Perioperative Immunotherapy ‘Is The Revolution’ in NSCLC

Perioperative immunotherapy for the treatment of non-small cell lung cancer (NSCLC) is starting to exhibit survival benefits among patients, research has shown.

Findings from the second interim analysis of the phase 3 KEYNOTE-671 trial showed that, among 797 participating patients, at a median follow-up of 36.6 months, 36-month overall survival rate (the time a patient lives, regardless of disease status) was 71% among patients treated with perioperative Keytruda (pembrolizumab), meaning it was administered both before and after surgery, versus 64% for patients who received placebo, according to data that were published in The Lancet.

“In that study, utilizing the [Keytruda] and in an all-comer population — we didn’t exclude those with EGFR or ALK [mutations] — we’re seeing this benefit in overall survival, which is statistically significant,” Dr. Heather Wakelee, Winston Chen and Phyllis Huang Professor and chief of the Division of Oncology at Stanford University in California and principal investigator for KEYNOTE-671, tells CURE. “And we see it in stage 2 as well as stage 3 [disease], we see it in the squamous and the nonsquamous [disease]. But we know that for patients with tumors with EGFR mutations or ALK translocations, they are better treated with adjuvant targeted treatment.”

“An overall survival benefit in one of these trials is remarkable and substantial,” says Dr. Coral Olazagasti, an assistant professor at the Sylvester Comprehensive Cancer Center, University of Miami, and a member of CURE’s advisory board. “And I think it’s something that really makes us think, ‘OK, this is really practice changing.’ ”

In the study, patients with resectable (removable by surgery) stage 2, 3A or 3B NSCLC were assigned to four cycles of presurgical Keytruda plus cisplatin-based chemotherapy, followed by surgery and 13 cycles of postsurgical Keytruda, or four cycles of presurgical placebo plus cisplatin-based chemotherapy, followed by surgery and then 13 cycles of placebo. The median event-free survival (the time after treatment that a patient does not experience complications from disease) was 47.2 months in the Keytruda group and 18.3 months in the placebo group.

Five perioperative immunotherapy trials have shown similar hazard ratios (a statistical measurement of how often an event happens) regarding event-free survival, Wakelee says, “but none of the others have yet shown a definitive overall survival benefit.”

“All the other trials are not mature yet, so we don’t know if they will show or not the overall survival [benefit],” explains Dr. Marina C. Garassino, a professor of medicine at the University of Chicago and one of Wakelee’s co-authors of the study published in The Lancet. “But this approach with the neoadjuvant (presurgical) [immunotherapy] followed by surgery, followed by adjuvant (postsurgical) [immunotherapy], is the only approach that was able to demonstrate an increase in overall survival.

So clearly, this can represent a great breakthrough for the patients.”

'I just want to get this thing out.'

Among the patients who have benefited from such a strategy is Tania Chomiak-Salvi, a retired former diplomat who lives in Washington, D.C.

Now 57, Chomiak-Salvi received a diagnosis of breast cancer nearly 30 years ago. She was treated via surgery and chemotherapy, became involved with breast cancer advocacy and proceeded with life as usual.

“I had 28 years of nothing after initial treatment, except for a short blip of a new cancer,” she says.

In 2023, she developed a persistent cough, with an X-ray revealing a mass in her lung.

“That launched me into a new cancer for me, and a new kind of treatment,” she says.

