Hoosier Cancer Research Network (HCRN).2This was evaluating pembrolizumab (Keytruda) in the same setting. In this study, it was very similarly structured in that patients with stage III unresectable NSCLC received upfront concurrent standard of care chemoradiation were eligible to enroll. Again, with the same timing of imaging, those patients who did not have disease progression were able to enroll in study and then receive pembrolizumab, which is 200 mg flat dosing every 3 weeks for up to 1 year.

Basically, this is recapitulating the same regimen, but looking at a different immunotherapy. They had very similar inclusion criteria for the study and a very similar distribution of patient demographic overall. In this study, time to metastatic disease or death with pembrolizumab in this setting was 22.4 months. And PFS was 17 months. This is very similar to what we saw with the PACIFIC trial in terms of PFS. OS has not been reached yet.

How do the 2 trials compare to one another?

When they looked at the comparison, although you can't really do a full comparison in terms of which agent may be better or worse, is when you look overall at the studies. Between PACIFIC and the HCRN trial, both had duration of median follow up, the HCRN study was actually slightly longer. The time to metastatic disease or death with the immunotherapy were very comparable between the studies, so there wasn't glaring stand out of a different. PFS was also very comparable, including at 12 and 18 months. That study doesn't necessarily change in standard of care just itself. Again, this is a nonrandomized phase II study. But what it does support is that there is probably a concept of immunotherapy effective in the consolidation setting, that will have to be born out with further monitoring.

How do you follow this patient?

That is a little bit more controversial, because there is no clear proof in how patients are followed. If you ask different doctors, they may all have a slightly different plan. Our institution generally monitors patients with clinical examination every 3 months for 2 years after completion of therapy, with every 6-month CT scans. That is through year 2. That is then followed by every 6-month clinical examinations and yearly CT scans through year 5.

After that, one has to look at what the risk of a second primary malignancy is and whether one would consider discussing the risk and benefits of annual low dose screening CT scans, based on the National Lung Screening Trial (NLST) data.3Although, the NLST trial excluded patients who had a prior lung cancer. We know that it is a very high-risk population.

Some institutions may follow a patient less frequently. There is no single clinical trial to guide us and suggest that one particular follow up plan is the best one or improve outcomes. We don't have that. So, in general, that follow up has been developed based upon previous clinical trials.

Case 2

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

A 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, with the largest one 8 mm. PET/CT imaging showed 18F-FDG uptake in the lung mass, left hilar and both mediastinal lymph nodes, and thoracic spine (T5/T6).

A bronchoscopy and transbronchial lung biopsy were performed and pathology showed grade III squamous cell carcinoma; PD-L1 expression by immunohistochemistry 22C3, tumor proportion score of 65%. He was later diagnosis stage IV squamous non—small cell lung cancer.

What are your general impressions of this patient?

This is a fairly standard presentation of a patient with newly diagnosed metastatic lung cancer. The issue with this patient that throws a greater challenge into the case is that he has a diagnosis of an autoimmune disease. So, the autoimmune disease has been stable and not requiring treatment, but it does factor in as we think about how we need to pay attention to this in the immunotherapy area, when in the past if a patient just got chemotherapy we didn't necessarily care.

This is a good performance status patient who has metastatic stage IV disease and who pathologically was demonstrated to have squamous cell carcinoma. So, this patient had a higher tumor proportion score by the 22C3 testing, and PD-L status of 65%.

Are you routinely testing for PD-L1 expression in newly-diagnosed patients?

Yes. This is a standard of care test now, and has been for some time after the initial data was presented, which demonstrated that single-agent pembrolizumab improved outcomes for patients with PD-L high disease versus the patients with PD-L low disease when pembrolizumab was approved in the upfront setting. We routinely test at the time of disease for stage IV disease for PD-L1 expression.

What are the treatment options for this patient?

In general, one would consider either single-agent pembrolizumab versus thinking about chemoimmunotherapy. In the past, people would also think about pembrolizumab versus just chemotherapy. There are some interesting questions with this.

The patient was started on pembrolizumab.

Is there a potential role for radiation therapy to address his symptoms of dyspnea or back pain?

This question isn't one that has a lot of conversation. The response that any oncologist would have is that if they are experiencing bone pain, then palliative radiation while you&rsquo;re starting systemic therapy is indicated to help with quality of life. It doesn't improve survival.

In this patient who has what looks like very small volume disease in the lung, palliative radiation is not going to improve their breathing, their dyspnea. So, there wouldn't really be a beneficial role for palliative radiation in that setting.

What is the rationale for the choice of pembrolizumab for this patient?

