COMMENTARY

Neoadjuvant Immunotherapy Data Suggest More Lung Cancer Cures

Mark G. Kris, MD

Disclosures

April 26, 2018

Hello. This is Mark Kris from Memorial Sloan Kettering. Today I want to talk about developments in lung cancer therapies discussed in the past few days at the annual meeting of the American Association for Cancer Research.[1,2,3,4,5] Recently, television, newspapers, medical meetings, and leading journals have reported vast amounts of data showing the benefit of immune checkpoint blockers in patients with lung cancer—every type, every stage.[1,2,3,4,5,6,7]

It is very gratifying to have new ways to fight lung cancer, and more important, we now have therapies that can lead to very long-term benefit, often even off therapy. [In some cases,] maybe even approaching what we really want for our patients: to cure their illness.[6,8]

All of us have had patients who have been put into remission with immune checkpoint blockers.[6] It's sadly a small group of people, but for those people, it's very, very dramatic and something you don't see with cytotoxic chemotherapies, or even with targeted therapies or angiogenesis agents. That's a really important development.

It's also important to think about using these immune checkpoint blockers with our best local therapies. There were very, very potent data about the use of durvalumab following concurrent chemotherapy and radiation, published late last year. That has changed the face of treatment of patients with locally advanced cancer, roughly 35,000 people per year in the United States.[9] This is an additional 35,000 people who could also benefit from combination therapy with the immune checkpoint blockers. Those people are folks with resectable cancer.

The report in the New England Journal of Medicine this week about the use of neoadjuvant nivolumab is a very hopeful one.[10] The data, from Johns Hopkins and Sloan Kettering, showed that the drugs can be safe and don't compromise surgery. They don't make it more difficult, they don't make it more dangerous. Also, with this approach, there is an almost unexpectedly high rate of pathologic response in the resection specimen. We know from treating lung cancers now for almost three decades that pathologic response from systemic therapy translates into long-term benefit and likely translates into a higher rate of cure.[4,11]

When immune checkpoint blockers are given alone, we are seeing very, very profound effects with usually just two doses. We have seen this both in the neoadjuvant nivolumab trial and in the data from the Lung Cancer Mutation Consortium, who will present a trial of atezolizumab at the upcoming ASCO meeting.[5,10,12]

All of these trials point to a profound benefit [of immunotherapy]. The benefit may be even greater in people who are surgical candidates, which is so important, because we already cure a proportion of people with concurrent chemoradiation. We can cure an even greater proportion of people with surgery, adding in immune checkpoint blockers with a high degree of benefit in the neoadjuvant setting.[9] We are also improving long-term progression-free survival after chemoradiation.[13] We have hope that we can improve rates of cure in these patients, and that's fantastic.

I'd like to provide some guidelines today. I'm not going to talk much about small-cell today, except to say that immune checkpoint blockers are useful there; most people now will use them after initial chemotherapy.[1,3,13]

In patients newly diagnosed with adenocarcinoma or squamous carcinoma, the choice of therapy with immune checkpoint blockers depends on the degree of dependence on PD-1 and PD-L1.[13] Patients who have high tumor burden, high PD-L1, can probably be treated with a checkpoint blocker, pembrolizumab alone, or the combination of ipilimumab and nivolumab, based on data from Hellman and colleagues, presented in Chicago and also in the New England Journal of Medicine.[1,2,3]

For people in the middle, it's tougher. It's very clear that patients getting immune checkpoint blockers and chemotherapy have higher rates of response and better overall outcomes.[3,7,13] It always makes sense to add an immune checkpoint blocker, particularly in those patients with symptoms.[3,7,13] However, the less dependent tumors are on the immune mechanisms to evade immune surveillance, the less helpful adding an immune checkpoint blocker is going to be.[13] There is some benefit [of immunotherapies] in people with zero PD-L1 expression, but it's much smaller than for people with high.[14]

In all patients, chemotherapy is a consideration—a top consideration in people with low expression of PD-L1 or tumor mutational burden, with lower use in people with very high tumor burden or PD-L1.[15]

Last, don't forget about the potential to increase rates of cure by adding both immune checkpoint blockers to surgery or radiation.[8] There are data now that it helps neoadjuvantly in patients facing surgery, and it helps in the consolidation phase for patients getting concurrent chemoradiation.[9,10]

We have a lot more tools at our disposal, and I encourage oncologists to make sure that every tool is used for every patient with this illness. We should constantly be thinking, Is there a better way, are there more things we could do to fight— and ultimately cure—our patients with lung cancers of all types?

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