After an initial biopsy, the prospect of perioperative immunotherapy was put on the table “immediately,” she recalls. “I was thinking, ‘I just want to get this thing out,’” she shares. “Interestingly, when I had my initial breast cancer, perioperative anything wasn’t on the table, so it was straight to surgery. And there is a discomfort in knowing that this thing is sitting in you, and you want to just get the knife and take it out. But I get the possibility of shrinking it, and certainly the time of watching it to see, ‘OK, how effective is this treatment going to be for adjuvant [therapy], for catching any last little bits? Let’s see how this tumor reacts, and then at least we know, should we continue with this treatment?’ ”

Chomiak-Salvi started treatment with Keytruda and cisplatin chemotherapy in December 2023, followed by surgery. Her first postsurgery scan revealed a new malignancy on the lining of her lung. So, the decision was made to switch to a different immunotherapy regimen, Opdivo (nivolumab) and Yervoy (ipilimumab). Under this new treatment plan, Chomiak-Salvi says

she’s been experiencing lung inflammation and dry skin. She loves hiking, skiing and traveling, so she maintains an active lifestyle. She incorporates yoga and Pilates into her routine while keeping food and nutrition in mind.

She’s also involved with a nonprofit organization, the LUNGevity Foundation, which her oncologist referred her to. “It completely shifted my perspective on the disease and what I was up against and what I could do and how I could manage the mental health side of things,” she says.

'We have seen great outcomes with this.'

The consideration of perioperative immunotherapy represents a change in mindset compared with past years.

“Before, every patient that had a resectable [tumor] … used to get surgery in the beginning, followed by chemotherapy or a different treatment afterwards,” says Olazagasti. “But now, in recent years, things have changed, and there have been instances where we have been doing up-front treatment — this means that we start with chemotherapy and a combination of immunotherapy to try to shrink down your tumor as much as possible, what we call in oncology ‘debulking’ — followed by surgery, and we have seen great outcomes with this.”

Findings from KEYNOTE-671 resulted in the October 2023 approval by the Food and Drug Administration (FDA) of Keytruda with platinum-containing chemotherapy as neoadjuvant treatment and with continuation of single-agent Keytruda as postsurgical treatment for resectable NSCLC.

That was followed in August 2024 by the FDA’s approval of Imfinzi (durvalumab) with platinum-containing chemotherapy

as neoadjuvant treatment, followed by single-agent postsurgical Imfinzi for adults with resectable NSCLC with no known EGFR mutations or ALK rearrangements, based on the findings of the phase 3 AEGEAN trial.

In October 2024, the FDA approved, based on the findings of the phase 3 CHECKMATE-77T trial, Opdivo with platinum-doublet chemotherapy as neoadjuvant treatment followed by single-agent Opdivo after surgery for adults with resectable NSCLC and no known EGFR mutations or ALK rearrangements.

“The marker for benefit is, after the patients get the surgical resection, how much viable tumor they have left,” says Olazagasti. “And so, for example, these studies with up-front treatment, you want to look into major pathological response, meaning that there’s less than 10% of viable tumor [remaining], or ideally complete pathological response, meaning that there’s really no tumor left whatsoever.

“And, where chemotherapy really didn’t have much benefit in these markers, when we look at the combination of immunotherapy with chemotherapy in the up-front setting, we’re really seeing great responses. For example, with [Opdivo], we saw that the complete pathological response was 24% compared to 2.2% in the patients that only received chemotherapy. The same with [Keytruda], which is another agent that was studied — when you compare [Keytruda] and chemotherapy, 18% of the patients had complete pathological responses, meaning no viable tumor, compared to only 4% of the patients that got chemotherapy alone.”

“What we learned in the last, I would say, six or seven years,” Garassino says, “is that if we start with immunotherapy before [surgery], we expose the T-lymphocytes that are the cells that are responsible for the immunity against the cancer. In that way, they are exposed to the cancer like a virus, so they can be activated and they can expand. And then, you remove the tumor, but you continue to maintain the activation of the T cells also after the surgery, so if there are very few cells after the surgery, the T cells’ activation continues to be active. And the second part, which is the adjuvant component in the perioperative setting, which is the adjuvant immunotherapy after the surgery, can continue to maintain the activation of the T cells.”

Not all patients are candidates for such treatment, as Olazagasti explains. To undergo perioperative immunotherapy, patients should have tumors larger than 4 centimeters, with good Eastern Cooperative Oncology Group performance status, which is an indicator of patients’ ability to complete daily tasks independently. Patients with EGFR or ALK mutations, she says, are generally advised to proceed directly to surgery.

