No Small Challenge: Emerging Therapies in Small Cell Lung Cancer

For Mari Casanova, it started with a weird, dry cough. Her doctor wasn’t alarmed and suggested cough medicine. But a few weeks later, the morning after a Pilates class in November, Casanova felt an unusual lump in her armpit. At first she wondered if she had pulled a muscle. Then she realized it was the size of small lemon, so she cleared her schedule and headed to her neighborhood hospital in Chicago.

A needle biopsy indicated cancer, but for nearly two months, her doctors couldn’t pin down the origin. Finally, they located a spot, about the size of the back of an earring, in her right lung. She received a diagnosis of small cell lung cancer (SCLC). Her doctors said the lump in her arm was already spreading, and she was scheduled to begin three months of chemo 10 days later. A second opinion didn’t happen. “I didn’t have time to get the right doctor,” she says.

On the treatment side, SCLC has been described as “a graveyard for drug development” in several studies, including one published in Frontiers in Oncology in 2020, where chemo alone was the standard for more than 40 years. And on the patient communication side, it was even more retro: Casanova’s doctor never told her she was facing one of the most aggressively dangerous cancers known. “Yeah, he forgot the part about death,” she says.

An aunt had died from breast cancer years ago, but otherwise, Casanova had no close personal experience with cancer. “I said, ‘This is going to be easy for me’ because I had no clue what chemo was,” she says. “‘In three months, I’m going to be fine. I’m going to beat this.’ I had no fear because I didn’t understand that I could die.”

She tolerated the chemo well. Meanwhile, her sister Martha had questions and had been doing some research. She came along for what was supposed to be the last appointment. And when Martha started to ask hard questions, the doctor shooed her away with a gesture and left the room. Casanova collected her records and found another oncologist.

“And the first thing he did was explain to me that I could die.” She pauses a bit at the memory. “Yeah, in a very sweet kind of way.” He laid out a treatment plan: one more round of chemo and some radiation for the spot on her lung and to prevent brain metastases.

Casanova was fortunate in that patients with SCLC are often very overwhelmed by their symptoms. “They usually come in in pretty significant distress,” explains Dr. Stephen Liu, director of thoracic oncology at Georgetown Lombardi Comprehensive Cancer Center in Washington, D.C. “This is not a subtle finding.”

“My approach is to be very upfront, very open, very honest,” Liu says. “Small cell lung cancer is an exceptionally lethal subtype of lung cancer. And I try to prepare patients for the journey that we’re going on.” Because it moves so fast, SCLC is almost always picked up at an advanced stage, and there’s almost no role for surgery. Median survival for people receiving treatment like Casanova was only 10 months.

“It’s a heartbreaking, terrible disease,” adds Trudy Oliver, a lung cancer researcher at Huntsman Cancer Institute and an associate professor of oncological sciences at the University of Utah in Salt Lake City. “It’s why we’re in the lab trying to find things that will make a difference

so that it doesn’t have to feel like such a such an overwhelming death sentence.”

Understanding SCLC

According to the Centers for Disease Control and Prevention, lung cancer is the third most common cancer in the United States after skin and breast/ prostate cancers, but most of that is non-small cell lung cancer (NSCLC). Its treatment has improved dramatically over the past two decades, marking one of the great success stories of modern oncology. SCLC makes up approximately 15% of lung cancers overall, or nearly 30,000 cases annually. Most SCLC can be linked to cigarette smoking. Its poor prognosis leaves few survivors, and the added burden of tobacco’s social stigma means that SCLC hasn’t benefited much from patient advocacy. But for more than a decade now, a dedicated cadre of researchers has been trying to crack one of the most challenging types of tumors in oncology.

“There was a period of time when small cell was largely ignored,” says Dr. Charles Rudin, medical oncologist and chief of thoracic oncology at Memorial Sloan Kettering Cancer Center in New York City. “People really felt like this disease was too hard and nothing worked.” That sort of negative reinforcement led to less research focus. Rudin’s lab undertook one of the first major projects to turn this around: sequencing the small cell cancer genome. That knowledge base led to trying to define new targets for SCLC and accelerated the critical process of defining subsets of disease. “There’s an opportunity to tease apart the biology of this disease and start to develop better and more focused therapeutic approaches,” Rudin says. “It’s not an uncommon disease at 15% of lung cancer. And there are few therapies that work, so patients are super eager to try something that’s going to change their fate. I think it really was just waiting for people to come to the table and start to work on it.”