Initially, the data from the KEYNOTE-024 study, which was randomized trial of pembrolizumab versus chemotherapy, compared our previous standard of care for patients with NSCLC, particularly squamous cell lung cancer.4It demonstrated that there was an improvement both in PFS, as well as OS with pembrolizumab compared with previous standard of care chemotherapy. It statistically significant for PFS, where PFS was 10.3 months with pembrolizumab versus 6 months of chemotherapy. The OS hadn't been reached in either arms.

This is for patients who had a high tumor proportion score, so PD-L status greater than 50%, so this is a selected population. The OS wasn't reached in either arm because many of those patients who had been randomized to chemotherapy upfront were then able to cross over and receive pembrolizumab after disease progression. Overall, treatment was well tolerated. Based on that study and the significant improvement in PFS, pembrolizumab was approved for patients with a tumor proportion score of 50% or higher with metastatic NSCLC.

Are there data to support the use of pembrolizumab for other patient populations?

At ASCO, the KEYNOTE-042 study was a randomized trial of pembrolizumab versus platinum-based chemotherapy.5It was a randomized phase III study in the same setting, but now with patients who had a P-DL status of at least 1%, not 50%. In this study, cross over was not allowed. Patient with stage IV lung cancer were randomized in a 1:1 fashion to pembrolizumab versus chemotherapy. That study showed that there was improvement in OS as well for patient receiving pembrolizumab upfront, versus chemotherapy.

In subset analysis, the bulk of that benefit was in patients who had a tumor proportion score of at least 50%, whereas patients who had a tumor proportion score that was lower, the OS was not significantly different and the hazard ration crossed 1. So, the weight of the benefit for the entire trial was those patients who had a tumor score of at least 50%. That helped to support further for patients such as this, who had a tumor proportion score of 55%. Pembrolizumab, as a single agent, would be better than chemotherapy and would be the preferred regimen.

Are there data to support the use of combination pembrolizumab?

The KEYNOTE-407 study was a very important study that was presented at ASCO this year.6And this was specifically for patients with squamous cell lung cancer. This, in addition to the IMpower131, that looked at specifically squamous cell lung cancer patients for whom we have not had chemoimmunotherapy before.7

The was a randomized phase III study and evaluated either standard of care chemotherapy versus chemoimmunotherapy with pembrolizumab. The patients who received standard of care chemotherapy were able to cross over to pembrolizumab at the time of disease progression. Additionally, enrollment was not based on any level of PD-L1 expression, so this allowed patients regardless of tumor proportion score.

The study demonstrated improvement in OS for patients receiving pembrolizumab in combination with chemotherapy. Chemoimmunotherapy for patients with squamous cell lung cancer had a median survival of 16 months versus 11.3 months on chemotherapy alone. That benefit extended across different subgroup analyses. When they looked at the tumor proportion score, the benefit of chemotherapy in combination with pembrolizumab was there for patients who had a high tumor proportion score, as well as patients with low tumor proportion score. The patients with greater than 50% PD-L1 expression did not reach statistical significance, even though there was impressive survival in both groups. That is because t the patients were allowed to crossover to pembrolizumab, in which case the chemotherapy arm is going to do much better than we would think as a standard comparison.

Are there additional immunotherapy agents that are currently being studied?

In similar fashion, the IMpower131 trial was a similar study of patients with squamous NSCLC who were then evaluating the addition of atezolizumab (Tecentriq), an anti-PDL1 therapy, versus chemotherapy. This study split the chemotherapy arms apart from each other to evaluate whether or not there is a difference between paclitaxel versus nab-paclitaxel with atezolizumab. The control arm was carboplatin plus nab-paclitaxel.

There was improvement in PFS with the addition of immunotherapy to the chemotherapy. The PFS was 6.3 months versus 5.6. This benefit was shown to be consistent across all levels of PD-L1 expression, although it lost statistical significance for the lowest population. The OS did not reach significance at its current analysis, but there is another analysis pending to see whether the tails on the curve eventually separate and improve outcomes. We do see an improvement when one heads to the 2-year mark with the addition of atezolizumab with chemotherapy. Whether that is going to be enough to say that would make people more excited than pembrolizumab in that population setting, probably not. But we&rsquo;ll have to see what the numbers look like.


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  2. Durm GA, Althouse SK, Sadiq AA, et al. Phase II trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179.J Clin Onc. 2018;36(suppl; abstr 8500).
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  6. Gandhi L, Rodriguez-Abreu D, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer.N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005.
  7. Jotte RM, Cappuzzo F, Vynnychenko I, et al. IMpower131: primary PFS and safety analysis of a randomized phase III study of atezolizumab + carboplatin + paclitaxel or nab-paclitaxel as 1L therapy in advanced squamous NSLC.J Clin Oncol. 2018;36(suppl; abstr LBA9000).
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