'Surgery is still the definitive cure.'

Among Olazagasti’s patients who have undergone perioperative immunotherapy for NSCLC was Antonio Maestegui, 60, of Clewiston, Florida. In January 2023 Maestegui, who works on cars for a living, began experiencing pain that he thought was from a pulled muscle due to heavy lifting.

He went to the emergency room to get the pain addressed.

“They didn’t see the tumor, so I kept on working,” he tells CURE.

He began seeing a physical therapist, but the pain persisted. Six months or so later, he returned to the emergency room, where a computerized tomography scan showed that he had stage 2 NSCLC. Maestegui underwent treatment with chemotherapy and Keytruda, followed by surgery in February 2024.

He continues to undergo infusions of Keytruda and says that although he was warned of potential side effects, he has experienced none, apart from pain from a rib that was cut during surgery.

“The pain is still there, but slowly it’s going away,” he says. Olazagasti notes that the side effect burden of the regimen has been shown to be tolerable in her practice.

At the time of its approval of perioperative Keytruda for NSCLC, the FDA noted that in KEYNOTE-671 the most common side effects reported in at least 20% of patients were nausea, fatigue, neutropenia (a low count of white blood cells known as neutrophils), anemia (a low count of healthy red blood cells), constipation, decreased appetite, decreased white blood cell count, musculoskeletal pain, rash, cough, vomiting, diarrhea and dyspnea (shortness of breath). Six percent of patients who received neoadjuvant Keytruda were unable to receive surgery due to adverse reactions, and 3.1% of patients who received neoadjuvant Keytruda and underwent surgery had delays in surgery due to side effects.

A question that remains for researchers regards the necessity of the adjuvant phase of treatment. “What does the adjuvant [therapy] add is usually the question, and we don’t have any head-to-head trials that have compared that,” Wakelee says, noting that such trials are being designed.

“In 20% of the [patients in the neoadjuvant or perioperative] trials, patients have had such a good response that we can’t find any tumor at the time of surgery, just from those cycles up front,” Wakelee says. “And so, we’re trying to figure out, do they need more treatment or not? So that’s one of the big questions.”

On the other hand, Wakelee notes, some patients may fare better by skipping the neoadjuvant immunotherapy phase and proceeding directly to surgery.

“Surgery is still the definitive cure,” she says. “So, you want to figure out who should just get surgery first, and who really is going to benefit from neoadjuvant [therapy]. And then after the surgery, we need better ways to figure out who’s done, who’s cured and who needs that additional adjuvant piece.”

And, as Garassino stresses, there is the factor of patient choice.

“I leave to the patients the freedom to decide whether they want to stop after the neoadjuvant [therapy] or they want to continue also with the adjuvant [treatment], because we don’t have any clinical trials that are comparing adjuvant and nonadjuvant after the neoadjuvant component,” she says. “I think that overall, we have really great results. The KEYNOTE-671 [trial] showed this, the only trial that showed the benefit in terms of overall survival, and this must be taken into account that that is a perioperative clinical trial. The neoadjuvant is only one small trial that is called CHECKMATE-816 [which led to neoadjuvant Opdivo plus platinum-doublet chemotherapy being approved by the FDA for resectable NSCLC in 2022]. There are a few patients randomized, and this is the only neoadjuvant-only trial. So, we have thousands of patients in the perioperative setting and one small trial in the neoadjuvant [setting].”

Still, Garassino says, these advancements have been revolutionary.

“Overall, in [the past] seven years, this is the revolution,” she says. “We know that the benefit that goes across all the patients … so as a clinician, I recommend to all patients with stage 2 and stage 3 [disease], a neoadjuvant approach followed by the surgery. And, with the final results, I have a full discussion with the patient [about how to proceed].”

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