A Paradigm Shift in the Treatment of Early-Stage Lung Cancer May Be Leading to More Cures

Every day while stuck in traffic heading home from work, Denise Lee saw the American Lung Association billboard along the highway, informing the 54-year-old lawyer that she should get screened for lung cancer if she smoked. But when she brought it up to her doctor, she learned she was a year too young for screening recommendations. After she turned 55, Lee talked to her doctor again and this time they made an appointment. She would be retiring soon and was about to spend a month vacationing in Sicily, so she scheduled the lung scan for the Monday after she returned.

The day after her scan, the pulmonologist called Lee and told her to come in immediately.

“At that point, in my head, I knew,” Lee says. “I couldn’t breathe.” But despite her insistence on getting screening as soon as she could, the news was a surprise: “They told me I had a mass on my lung.”

Denise Lee was enrolled onto the ALCHEMIST trial, a study assessing the efficacy of Keytruda plus chemotherapy in early-stage non-small cell lung cancer that had been removed by surgery.

She received the results of a biopsy on Valentine’s Day 2018: The mass was lung cancer but fortunately, scans suggested it was stage 2b or 3a, meaning they had caught it early enough for surgery. It wasn’t until surgeons removed the upper lobe of her lung and 17 lymph nodes that her cancer was downgraded to stage 1b. But Lee had risk factors that increased her likelihood of the cancer returning, so her oncologist recommended chemotherapy after surgery to increase her likelihood of survival. During her chemotherapy treatments, he told Lee she qualified for the ALCHEMIST clinical trials, a group of studies exploring different experimental treatment options in people who had early-stage non-small cell lung cancer (NSCLC) completely removed by surgery and treated with chemotherapy, but who still had a high risk of recurrence.

The ALCHEMIST trial Lee joined was testing a treatment that was unheard of for early-stage NSCLC just five or six years ago: immunotherapy.

One of the ways cancer takes over the body is by blocking the immune system’s ability to attack the cancer. Immunotherapy drugs are lab-grown antibodies that work by removing those roadblocks and teaching the immune system how to fight back. But until recently, immunotherapy had been used only in stage 4 metastatic lung cancer.

“The research tends to start in the metastatic setting because those patients have incurable disease,” says Dr. Catherine A. Shu, a thoracic medical oncologist at Columbia University Cancer Center in New York City. “If there is something that’s really promising and is approved in the metastatic setting, it is often brought into the earlier-stage setting. This is the traditional paradigm for all cancer research.”

Shifting the paradigm

For more than 30 years, the standard treatment for stage 3 NSCLC was daily radiation for six weeks plus chemotherapy, explains Dr. Neal Ready, a professor of medicine at Duke Cancer Institute in Durham, North Carolina.

“All sorts of things were done to improve on that and basically none of them worked,” he says. But immunotherapy has been moving into metastatic NSCLC for nearly a decade now and “it’s transformed the field,” Ready says.

Of note, immunotherapy is a standard now for stage 3 after a patient has completed chemotherapy and radiation. As it moves into earlier stages now, “the care for early-stage lung cancer is changing pretty rapidly,” he adds.

“This (immunotherapy) is changing our treatment options for patients with early-stage disease and actually leading to more cures, so it’s a really exciting time,” says Dr. Heather Wakelee, chief of the Division of Oncology at Stanford University and deputy director of the Stanford Cancer Institute in California. “We think immunotherapy is really going to change overall survival because immunotherapy changes the whole body’s response to the disease. If you get the body to recognize the tumor and mount an immune response, that can be permanent even when the drug is stopped.”

Aside from skin cancer, lung cancer is the second most common cancer after breast cancer in women and prostate cancer in men. More than 236,000 new cases are expected in 2022 and about 130,000 people die from the disease each year. Most cases (84%) are NSCLC and although new cases have been declining, five-year survival rates remain low, particularly for later stages, making early detection paramount. “Early” can refer to anything before stage 3b or 4, when the cancer has spread too far for resection — surgical removal. Stages 1 and 2 are resectable, and stage 3a can be, Wakelee says.

“The first really definitive new treatment in early lung cancer was adding an immune therapy for the treatment of stage 3 lung cancer,” Ready says. “The PACIFIC trial was the first trial that moved immune therapy into standard treatment for potentially curable non-small cell lung cancer.”

The PACIFIC trial tested the immunotherapy Imfinzi (durvalumab) in patients with stage 3 unresectable NSCLC. All patients received radiation and chemotherapy before randomly being assigned Imfinzi or placebo. Imfinzi improved five-year overall survival rates by 31%, which were 33% with placebo and 43% with Imfinzi. The Food and Drug Administration (FDA) approved Imfinzi in early 2018 as the first NSCLC immunotherapy before stage 4.

