Konduri Considers Alternatives to Surgical Resection in a Patient With Stage III NSCLC

Kartik Konduri, MD

Kartik Konduri, MD

Kartik Konduri, MD, discussed with a group of physicians in a recentTargeted Oncologylive case-based peer perspectives presentation the diagnostic workup and treatment considerations he makes when he sees a patient with non—small cell lung cancer (NSCLC) in the clinic. Konduri, the co-medical director of the Lung Cancer Center of Excellence at Charles A. Sammons Cancer Center, Baylor University Medical Center in Texas, explained his treatment decision making based on the case scenario of a patient with locally advanced NSCLC.

Case

A 63-year-old man presented to his primary care physician with intermittent cough and difficulty breathing on exertion. He had a medical history of prior hyperlipidemia, which was well managed on simvastatin; hypothyroidism, which was managed on levothyroxine; and chronic obstructive pulmonary disorder that was managed on inhalers. He recently quit smoking and had a 40-pack-year history. On physical exam intermittent wheezing was noted and he had an ECOG performance status (PS) of 1. His creatinine clearance was within normal limits.

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 was also noted. A PET scan confirmed a lung lesion and mediastinal lymphadenopathy without evidence of distant metastases. A brain MRI was negative for brain metastases.

A pulmonary function test (PFT) demonstrated a forced expiratory volume in 1 second of 1.2 L and a diffuse capacity of the lungs for carbon monoxide of 35%. 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 diagnosed with NSCLC 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.

Targeted Oncology™:What is your thought process as to what is deemed as malignant disease and what is deemed as a tumor that can be resected?

Konduri:Many times, the thoracic surgeon feels as if anything is possible to be operated on. Of course, we try to put some brakes on that. Often, when you see these patients, they have already been operated on, and their pathological status is there are 4 lymph nodes in the mediastinum that are positive and now you are thinking, “How did that happen?” It does happen, and that brings us to the issue of how we treat these kinds of patients.

I feel that neoadjuvant chemoradiation has gone down, in terms of my experience. Things have changed, and now we have neoadjuvant immunotherapy trials. But what has happened is that our surgeons have become a little gunshy because we have been bombarding them with this thought process about backing off [of surgical therapy in] patients with stage III disease, or those patients with bulky lymph nodes and multistation lymph nodes, without having to go through surgery.

Neoadjuvant chemoradiation followed by surgery was exam­ined in INT-0139 [NCT00002550], and that was the standard circumstance that went along as one goes about over a period of time and looks at the clinical trial data.¹There is a suggestion of benefit, but the curves do not vary significantly, especially in circumstances where you end up with a major surgery like a full pneumonectomy. It has become more complicated. Every one of us understands that there is not 1 correct answer.

The intention of surgical resection with a large volume of tumor only happens at large-volume centers with neoadjuvant chemoradiation. Many surgeons do not want to go past 45 Gy, but now many surgeons are used to doing it after 60 Gy of radi­ation and then can proceed and do surgical intervention. I agree that multinodal disease is very difficult to clear and the down­staging is partly there, but it does not completely take care of the problem in stage III disease.

Targeted Oncology™:What are the chemotherapy options for the neoadjuvant and adjuvant settings?

Konduri:The various possible options are listed in the National Comprehensive Cancer Network [NCCN] Clinical Practice Guidelines.²I would be surprised if the top 3 options, [which involve cisplatin plus vinorelbine at different dose levels], are ever used as neoadjuvant therapy in this country when given either by themselves or with radiation. Those are not things we generally use in the United States. Even in the case of cisplatin plus gemcitabine, I do not know how many people use this at any point in time. But of course, pemetrexed [Alimta] has been utilized, and cisplatin plus etoposide is a very common regimen that we know about.

There is debate on whether or not you need to give [chemother­apy] consolidation with these treatments in smaller doses. It was the norm to consider it, and you can discuss that ad nauseam but given the advent of immunotherapy, things have changed.

Case (continued):

The patient underwent therapy with cisplatin plus etoposide and concurrent thoracic radiotherapy. Follow-up imaging showed a partial response (PR), with shrinkage of the primary and nodal lesions.

