Episode #41: The Promise of Lung Cancer Precision Medicine with Dr. Jonathan Spicer

Dr. Albert Rizzo:
Welcome to Lungcast, the monthly respiratory health podcast series from the American Lung Association and medical news site HCP Live. I’m your host, Dr. Albert Rizzo, Chief Medical Officer of the American Lung Association.

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Today’s episode is our first foray into lung cancer in 2024. While some of our latest interviews on cancer have focused on screening and diagnostics, today we’re talking about an exciting emerging drug class with one of the most prominent investigators involved with its clinical utility.

We know that lung cancer is the leading cause of cancer death, with about five-year survival after diagnosis of around 20%. It’s also recognized as one of the most preventable cancer types. Survival is clearly associated with the cancer stage, and lung cancer screening in a high-risk population has been shown to reduce lung cancer–related mortality, mainly because of stage shifting to early disease at the time of diagnosis.

Currently, it’s estimated that approximately 20–25% of patients who receive a diagnosis of non-small cell lung cancer are at an early stage and can benefit from curative surgical resection at the time of diagnosis. Anatomical surgical resection with systemic mediastinal lymph node dissection is currently the mainstay of therapy for these early-stage non-small cell lung cancers with a goal of cure.

However, 30–55% of these patients who undergo this curative surgery have recurrence and ultimately die of their disease. Because of this recurrence, therapeutic options are being pursued to address it. This includes the role of perioperative neoadjuvant treatment, whose aim includes reducing tumor size, increasing operability, eradicating micrometastases, and reducing recurrence rates in these early-stage diseases.

Now to learn more about the role of neoadjuvant therapy for lung cancer surgery, we have with us today Dr. Jonathan Spicer, Medical Director for McGill University Thoracic Oncology Network. Dr. Spicer has been involved with and published on some of the pivotal trials assessing the role of adding immunotherapy as part of perioperative neoadjuvant therapy in non-small cell lung cancer. These articles have appeared in the New England Journal of Medicine in May 2022 and more recently in August 2023.

Thank you for being with us today, Dr. Spicer.

Dr. Jonathan Spicer:
Thank you for having me. It’s a pleasure.

Dr. Rizzo:
A question or two before we get to those studies. I mentioned the importance of stage shifting in early disease as a result from low-dose CT screening. Would you please explain some of the current experience in Canada with low-dose CT screening? In the United States, the rates continue to be lower than we would like and are only slowly increasing, which is frustrating for such a potentially life-saving test.

Dr. Spicer:
We’ve been working on this for quite some time, much like what’s been going on in the U.S. In Canada, health care tends to be provincially adjudicated, so we have some provinces further down the road of having formally established screening programs. Ontario was the first to get that afoot. Now we have one that’s on the verge of being deployed here in Quebec, and there are several other provinces moving in that direction.

We definitely see those patients coming through, but because we’re still so early in the deployment of this broad effort, I don’t know that we’ve really generated statistics to know where we stand in comparison to some of the efforts in the States.

There’s no doubt that getting patient engagement for these types of efforts continues to be a challenge. We see that, but there are more and more patients coming through our clinics who’ve been identified through these efforts and for whom we’re offering an opportunity for curative treatment.

Dr. Rizzo:
To level set for our audience, can you speak to the evolution of adjuvant and neoadjuvant therapy when it comes to lung cancer surgical therapy, and explain the perceived benefits and maybe some of the potential risks of this approach?

Dr. Spicer:
Our efforts—capital “R”—have been longstanding for many years. I always quote the first couple of studies in the early 1990s. One was out of the Spanish Cooperative Group led by Rafael Rosell, and the other by MD Anderson with Jack Roth. Those studies, published in 1994, showed that when you added chemotherapy to surgery for stage III disease, you had a dramatic impact on survival. Both trials had to be stopped halfway through because of the benefits of adding systemic treatment to a local modality.

Then, really, 30 years have gone by trying to pair all the different options—surgery, chemo, radiation—and introducing new treatments into that mix. It’s been rearranging chairs for decades: do you give it before, do you give it after, what do you give, is surgery required, what’s the role of radiation? Nothing truly definitive emerged until more recently.

Incremental steps forward have happened, but now we’re starting to see the benefits of innovations in the metastatic setting influence what’s happening in early stages. We still struggle to tease out who has micrometastasis and needs systemic treatment to prevent recurrence, versus who will do fine with local therapy alone.

Dr. Rizzo:
I was surprised to see that statistic of 30–50% of people with stage I disease having surgery still recur. That’s concerning and certainly speaks to why new treatments have developed. I mentioned those studies earlier. Do you want to talk more about them and their role in guiding how these therapeutic options are being used in lung cancer patients?

Dr. Spicer:
Yes. I was fortunate to be part of the CheckMate 816 trial, published in 2022. It was pivotal as the first neoadjuvant trial—meaning giving systemic treatment before surgery—to complete accrual and be positive for two important endpoints: pathological complete response and event-free survival.

Pathological complete response means that after completion of pre-operative therapy and surgery, the pathologist finds no cancer left in the specimen. Event-free survival was also significantly improved. These results really switched on a light bulb globally, showing this approach could be implemented in care pathways and open up surgery for patients not previously considered candidates, mostly stage III.

