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Medicine Matters oncology

Hello, I'm Jessica Donington. I'm Professor of Surgery at the University of Chicago and the chief of the section of general thoracic surgery. I'm a lung cancer surgeon specialist.

When I think about what information I need when making a decision for patients with newly diagnosed early-stage lung cancer, it really starts with staging. I need a CT scan. I need a PET scan. I need to know that I have resectable disease.

Once I've determined the risk for mediastinal nodal involvement, and if that risk is substantial due to tumor size or location, then I also need mediastinal staging. Again, I want to get a really good idea of what the patient's stage is before I start.

The next things I need are assessments of patients physiologically. Lung cancer is a disease of the elderly. It's a disease frequently seen in patients with smoking-related comorbidities, so I almost always need pulmonary function tests, frailty assessments, and a little bit of an understanding of their overall health.

Once I've gotten to that point, I'm at a point when I can make a decision as to, is this patient a surgical candidate? And then the next question is, is surgery the next best first step in their care?

When I think about key biomarkers for early-stage treatment decisions, this is kind of a whole new area now. For most very early-stage patients with stage IA lung cancer, there really isn't a need for extensive biomarker testing. Surgery is the standard of care. And there is not an indication for adjuvant therapy, be that chemotherapy, targeted therapy, or immunotherapy.

Once we start to move into later stages, IB, II and IIIA, we have a much greater consideration for the need of tissue-based biomarkers prior to starting therapy. With the approval of immune checkpoint inhibitors plus chemotherapy for that stage of disease, I think our medical oncologists would be interested in knowing things like PD-L1 status, EGFR, and ALK prior to starting therapy. For patients who are going to start with resection, there is less of a need to know that from small biopsies. But from patients who are going to receive induction therapy prior to resection, that's information we will need off of small biopsies.

In patients who go to the operating room first and then are being considered for adjuvant therapy, biomarkers are essential now, with the ADAURA data demonstrating a significant benefit to the use of osimertinib in EGFR-positive patients and with the IMpower010 and PEARLS data demonstrating adjuvant immunotherapy is useful after chemotherapy, again, we want to know PD-L1 status, EGFR status, and ALK status prior to taking on treatment.

Outlining the evidence in terms of adjuvant and neoadjuvant immunotherapy-- so we've entered this incredibly interesting time right now. We have so many different options for our patients. And surgical care is fitting in in whole new ways, to the medical oncology side, in terms of adjuvant and neoadjuvant approaches.

The first introduction of immunotherapy into the surgical population was in the adjuvant setting and the data from the IMpower010 trial. This was a large randomized trial, which took completely resected patients with stage IB through IIIA disease. They underwent resection and then adjuvant chemotherapy, and then were randomized to receive year of atezolizumab versus placebo.

And there was an impressive improvement in disease-free survival for patients who received atezolizumab compared to placebo. That response was greatest in patients who were PD-L1-positive and really quite impressive in those who had PD-L1 expression greater than 50%. There was FDA approval in the United States granted for patients with resected II to IIIA disease that was PD-L1-positive We're still waiting for overall survival benefits and more information from this trial. I think a lot of us are curious as to what might happen in the IB population and in those with PD-L1 status 1 to 49.

Recently, there was PEARLS data which was presented at ESMO, which took a very similar approach, but used [pembrolizumab] instead of atezolizumab. The results were a little surprising and difficult for me to fully understand. But the very impressive and significant survival advantage, which was seen in the IMpower trial for the patients with PD-L1 greater than 50%, really wasn't seen. Overall, patients had a survival improvement with [pembrolizumab].

But that greater than 50% population, the survival advantage was quite small and didn't really seem to reach the same type of statistical significance. So it's a little confusing. Is this trial design? Is this patient selection? Is this the antibodies we test with? I don't know. But I think it may have introduced more questions than it answered.

So that's currently the evidence in terms of adjuvant immunotherapy. And we expect more trials to report out in the near future. There are at least three more worldwide we should see.

On the neoadjuvant trial, the main trial we've been looking at and which has garnered the most enthusiasm is the CheckMate 816 trial. This took a similar patient population, patients with resectable IB to IIIA lung cancer. And they were randomized to receive either three cycles of platinum-based chemotherapy or three cycles of platinum-based chemotherapy plus nivolumab.

They have reported their results at AACR last year, and then again this year, and at ASCO. And we've gotten little bits of the results as we go. At AACR in 2021, they reported their path CR rates. And they saw a dramatic, a nearly 12-fold increase in pathologic complete response with the addition of nivolumab to chemo from 2% to 24%.

At ASCO, we received surgical endpoints. So how did the surgery go? How many patients went to surgery? Were there increased complications? Were surgeries harder? And what we found was that, actually, it looked like surgery was at least as safe as chemotherapy alone, with the addition of nivolumab, and maybe even easier, although there was not a lot of statistically differences between the two populations.

And then finally at AACR this year and in their New England Journal publication this year, we got the event-free survival. And what we've noted is that there is a significant improvement in event-free survival at 2 years with the addition of nivolumab to chemotherapy alone. While we saw this benefit in all subsets, it was most pronounced in patients with IIIA disease, patients who were PD-L1-positve adenocarcinomas, so not surprising subset where we would expect to see those differences. But it is also an important trial because it really is one of the largest in lung cancer, where we may be able to correlate event-free survival with path CR, as we look for ways to move our trials-- our agents into care sooner.