Targeted Oncology™:What would be the next step for this patient?

Konduri:The patient goes on for treatment with cisplatin plus etoposide and has a PR to treatment. Do you stop here or not? Let us say the patient has multinodal station disease or both a tumor disease and stage III. Let us say surgery is not a consideration. I am considering durvalumab [Imfinzi] because that is the only agent that is approved in stage III disease. It is the standard of care.

Targeted Oncology™:What is your reasoning behind treating this patient with durvalumab?

Konduri:In our world, medical oncology changed for the stage III disease with the PACIFIC trial because it brought in immunotherapy for this setting.^3,4Nothing has been very significantly established as a steadfast standard for stage III disease. Patients in this group had median survivals of 20 to 25 months, and essentially would have progression [of disease] in 10 to 11 months.

The PACIFIC trial came along [and] gave patients with stage III disease treatment with durvalumab after treatment with chemo­radiation. They could have any chemoradiation, but they had to have 2 cycles of platinum-based chemotherapy. They did not specify which 2 cycles it was. [In the total cohort, 26.8%] of patients had induction chemotherapy, but the majority had just chemoradiation. They were then randomized 2:1 to either durvalumab or placebo. The coprimary endpoints were progres­sion-free survival [PFS] and overall survival [OS].

I have not seen a trial [that] has been published twice in theNew England Journal of Medicine; this was published in 2017,⁴and then it was published again in 2018.4 One behind the other, the same trial with an update. That is amazing. The fact that they would allow that to be published twice…The first part was the section about the PFS data, and the second part was the update on the OS data.

The update for PFS was similar to that seen in the first published report, with a median of 17.2 months with durvalumab versus 5.6 months with placebo [HR, 0.51; 95% CI, 0.41-0.63].4 I have always had a concern as to why 5.6 months is kind of low. In general, we do not expect our patients to relapse or progress within 5 months. The data show median PFS is about 10 to 12 months; that is basically what it is. If you look at the studies from the Hoosier Oncology Group, where they followed chemoradia­tion with consolidation docetaxel or not, even in the observation arm, the median PFS is approximately 10 to 11 months.⁵So having 5 to 6 months for PFS was a little bit surprising to me. But someone told me that one of the considerations that could have been censoring events were that the data [were] collected after the patients had chemoradiation completed, and then they collected the data for PFS.

Targeted Oncology™:Would you treat histological subgroups differently with another agent?

Konduri:There was a subgroup analysis of the patients with squamous-cell and nonsquamous-cell disease. The patients did OK. There [are] not very good data in patients withEGFRmutations right now. If you look at the label, it does not clarify that patients withEGFRorALKmutations should or should not get immunotherapy in stage III disease. Right now, there is no such labeling, and the reason is that it was never meant to be a consideration. But if you look at the break-up of these patients in the mutant [EGFR] popula­tion, the hazard ratio is not very significantly strong [HR, 0.76]. And it goes with the fact that immunotherapy for patients with targeted tumors does not do a whole lot of good on its own. Is that really the case here, we do not know.

Targeted Oncology™:What is significant about the OS data that came out in the most recent publication of the results?

Konduri:This is the second issue that came up in the second publication in theNew England Journal of Medicine, [and it] is that the land­mark analysis of [the] 24-month rate of OS was 66.3% versus 55.6% in patients taking durvalumab and placebo, respectively. Those are the current data as is, and we will probably get more on that as the time goes along. That is the difference between the outcomes as we know it now.

That difference is significant because of the issue I raised about the 5.6-month median PFS. The average outcome for median OS is anywhere between 22 to 27 months in patients with stage III disease, and you give or take a few months this way or that way, at least it does not seem to be failing. The placebo-based arm, even though the placebo does not have a good PFS [in PACIFIC], at least it does not seem to be doing any worse than I would generally see in terms of standard-of-care treatments.