Oliver took up this challenge after learning that existing mouse models of SCLC were slow, with tumors developing in the second year. The wait slowed research and limited its value in such short-lived organisms. Engineering a mouse to study a particular cancer is complex science. But after years of work, her lab succeeded: Its mice would get sick in just a few months. In the process, the researchers unlocked some small cell secrets.

“The tumors looked and behaved a little differently,” Oliver says. “That was really our first clue that not all SCLC behaves the same way.” Working with a group in Germany, she discovered her model was very sensitive to a particular class of drugs. SCLC could no longer be viewed as one disease, and that makes a difference in the clinic.

Dr. Lauren Averett Byers, an associate professor in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston, also jumped into the SCLC challenge. Her group is also focused on defining — and attacking — the molecular subtypes of SCLC.

Among the first things Byers worked on was defining SCLC’s differences at an elemental level. SCLC is considered a neuroendocrine tumor, which is a cancer that begins in neuroendocrine cells with similar traits to hormone- producing cells and nerve cells. Its fundamental biology is rooted in how the cells of the nervous and hormonal systems work. NSCLC features a number of highly accessible biologic targets that have allowed major therapeutic advances. SCLC is more cryptic, Byers says. “It wasn’t going to be as straightforward.”

As computational biology advanced, one approach was to let the data talk. Her team deployed a battery of algorithms to analyze the growing library of SCLC tissue samples. “How many types of small cell lung cancer are there?” she asks. “Let’s not be biased by what we think we know. Let the data tell us.”

Impact of Immunotherapy

A year after Casanova began her SCLC treatment, John Williams was running a snowblower on his block. He was a few miles away, also in Chicago, and a heavy snow had been falling that January night.

Now 77, Williams is fit and retired, and he takes pleasure in helping out his neighbors. He had already cleared the sidewalks and was finishing a neighbor’s driveway when it suddenly became difficult for him to breathe. He struggled to make it back to his house and collapsed into a chair. A few days later, he was still having breathing issues and was admitted to the hospital. They drained two liters of fluid from his lungs and ran a battery of tests: a PET scan, CT scan, an MRI, blood tests and a needle biopsy.

A few days later, Williams met with an oncologist, who told him he had SCLC and started talking about palliative care. She forecasted he had two to four months, maybe a year.

“This can’t be me,” he thought, his mind shifting into overdrive. “I’m the active, ‘go get ’em’ kind of guy.” But it was him, and the very next day, he was getting chemo. And not just chemo. In March 2019, the Food and Drug Administration (FDA) approved Tecentriq (atezolizumab) as part of the first immunotherapy-plus-chemotherapy regimen for SCLC. But the data that would lead to this approval had been released in September 2018, and Williams’ doctors were already putting it to use. Williams laughed when his infusion nurses couldn’t pronounce the drug name and suggested they call it “Bob.”

“This is what I call a really major stroke of luck,” he says, and he spent a lot of time thinking about his circumstances. “I’ve got absolutely no control over the doctors, the medication, the progression of the disease. I can do nothing. The only thing I can control, really, is my attitude. I can be negative or I can be positive,” he says. “So I focused on the positive from that point forward. And that’s an extremely difficult road because there’s so much negativity around.”

He can’t prove it, but he thinks the combination worked. “I’m thinking that the Tecentriq and attitude had a major, major effect on my physiology.”

Williams was playing golf by the time the season opened a few months later. He lost his hair and discovered — to the detriment of his golf game —that eyebrows actually serve a purpose: They help keep the wind out of your eyes.

In fact, once the fluid was gone from his lungs, he felt no symptoms of his cancer. One of the major challenges comes with the tumor location; SCLC can quickly encroach on major airways and blood vessels. This challenge is mitigated by the disease being responsive to so many types of chemotherapy. “You can see double-digit response rates to over a dozen different chemotherapy drugs or two- or three-drug combinations,” Liu says. “You can actually get response rates that are quite high.” Although patients might feel like things have gone back to normal, maintaining that response and preventing relapse is the real challenge. “We can’t rest on the laurels of that initial response,” Liu says. “We have to prepare for what will be in many cases an inevitable relapse.”

