The other, smaller (cell) lung cancer

Approximately 125,000 people in the U.S. will die from lung cancer this year and more than twice as many will die from colorectal cancer, which is the second most common cancer death, according to American Cancer Society projections.

Even so, lung cancer is indisputably one of the success stories of cancer prevention and treatment. Lung cancer incidence has been falling since the mid-1990s among men and since the mid-2000s among women because of declining smoking rates.people smoke. Mortality rates have moved in a similar direction. Recent treatment advances have accelerated the improvements in mortality.

Lung cancer is classified into two main types: non-small cell lung cancer, which accounts for approximately 80% of cases; and small cell lung cancer, accounting for approximately 14%. As the names suggest, the classifications are by the relative size of the cancer cells. Smoking causes both non-small cell and small cell lung cancer, so lower smoking rates have affected trends for both. However, small cell lung cancer is an especially aggressive form of cancer, meaning it grows quickly. Untreated patients have a median overall survival rate of only two to four months.

Even with treatment, patients with small cell lung cancer who are diagnosed at a more advanced stage have a median overall survival of only six to 12 months. According to the American Cancer Society, the five-year relative survival rate for lung cancer is 25% overall and is 8% for small cell lung cancer.

Lines of treatment

W. Jeffrey Petty, M.D., of Wake Forest University in Winston-Salem, North Carolina, and Luis Paz-Ares, M.D., of Hospital Universitario in Madrid, Spain, wrote a review article about emerging treatment strategies for small cell lung cancer that was published last year in JAMA Oncology. They noted that small cell lung cancer has traditionally been staged into two broad categories: limited stage and extensive stage. Approximately 30% of patients are diagnosed in the limited stage and 40% are diagnosed in the extensive stage, with the rest not classified, according to the Petty and Paz-Ares.

Patients in both stages are treated with chemotherapy that includes platinum-based drugs (cisplatin and carboplatin). Recent studies of patients with extensive-stage disease have shown that overall survival improves by adding Tecentriq (atezolizumab) or Imfinzi (durvalumab) to chemotherapy, according to Petty and Paz-Ares’ overview. Other immune checkpoint inhibitors — Keytruda (pembrolizumab) and Opdivo (nivolumab) — have been investigated but the results have been mixed.

For many years, Hycamtin (topotecan), a topoisomerase inhibitor, was the only second-line treatment that had been approved by the FDA. In 2020, the FDA approved another second-line drug, Zepzelca (lurbinectedin), which is an alkylating drug that interferes with cancer cell division.

Enter tarlatamab

Currently, there are no approved therapies for third-line treatments for small cell lung cancer. However, there are some innovative immunotherapy drugs in development. “The use of a patient’s own immune system to fight their cancer has transformed the meaning of hope for many [patients with] lung cancer,” says Daniel Boffa, M.D., the division chief of thoracic surgery at the Yale Cancer Center in New Haven, Connecticut. Boffa explains that immunotherapy has mainly focused on “patients whose cancer cells had tricked their immune systems into ignoring them. However, this only works if the patient’s immune system recognizes the cancer cells as being different from the rest of their body, which is less common.”

Daniel Boffa, M.D.

Tarlatamab, developed by Amgen, uses a different approach. Tarlatamab is a type of immunotherapy drug, called a bispecific T-cell engager (BiTE). The drug simultaneously attaches to both CD3 on T cells and DLL3 on cancer cells, bringing them close together. This helps the patient’s immune system recognize and destroy the cancer cells. Boffa compared the mechanism to “handcuffing a dangerous criminal to a police officer.”

“Instead of counting on the immune system to recognize the cancer as being dangerous, the treatment binds to both molecules that most small cell lung cancer cells have on their surface, and to immune cells capable of killing the cancer cells, creating a bridge,” he says.

The DeLLphi-301 phase 2 trial was conducted to assess the efficacy and safety of tarlatamab in patients with previously treated small cell lung cancer. The primary goal of the study was to assess participants’ complete or partial response, as evaluated by independent review using established evaluation criteria for solid tumor response.

The Amgen-sponsored trial included more than 200 patients with advanced small cell lung cancer whose cancer had progressed after at least two previous lines of treatment. The participants received tarlatamab intravenously every two weeks at a dose of either 10 milligrams (mg) or 100 mg.

The results were published on Oct. 20, 2023, in The New England Journal of Medicine. Paz-Ares was the corresponding author. The results he Paz-Ares and his colleagues reported showed that tumor size decreased in 40% of participants who received then 10-mg dose and in 32% of those who received the 100-mg dose. In more than half of the patients whose tumors shrank, the cancer did not progress for at least six months. The most common side effect was cytokine release syndrome, which is a systemic inflammatory response.

Out of options

The trial did not directly compare tarlatamab with other therapies for small cell lung cancer. Additionally, more research is needed to help predict which patients are more likely to respond to tarlatamab.

“Importantly, the study focused on [patients with] small cell lung cancer who were running out of other options, having already [experienced multiple treatment failures],” says Boffa, who was not involved in the study. Tarlatamab demonstrated “a reasonable safety profile and an impressive anticancer effect, as the cancer stopped growing in 30% of patients. And in 40% of patients, the amount of cancer was actually reduced,” Boffa says. “This is particularly interesting, because [more than] 70% of these patients had [experienced treatment failure with] other forms of immunotherapy.”

In December 2023, the FDA designated tarlatamab for priority review, and the FDA’s Prescription Drug User Fee Action (PDUFA) target for deciding whether to approve it is June 12, 2024. If approved, tarlatamab would become the first BiTE immunotherapy agent indicated for a major solid tumor.