Promising results from two other trials followed as researchers tested immunotherapy in patients with resectable cancer, both after surgery (adjuvant) and before surgery (neoadjuvant). The IMpower010 trial added Tecentriq (atezolizumab) after chemotherapy in people with resected stage 1b to 3a NSCLC. Researchers reported in October 2021 that Tecentriq improved disease-free survival (length of time after primary treatment for a cancer ends that the patient survives without any signs or symptoms of that cancer) by 21% for all patients at three years and by 34% for a subset of patients whose genetic testing shows tumor expression of PD-L1 above 1%. PD-L1 is a protein produced by some tumor cells that acts as a “stop” signal to immune cells and dampens their attack on cancer cells.

Tecentriq, an anti-PD-L1 drug, blocks the protein, so it makes sense that a PD-L1 inhibitor would be more effective against tumors producing more PD-L1, although it is not a perfect biomarker. The FDA approved Tecentriq for patients with stage 2 to 3a NSCLC with tumors with at least 1% PD-L1 expression.

The CheckMate 816 trial tested Opdivo (nivolumab) as a neoadjuvant (presurgical) therapy: Patients with stage 1b to 3a resectable NSCLC received Opdivo with chemotherapy or chemotherapy alone before surgery. Adding Opdivo improved event-free survival (32 months vs. 21 months), with a complete pathologic response in 24% of patients compared with 2.2% receiving chemotherapy alone, leading the FDA to approve Opdivo plus chemotherapy for neoadjuvant use in people with stage 1a to 3a NSCLC.

More options earlier in treatment

Lung cancer is very aggressive and can involve microscopic spread below what tests can detect, Ready says, and that’s what immunotherapy appears to help with. “The medical treatment can potentially wipe out whatever microscopic disease is left” after resection, he says. Ready adds that lung cancer experts are optimistic that the improvements they’re seeing in clinical trials “will translate into clearly better outcomes at three to five years — the gold standard in early stage lung cancer.”

So far that’s the case for Linda Cimino, a 60-year-old nurse practitioner in New Jersey who developed a dry cough in March 2020. Cimino tested negative for COVID-19 and knew dry coughs aren’t common with most infections. Because she’s otherwise active with yoga, Pilates and daily 5-mile runs, she already suspected cancer when she called her doctor.

But the pandemic delayed each appointment, first more than five weeks to get an X-ray and CT scan because radiology centers were closed, and then another couple of weeks before she got a biopsy in late April. The diagnosis: stage 3a NSCLC. Cimino couldn’t begin chemotherapy until July, and when she asked about genomic testing, the doctor at her small community hospital said they didn’t have enough tissue for it. So she switched to Memorial Sloan Kettering Cancer Center in New York City and a full genomic work-up revealed she had high PD-L1 levels and a high tumor mutation burden, both advantageous for success with immunotherapy.

Meanwhile, the chemotherapy she was receiving wasn’t working. The tumor continued to grow into her middle and lower lobe and surgery would have required the removal of most of her lung. So instead of surgery, she underwent three weeks of radiation in December that shrank her tumor by half. Before the PACIFIC trial, Cimino’s only options would have been radiation, surgery and chemotherapy. Now, immunotherapy was an option for Cimino. Given her relatively high PD-L1 levels (42%), she followed her oncology team’s advice to opt for immunotherapy and began receiving Opdivo plus Yervoy (ipilimumab) in January 2021. A month later, Cimino had no evidence of disease. She continued immunotherapy for nine months until she developed pancreatitis, an autoimmune complication that, like other autoimmune complications, can happen with immunotherapy. It stopped in September.

“With immunotherapy, I felt great. I had energy, I was functional,” Cimino says. “I’m not going to lie and say there aren’t side effects, but it’s not like chemo. I almost died from chemo. It doesn’t kill the good cells. It boosts the body’s natural defenses to fight cancer.”

Cimino was frustrated that her first cancer center said she wasn’t eligible for immunotherapy. It was joining the support network LUNGevity soon after diagnosis that prompted her to switch providers to get genomic testing, which doesn’t drive all immunotherapy decisions in early-stage lung cancer but is recommended for all patients at any stage of diagnosis, Wakelee says. “It’s very important that we know the mutations and the PD-L1 level before making a decision,” she says.