Dr. Rizzo:
And that trial included some early-stage patients, or was it all stage III?

Dr. Spicer:
It was predominantly stage III, with about two-thirds stage III and the remaining one-third stage II, based on the AJCC 7th edition. If you applied the 8th edition, it would be stage IIA to IIIB. Stage IA patients were not part of that trial.

Dr. Rizzo:
Were these patients the ones that included immunotherapy, or was that another trial?

Dr. Spicer:
CheckMate 816 randomized patients in an open-label fashion to three cycles of chemotherapy with nivolumab, a checkpoint inhibitor, versus chemotherapy alone. Both arms were then followed by surgery. Patients could get adjuvant treatment according to investigator choice, followed by survival monitoring.

One nice aspect of the trial was the minimal additional treatment over standard preoperative chemo—just three doses of immunotherapy. We now have three- and soon four-year data showing durable benefits in event-free survival with minimal adverse events.

More recently, the KEYNOTE-671 trial expanded the effort to not just preoperative immunotherapy but also postoperative continuation. Preclinical data suggested perioperative treatment—before and after surgery—was superior. Patients who got chemoimmunotherapy before surgery and continued immunotherapy afterward did better than those with chemo alone. This trial was positive for both event-free and overall survival—the first perioperative trial in decades to show an overall survival benefit in the intent-to-treat population.

Dr. Rizzo:
Some people worry that neoadjuvant therapy could make patients inoperable due to delays or side effects. Did that happen often?

Dr. Spicer:
The ideal study would compare direct-to-surgery patients versus neoadjuvant therapy, but that trial doesn’t exist yet. Comparing purely preoperative chemoimmunotherapy versus perioperative therapy versus upfront surgery will take 5–10 years to complete.

From a patient perspective, the concern about missing a surgical window is valid. But many early-stage patients who go directly to surgery still recur. The neoadjuvant approach can spare some patients from unnecessary surgery, which removes functional lung and impacts quality of life. We explain to patients that progressing on the most active systemic treatment is unlikely to have been prevented by upfront surgery.

Dr. Rizzo:
That’s a very clear way to explain the benefit of the delay. Thank you.

Many new lung cancer patients have biomarker testing to guide therapy. NCCN guidelines highlight around 11 specific targeted mutations and immunotherapy markers like PD-1/PD-L1. Can you speak to the significance of these biomarkers and whether you use tumor mutational burden or circulating tumor DNA in practice?

Dr. Spicer:
This is critical. Reflex testing—automatic molecular characterization—is not pervasive worldwide, and access is limited, particularly for early-stage patients. Data show that patients with next-generation sequencing before starting systemic therapy have better overall survival, which makes sense: not all lung cancers respond the same way. Exposing a patient to the wrong therapy can make the next, correct therapy more toxic.

In Quebec, delays exist due to the public health system, but the urgency is not just to start treatment—it’s to start the right treatment. Immunotherapy is promising in early-stage disease, but it’s not the only innovation. The ADAURA trial showed that postoperative targeted therapy for EGFR mutations improves survival. The ALINA trial showed disease-free survival benefits for ALK-altered cancers. If a patient has one of these mutations, immunotherapy is usually less effective, so proper molecular profiling is vital.

PD-L1 status is useful to estimate likelihood of response, but I don’t use it as a strict decision tree. Other biomarkers like TMB or T-cell infiltration need more data, especially in early-stage disease. At a minimum, testing for EGFR, ALK, and PD-L1 is essential, with additional gene targets considered when relevant.

Dr. Rizzo:
Your perspective is excellent. Lung cancer treatment has changed dramatically in the last 10–15 years with mutation targets, PD-L1 markers, and now advancements in neoadjuvant and adjuvant therapy. Where do you see lung cancer therapy going in the next few years?

Dr. Spicer:
It’s incredibly exciting. We’re entering a complex era with many options. Lung cancer remains the most lethal common cancer, but it’s a collection of rare diseases, making comparative studies challenging and requiring global collaboration.

The most exciting aspect is that patients achieving complete pathological response with chemoimmunotherapy show remarkable survival. Three-year data suggest roughly 95% are alive. If systemic treatment eradicates cancer—and surgery confirms it—this is extremely good news. It could eventually allow de-escalation of local treatments and reduce morbidity, similar to treating pneumonia with targeted therapy until the infection is cleared.

Dr. Rizzo:
So precision medicine—right drug, right patient, right time—is the goal.

Thank you again for joining us today. We have an archive of other lung cancer discussions featuring Dr. David Cook (UC Davis), Dr. Carla Lamb (Mayo Clinic), and Dr. Carolynn Presley (Ohio State University). Today, we’ve added Dr. Spicer, a thoracic surgeon providing perspective on neoadjuvant therapy.

Be sure to subscribe and rate Lungcast on your preferred platform, and visit lung.org and hcplive.com for more news and resources.

Until next time, I’m Dr. Albert Rizzo, reminding you that if you can’t breathe, nothing else matters.