Clearly, durvalumab is the standard of care at this point in time as far as consolidation, provided the patient can take an immunotherapy drug. Essentially, that is what changed for us in terms of talking to our surgeons. If you have a single station <2 cm, or tops 3 cm, or if the mean tumor is invading into the mediastinum that has become stage III, technically that is some&shy;thing that if you give chemoradiation and you can get it away from the mediastinum, maybe you could operate on it. That might be a consideration, but the standard bread-and-butter stage III disease is not resectable. We can tell our surgeons that we are not sure that surgery helps these patients and at least we now have something else to offer.

Targeted Oncology&trade;:How long are you willing to wait after radiotherapy before starting immunotherapy?

Konduri:Originally, the way the trial was designed was patients had to start within a few weeks. Then there was a big issue with the trial because some community doctors [had trouble] getting patients who are basically in the middle of chemoradiation to come in and do immunotherapy. So they said, &ldquo;OK fine, 6 weeks.&rdquo; It was a protocol amendment. I remember this when we [were] doing the trial that it changed from 2 weeks to 6 weeks and they allowed incorporation. They did capture some patients who were randomized in <14 days and the others who were randomized beyond that, and it seems like there is a shift in the hazard ratios toward a benefit that seems to be present for patients who are randomized in <14 days [HR, 0.39] compared with those &ge;14 days [HR, 0.63]. This is some kind of abscopal effect that is happening during the active period of time, when the patient is having a benefit of the chemora&shy;diation that is drawing the tumor then releasing the antigens and that [the antigens] are priming the immunotherapy. That is theoretical. I do not know if we exactly know. This is an inter&shy;esting piece of data.

Targeted Oncology&trade;:What are the adverse events (AEs) associated with durvalumab treatment?

Konduri:In this particular trial, if one looks at it, it was not like the patients who were coming off treatment [were doing so based upon] significant problems from the treatment. Anything leading to discontinuation occurred in 15.4% of the durvalumab-treated patients and 9.8% of those on placebo. There were many patients who were progressing during treatment and a whole bunch of them came off because of progression of disease, but it was not related to AEs. There were some grade 3/4 AEs in comparison to the placebo arm, but in general, there were no major problem [with this agent].

Durvalumab made it into the latest version of the NCCN guidelines as a category 1 recommendation after concurrent chemoradiation as consolidation therapy.²In general, you should not be using the additional 2 cycles of chemotherapy if the patient has not received the full dose of chemoradiation.

Targeted Oncology&trade;:In the community setting, how many patients are able to complete chemoradiation and are eligible for durvalumab?

Konduri:If anyone was taking more than 10 mg of prednisone, they were excluded. Generally, that is what the immuno-oncology exclu&shy;sions are. I draw a line if the person is having a major autoim&shy;mune disorder that is necessitating an active disease-modifying agent. This is not stage IV disease where you have no other option. But if you have a patient who has psoriasis on the edge of the joint or another area on the skin, you can have a discus&shy;sion with them. I feel the same with rheumatoid arthritis. But if the patient has active lupus with nephritis, that might be a patient we do not treat with durvalumab.

References:

1. Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non—small-cell lung cancer: a phase III randomised controlled trial.Lancet. 2009;374(9687):379-386. doi: 10.1016/S0140-6736(09)60737-6.
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non—Small Cell Lung Cancer, Version 4.2019—April 29, 2019. NCCN website. nccn.org/professionals/physi&shy;cian_gls/pdf/nscl.pdf. Accessed May 3, 2019.
3. Antonio SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemora&shy;diotherapy in stage III non—small-cell lung cancer.N Engl J Med. 2017;377(20):1919-1929. doi: 10.1056/NEJMoa1709937.
4. Antonio SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC.N Engl J Med. 2018;379(24):2342- 2350. doi: 10.1056/NEJMoa1809697.
5. Jalal SI, Riggs HD, Melnyk A, et al. Updated survival and outcomes for older adults with inoperable stage III non—small-cell lung cancer treated with cisplatin, etoposide, and concur&shy;rent chest radiation with or without consolidation docetaxel: analysis of a phase III trial from the Hoosier Oncology Group (HOG) and US Oncology.Ann Oncol. 2017;23(7):1730-1738. doi: 10.1093/annonc/mdr56