Tecentriq improved those odds for the first time in more than 30 years. It didn’t move the bar much, adding just a couple of months, but Liu still considers it a breakthrough. “I appreciate that it’s not necessarily the breakthrough that everyone wanted, that the survival gains aren’t of the magnitude that people are waiting for, that patients deserve,” he says. “I’d consider it the first step; hopefully, the first step of many. When we add immunotherapy to chemotherapy, we improve survival. There’s no doubt about it.”

In 2020, a second immunotherapy agent, Imfinzi (durvalumab), was granted FDA approval in combination with chemo. It is not the same as Tecentriq, but both are anti- PD-L1 agents with very similar survival results. In Liu’s mind, they are equivalent.

Rudin also acknowledges that although Tecentriq and Imfinzi don’t extend survival tremendously, they represent a significant advance. “A subset of patients between 10% and 15%, maybe 20%, do derive significant benefit from immunotherapy. That can be transformative for those patients,” he says, providing hope even for patients with advanced stage disease. “That gives us an important proof of principle that this is a disease that can be amenable to appropriate therapy.”

A quick look at the numbers makes it easy to tell when a subset of patients in a clinical trial is doing significantly better, raising expectations like an A student breaking the curve. The real challenge comes in finding out why. Often the idea behind a drug points the way, and simply testing biomarkers for the drug pathway yields the answer.

SCLC hasn’t been so transparent, which is part of what drove Byers’ computational group. As expected, their analysis confirmed three of the major variations the field has been defining. But the project also unmasked a fourth group, which they described as inflamed SCLC. It hadn’t been on anybody’s radar. “It was incredibly exciting because we’ve really struggled in SCLC to understand who gets the most benefit from immunotherapy,” she says. Although obvious biomarkers haven’t worked out, this new, computationally defined group appears to survive almost twice as long as the other groups treated with chemo plus immunotherapy.

Inflamed SCLC had higher markers of immune infiltration and of important immune checkpoints. Immunotherapy works by manipulating the body’s immune system, and now researchers have a footprint to work with. “There are obviously many questions and things left to test,” Byers says.

Looking to the Future

Tecentriq worked for Williams for an estimated 10 months (from February to December 2019), then he was put on Abraxane (paclitaxel). In the autumn of 2020, his cancer returned and is now trying to take hold in his liver. Relapse is a scary time for all patients with cancer, but particularly for patients with SCLC. “Our first shot is always our best shot, and part of that is because when small cell lung cancer does relapse, it does so unforgivably,” Liu says. Many patients never get more than first-line treatment.

But once again, Williams is just in time for another new treatment. Zepzelca (lurbinectedin) received FDA accelerated approval in June 2020, the first approved use of the new agent. It is exciting for patients with SCLC because the only other approved chemo drug at this stage is topotecan, known for its extensive list of uncomfortable and brutal side effects. Zepzelca presents its own difficulties but is generally easier to handle and can be effective against cells that have developed early resistance to platinum-based chemo.

Zepzelca is a welcome addition to a limited armamentarium, though its future was clouded when its phase 3 trial came up short of expectations in December 2020. “We see a lot of patients with recurrent disease,” Rudin adds. “We’re exploring many of the new therapeutic targets in patients with recurrent disease.”

Oliver describes the unique challenge of SCLC using M&M’s. Imagine your newly treated cancer is a bag of blue M&M’s, and you’re fortunate to have a cancer drug that wipes out blue M&M’s. “If my bag of M&M’s was all blue, I could wipe out that bag pretty quickly,” she says. But if your bag contains five colors of M&M’s, the blue drug is going to be limited. With SCLC, what actually happens is that some blue M&M’s die, but others change color. “That ability to evolve and change rapidly and easily? That’s a massive challenge,” Oliver says.

“That’s how they escape or adapt,” Byers adds. Researchers need to figure out how they’re switching colors and how to block that. They can also refine the classic cancer strategy of combining drugs that hit more than one color. “I think that’s doable,” she says. As hard as drug development has been for SCLC, she says it may be one of the most amenable tumors for developing a so-called liquid biopsy: using genetic information available in blood to target the disease.

“My hope is that within the next five years, we will start having biomarker testing to guide treatment,” Byers says.

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