Immunotherapy Must Become More Precise and Personalized in Lung Cancer

Roy S. Herbst, MD

Physicians treating lung cancer can point to significant, but qualified, successes over the past 20 years, said Roy S. Herbst, MD. To continue making progress, investigators must keep pushing the science in new directions even as immunotherapy becomes more available in earlier lines of treatment.

Lung cancer incidence and mortality have declined by 51% for men since 1990 and by 26% in women since 2002, in large part due to reductions in smoking. Over that same period, oncologists have added targeted therapies and immunotherapies, as well as new, more effective, chemotherapy regimens to the armamentarium.

However, lung cancer remains one of the world’s leading causes of death, accounting for more than 2.21 million cases annually.¹ Most patients, 78.9% in one study, with small cell lung cancer will relapse despite initially responding to chemotherapy.² In real-world results from the KINDLE study, 62% of patients with resectable non–small cell lung cancer (NSCLC) worldwide relapsed following frontline treatment.³ Herbst noted that the recurrence rate can be as high as 80% in patients with stage III disease.

“But I think the future is bright, and it’s really very exciting. I would say that what happens in medicine and oncology, and [what] we have to avoid, is just combining drugs,” Herbst said. “It may work once in a while, but we really need to use science. We have to understand why the tumor is resistant to immunotherapy, to targeted therapy and how we can more precisely [target that resistance] . . .That’s what I would propose be the next step—understanding resistance and then targeting it more specifically.”

Herbst, the 2022 Giants of Cancer Care^® award winner for lung cancer, delivered the Giants address during the 20th Annual Winter Lung Conference. He is the Ensign Professor of Medicine (Medical Oncology) and professor of pharmacology; director, Center for Thoracic Cancers; and assistant dean for translational research with the Yale School of Medicine; chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital; deputy director, Yale Cancer Center; and co-principal investigator and community outreach co-leader for the Cancer Disparities Firewall Project in New Haven, Connecticut.

Looking at immunotherapy, Herbst said that some patients have “cold” tumors—T cells in the tumor microenvironment are either absent or do not respond to signals to attack the tumor. “You can do everything you want to that tumor, the tumor just doesn’t care, and you never get the T cells in the tumor. We call that immune desert,” he added.

The challenge going forward, he said, is learning how to make those tumors “hot” so they respond to immunotherapy and detecting the patients most like to benefit. Identifying biomarkers is key, but the value of tumor mutational burden (TMB) is still being refined.

“Smoking status and having smoked, ironically, is a better predictor of who’s going to benefit from immunotherapy,” Herbst said. “Why? Because if you smoked, you have more mutations in your tumor and you have more chance of having activity from the drugs.”

Immunotherapy Moves Into Earlier Stages of Therapy

Herbst reviewed some of the latest data for immunotherapy that are remaking lung cancer care. The FDA approved pembrolizumab (Keytruda) as adjuvant treatment following resection and platinum-based chemotherapy for stage IB, II, or IIIA NSCLC based on findings from the multicenter, randomized, triple-blind, placebo-controlled KEYNOTE-091 trial (NCT02504372).⁴

Investigators randomly assigned patients who had not received neoadjuvant radiotherapy or chemotherapy to 200 mg pembrolizumab or placebo intravenously every 3 weeks for up to 1 year. Patients were stratified by receipt of adjuvant chemotherapy and region of the world. Of the 1177 patients who were assigned to therapy, 1010 (86%) received adjuvant platinum-based chemotherapy following complete resection.

The median disease-free survival, the primary end point, was 58.7 months in the pembrolizumab arm (95% CI, 39.2-not reached [NR]) vs 34.9 months (95% CI, 28.6-NR) in the placebo arm (HR, 0.73; 95% CI, 0.60-0.89).

“Now we’re using pembrolizumab as an adjuvant therapy, the earliest stages of disease,” Herbst said. “Actually, I think this is the most amazing trial. This sort of changed the world.”

He noted that, based data from the phase 3, global, multicenter, open-label, randomized IMpower010 trial (NCT02486718), physicians have incorporated adjuvant atezolizumab (Tecentriq) into their practices. The trial assessed the anti–PD-L1 monoclonal antibody vs best supportive care (BSC) for patients with stage IB-IIIA NSCLC.

Investigators in IMpower010 assigned 507 patients to 16 cycles of 1200 mg atezolizumab every 3 weeks. In the control group, 498 patients were assigned to BSC. Patients in both groups received either IV cisplatin 75 mg/m² on day 1 of up to four 21-day cycles, IV vinorelbine 30 mg/m² given on days 1 and 8, IV docetaxel 75 mg/m² administered on day 1, IV gemcitabine 1250 mg/m² given on days 1 and 8, and IV pemetrexed 500 mg/m² administered on day 1.⁵

After a median follow-up of 32.2 months (interquartile range, 27.4-38.3), atezolizumab treatment improved disease-free survival (DFS) compared with BSC in the intention-to-treat population (HR, 0.81; 95% CI, 0.67-0.99; P = .040). Atezolizumab also induced superior DFS overall (HR, 0.79; 95% CI, 0.64-0.96; P = .020) and in patients whose tumors expressed PD-L1 on 1% or more of tumor cells (HR, 0.66; 95% CI, 0.50-0.88; P = .0039).

In findings from the neoadjuvant CheckMate 816 trial (NCT02998528) published in 2022, nivolumab (Opdivo) in combination with platinum-based doublet chemotherapy extended event-free survival (EFS) in patients with stage IB-IIIA non–small cell lung cancer (NSCLC).⁶

At a median follow-up of 29.5 months, the median event-free survival (EFS) was 31.6 months (95% CI, 30.2 -NR) with nivolumab plus chemotherapy vs 20.8 months (95% CI, 14.0-26.7) with chemotherapy alone (HR, 0.63; 97.38% CI, 0.43-0.91; P = .005). Twenty-four percent of patients in the experimental arm had pathologic complete response ([pCR] 95% CI, 18.0-31.0) compared with 2.2% (95% CI, 0.6%-5.6%) in the placebo arm (odds ratio, 13.94; 99% CI, 3.49-55.75; P <.001). Outcomes for EFS and pCR favored the nivolumab/chemotherapy combination in most subgroups evaluated.

The median overall survival was not reached in either group (HR, 0.57; 99.67 CI, 0.30-1.07; P = .008).

“It’s hard to do neoadjuvant therapy. You have to have a tumor board and want to discuss it,” Herbst said. “But I think it’s going to change the way we think about lung cancer and the way we collaborate and work together.”

References

1. World Health Organization. Fact sheets: Cancer. February 3, 2022. Accessed February 7, 2023. https://bit.ly/2CSR75X
2. Yu L, Xu J, Qiao R, Zhong H, Han B, Zhong R. Patterns of recurrence and survival rate after complete resection of pathological stage N2 small-cell lung cancer. Front Oncol. 2021;11:675354. doi:10.3389/fonc.2021.675354
3. Jazieh AR, Onal HC, Tan DSW, et al. Real-world treatment patterns and clinical outcomes in patients with stage iii nsclc: results of KINDLE, a multicountry observational study. J Thorac Oncol. 2021;16(10):1733-1744. doi:10.1016/j.jtho.2021.05.003
4. FDA approves pembrolizumab as adjuvant treatment for non-small cell lung cancer. News release. FDA. January 26, 2023. Accessed February 7, 2023. https://bit.ly/3EbREzt
5. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5
6. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170