That's kind of where we sit right now. Now we expect to hear there are many more trials to be reported in this short-term future. Many of those going forward look at immunotherapy in combination with chemotherapy and do so in a perioperative setting, getting both adjuvant and neoadjuvant therapy. And the newest realm of trials is looking for new agents to combine with the immune checkpoint inhibitors, be that things like SBRT or TIGIT to further path CR and long-term survival.

It is important to note that none of these trials to date have reported overall survival. All of the survival endpoints are disease-free survival or event-free survival. This has caused some in the community to have hesitation about really adopting this as the standard of care. But I think when we see the dramatic hazard ratios that we see in stage III, there is little reason for us to be hesitant about adding neoadjuvant immunotherapy or adjuvant immunotherapy to our patients, especially because of its really good toxicity profile.

Are there unmet needs in early-stage lung cancer? There's lots of unmet needs in early-stage lung cancer. We are still a disease that does not see the survival we would like. Even for our earliest stage patients, we can only quote them survivals of 80% to 90% following complete resection. So I think we have a long way to go in terms of improving our overall survival.

I think there is a need right now to try and attempt to identify populations within stage I, be it IA or IB, where adjuvant therapy or neoadjuvant therapy would be useful. Right now, there's no indication in IA and a very limited indication in IB. But really identifying those patients at risk for recurrence would help in moving adjuvant and neoadjuvant therapies to that group of patients. That could be things like genomics, cancer genomics, proteomics, things like that, information from the tumor itself, or looking for microscopic residual disease in terms of circulating DNA and such.

I think we also probably need a more targeted approach to our patients with stage II and stage IIIA. Right now, everyone kind of gets this universal look. But the reality is we should be able to use biomarkers within the tumor to better tailor which approach we take.

I think we are all anxious to maybe see a little more overall survival data to help us understand for those IB and II patients which approach is it better. Will it be adjuvant or neoadjuvant therapy? But I think for the IIIA, we are-- the neoadjuvant approach will stay as what is popular. But I think there's lots of unmet needs. And we're going to spend probably the next 10 to 15 years looking for careful ways to combine our current therapies and to be moving more targeted agents into earlier stage disease.

What ongoing trials am I excited about? So I think, like I said, I'm excited about trials that bring more agents into earlier stage disease. And I'm really excited about those which use other things than chemotherapy to prime the immune system and to present antigens. So there's a lot of excitement over using things like SBRT with immune checkpoint inhibitors as possibly a less toxic and more efficacious way to do antigen presentation and really prime the immune system to work well with the immune checkpoint inhibitors.

And again, I'm super excited. There are some early-stage trials, which will use ctDNA to help pick which patients should go on to additional therapies after surgery. So I think those are very exciting.

So as we move into this era of immune checkpoint inhibition and adjuvant in both the neoadjuvant and adjuvant setting, I think surgeons have a big role to play. And I think that role starts at the initial presentation to a patient in your clinic. We no longer accept that surgery alone is curative for most patients with IB through IIIA disease.

We represent a portion of the treatment, but we do not represent all of it. And as such, we really have an important role to play in appropriately executing these therapies. It starts with, one, educating our patients.

We can no longer go in and tell a patient, oh, I got it all or it's all taken care of. The reality is I think you have to set the plate for them very early that surgery is one part of their treatment. But the reality is we can improve their chance for long-term survival by combining surgery with other therapies.

Two, we have to be very careful about our biomarkers. We have a very important role in making sure that we get all the information needed from a tumor upfront. And that requires us to be engaged and to recognize what we need from resected specimens early, and not have someone be delayed by weeks to months because we didn't order the appropriate tests.

I think it's also really important now that we're not seeing ourselves as the only treatment option for our patients, but just as part of a larger treatment plan, that we have to really be very careful with our procedures. It is exceedingly important that we not have complications and that we get our patients back to their healthy state as soon as possible. There is a term RIOT, return to intended oncologic therapy, and how important it is for our patients to RIOT.

We need them healthy so that they can go on to this therapy. A procedure which is complicated with pneumonia or long hospitalizations, time in rehab, will not allow patients to go on to receive chemotherapy or immunotherapy. So I think it's more important than ever that we assure a very smooth and rapid progression through surgery. So that includes using minimally invasive procedures so that our patients recover over 3 to 4 weeks instead of over 6 to 8 weeks. We assure that they are on ERAS protocol so that they are up and walking and having limited complications.

What it doesn't mean is that we should have shortcuts in the operating room. We still need to do an excellent oncologic operation. We need to collect all of our lymph nodes. We will never know if a patient needs or requires adjuvant therapy or whether that's something that can be offered to them if we don't do good mediastinal lymph node staging.

And that is an absolutely essential part of what we do. So yes, as a surgeon, keeping a patient on an appropriate protocol, allowing them to have access to these really exciting medications requires us to, one, prepare them emotionally and physically, two, get all of the tissue we need and get the biomarkers needed to appropriately stage them again. And that means doing an oncologic operation with a lymph node dissection, and three, doing it in a timely fashion. So I think surgeons have a big role in making sure we can deliver this new and exciting care to our patients.