All the immunotherapy drugs currently approved for early-stage lung cancer are PD-1 or PD-L1 inhibitors, so patients with high PD-L1 expression in their tumors typically respond better to immunotherapy. People with the EGFR mutations or ALK genetic translocations typically have fewer overall mutations and it can be harder for the immune system to recognize the cancer and attack. That means patients with EGFR or ALK can benefit less from immunotherapy and are instead treated with therapies targeting the abnormal proteins resulting from EGFR and ALK genomic anomalies.

Many other trials are testing immunotherapy agents in early‑stage lung cancer. In addition to testing Opdivo, the ALCHEMIST trial that Lee was in is testing Keytruda (pembrolizumab), as are the PEARLS/KEYNOTE-091 trial and KEYNOTE-671 trial. In July 2021, results from the Impower030 trial — testing Tecentriq as both a pre- and postsurgery therapy — showed 90% of patients improved to the next lower stage. And the AEGEAN and MERMAID-1 trials are testing Imfinzi as pre- and postsurgery treatments. Other trials’ immunotherapy drugs have different targets, such as TIGIT, LAG3 and CTLA-4, which Yervoy inhibits.

Progress marches on

The ultimate goal in using immunotherapy is to “improve cure rate and overall survival,” Shu says, but it takes years to collect those data, limiting disease recurrence and progression becomes a surrogate measure along the way. Meanwhile, the paradigm shift in treatment regimens has made it particularly important to have multidisciplinary oncology teams, including a medical oncologist, a pathologist, a radiation oncologist and a surgical oncologist, Shu says. A team looks at each person’s situation to determine the best treatment plan for them.

“It makes everything a little bit more complicated but also a lot more exciting” to individualize care for each patient, Shu says.

Among the barriers to immunotherapy use in early-stage lung cancer are patients’ lack of awareness of their options, inadequate insurance coverage for the drugs and not getting genomic testing done. Some patients may also struggle with a treatment schedule that involves coming in every week for infusions or taking a pill for several years, Shu says, “but most patients want the treatment if it’s been shown to work.” Side effects are usually less toxic than with chemotherapy, but toxicity may be an issue for some patients. Although rare, severe toxicities may prevent a patient from being able to undergo surgery.

But multidisciplinary teams help overcome other barriers. “Another challenge is that you’re changing a paradigm for surgeons: They usually take patients for surgery right away and now you’re telling them that you are going to give the patient this treatment first,” Shu says. “Sometimes there may be reluctance from the surgeons,” who worry the tumor will grow or they won’t be able to operate.

Patients can have those doubts, too. “A lot of patients just want their tumors out,” Shu says. “They don’t want to wait three months getting treatments before surgery.”

She explains that presurgery treatment with chemo and immunotherapy can often improve cure rates.

“We know that how necrotic (dead) the tumor looks at the time of surgery is much better with chemotherapy and immunotherapy, which we think means the cancer has less chance of spreading.”

And if the cancer does spread? Research and drug development are moving so quickly that patients may already have another option available to them by then.

“(With) all this research, we are actually seeing results in real time for patients,” Shu says. “Patients are always asking what’s next, and we’re coming up with it. I have patients who are on one line of treatment and by the time they’ve progressed, we’ve already come up with an FDA approval for another line of treatment for them. I have patients who have had metastatic disease for seven or eight years and are doing great.”

That was unheard of in the past, she says.

“The addition of the immune therapy in early-stage diseases is going to be transformative; it’s going to lead to improved progression free-survival and overall survival,” Ready says. “There’s still going to be a lot of biomarker analysis to identify patients who will benefit the most and patients (who) won’t benefit at all, so that’s not clear yet, but it’s clear it’s going to have a major impact.”

Despite stopping immunotherapy early last September after the pancreatitis, Cimino still has no evidence of disease, which she credits partly to immunotherapy.

“I think immunotherapy has a bigger role to play in future cancer therapies, especially for patients with other issues, because chemo is tough,” Cimino says. “All the chemo is doing is telling the body to kill everything. It’s not teaching the body anything.”

Lee also has no evidence of disease and got her last CT scan at the end of January. The only side effect she had from Opdivo was some stomach upset. She thinks it’s “fantastic” that immunotherapy is being used earlier in lung cancer treatment. It is important to note that patients may experience more side effects associated with immunotherapy use, some of which can be serious and permanent, even fatal.

“That’s one of the reasons I wanted to do the clinical trial,” Lee says. “The people who were suffering from lung cancer or any type of cancer before me, they went through a lot to test various drugs and basically made it easier for me. Somebody’s got to help with the research, so I wanted to do that.”

Her reward has been seeing just how quickly progress is chugging along.

“For people just diagnosed with lung cancer, it is scary,” Lee says, “but there have been so many advances in the treatment of lung cancer that there’s a lot more hope now than there was, say 10, 15, 20 years ago.”

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