Building on Momentum Is Vital in Lung Cancer

Suresh S. Ramalingam, MD, FASCO, the Roberto C. Goizueta Chair for Cancer Research, professor, Department of Hematology and Medical Oncology, and deputy director of the Winship Cancer Institute of Emory University

Suresh S. Ramalingam, MD, FASCO

Advancements in the prevention and treatment of patients with lung cancer have picked up momentum over the past decade and now is the time to build on that progress according to Suresh S. Ramalingam, MD, FASCO. In a presentation at the 2020 Winter Lung Cancer Conference^® Ramalingam reviewed major advancements in lung cancer and identified key areas of focus for the field.¹

“There are a lot of challenges, but I think it is fair to say that we have made substantial progress in lung cancer—patients are living longer and better and it is up to us to build on this momentum,” Ramalingam said. He is the Roberto C. Goizueta Chair for Cancer Research, professor, Department of Hematology and Medical Oncology, and deputy director of the Winship Cancer Institute of Emory University.

Building on the advancements in molecular classification, continued exploration of the utility of plasma circulating tumor DNA (ctDNA) and making preventative CT screening accessible for high-risk individuals are 3 important areas for research and education.

Personalizing Medicine In Lung Cancer Holds Strong

Since the detection of EGFR in 2004, lung cancer has been at the forefront of precision medicine. With agents available in the first-line setting for patients with EGFR, ALK, ROS1, BRAF, and NTRK mutations; in the second-line setting for patients with EGFR and ALK mutations; and in the third-line setting for patients with ALK mutations, Ramalingam noted that these therapies have “made survival possible for years as opposed to months when lung cancer was just consistently treated with chemotherapy.”

Looking at EGFR specifically, Ramalingam noted that there have been significant advances in the past 15 years. Five agents are approved to target the mutation, with osimertinib (Tagrisso) approved in both the first- and second-line settings. Recent osimertinib data demonstrated its continued utility 5 years after its approval.

The FLAURA study (NCT02296125) examined osimertinib in the frontline setting compared with the standard EGFR TKIs gefitinib (Iressa) and erlotinib (Tarceva). Osimertinib demonstrated a median overall survival (OS) of 38.6 months (95% CI, 34.5-41.8) compared with 31.8 months (95% CI, 26.6-36.0) with erlotinib or gefitinib (HR, 0.799; 95% CI, 0.641-0.997; P = .0462). The 12-, 14-, and 36-month OS rates were 89%, 74%, and 54% for osimertinib (n = 279) and 83%, 59%, and 44% for the comparator EGFR TKI arm (n = 277), respectively.²

At 3 years, 28% of patients in the osimertinib group and 9% in the comparator group continued on treatment and the median exposure was 20.7 months and 11.5 months, respectively.²

“There is a lot of exciting progress happening in the space and this has been made possible by technologies that allow us to sequence patient’s tumors and help identify the best treatment option for a given patient,” Ramalingam said.

However, molecular testing is not done as often as it should be, according to Ramalingam. Data from a global survey conducted by the International Association for the Study of Lung Cancer demonstrated that 50% to 60% of respondents (N = 2537) said that they are performing molecular testing in their clinic, however 61% reported that most patients in their country do not receive molecular testing. The primary barriers for molecular testing are time, awareness, access, quality, and cost.³

Guided Therapy Using ctDNA Is the Future

The role of ctDNA in lung cancer is in molecular testing to understand mechanisms of resistance to targeted therapy, yet there are data to suggest that ctDNA appears to have a prognostic ability to identify acquired resistance following treatment with an EGFR TKI.

Results from the AURA3 study (NCT02151981) demonstrated that early clearance of mutations in ctDNA is predictive of outcomes. Plasma samples were collected at baseline and at 3 weeks and again at 6 weeks following treatment with second-line osimertinib and samples were considered to be cleared if both EGFR TKI—sensitive and t790M EGFR mutations were undetectable. The median progression-free survival was longer in patients with clearance of plasma EGFR at 6 weeks (11.1 months; 95% CI, 8.3-12.6) compared with those patients who had detectable mutations (5.7 months; 95% CI, 4.1-7.7).⁴ Additionally, overall response rate was higher in patients with clearance of plasma (87% vs 53%, respectively).

Based on this data, Ramalingam suggested that future clinical trials should be designed to examine therapies introduced at 3 and 6 weeks based on plasma clearance. “Based on 3- and 6-week samples, we need to develop more aggressive strategies for those patients who come with persistence, that’s a point where you would bring in chemotherapy or other novel combination therapy approaches,” he said.

ctDNA has also shown utility in the early identification of patients who will progress down the line on therapy. In more data from the FLAURA trial, ctDNA monitoring identified patients who progressed on first-line EGFR-TKI therapy as well as detected EGFR-mediated resistance mechanisms in advance of disease progression. Of 122 patients in the analysis population, 80 (66%) had ctDNA that was able to identify the emergence of resistance earlier than scans showed.¹

Based on these data, potential uses of ctDNA include screening, risk stratification, and response assessment; however, more research is needed for validation.

“ctDNA has a lot of promise and establishing its role in initial work up in advanced-stage disease is evolving,” Ramalingam said. “There is enough of a case to say that in a patient with newly diagnosed lung cancer you would want both tissue-based and plasma-based samples [taken] at the same time so you do not miss a mutation...Adapting therapy based on ctDNA clearance is ripe for the taking for the next wave of studies in the landscape.”

Early Detection

Despite the benefits seen with preventative CT screening, Ramalingam says that uptake in clinical practice for at-risk patients remains slow. Data from the NELSON trial, which randomized patients to assess lung cancer mortality with volume CT scanning, demonstrated a consistent reduction in mortality. At the 10-year follow-up, the cumulative ratio for death from lung cancer was 0.76 in men (n = 13,195; 95% CI, 0.61-0.94; P =.01) and 0.67 in women (n = 2594; 95% CI, 0.38 to 1.14) compared to those who did not undergo screening.⁵

Despite the data, early screening with CT has yet to become a standard in lung cancer as it is in colorectal and breast cancer. “I do not think early detection has been factored in [to the decline in lung cancer mortality]. We need to take what we’ve learned and how to apply that to our patients,” Ramalingam added, noting that awareness is 1 of the primary barriers to delivering care.

In analysis of the National Health Interview Survey, 3.9% of an estimated 6.8 million eligible subjects underwent preventative screening in 2015. There was not a significant increase in the number of screenings in the 5 years prior (3.3%) despite Medicare coverage. Further, only 36% of the physicians who participated in the survey were aware of the screening criteria.⁶

“We know that screened patients are 70% more likely to have stage I, II, or III disease, whereas unscreened, routine detected [patients with] lung cancer have a 50% chance of being diagnosed with stage IV disease and we know that we can cure more patients with stage I disease than stage IV disease,” Ramalingam said.

References

1. Ramalingam SS. Lung cancer therapies: exciting advances and opportunities. Presented at: 2020 Winter Lung Cancer Conference. February 7-9, 2020; Miami Beach, FL.
2. Ramalingam SS, Vansteenkiste J, Planchard D, et al; FLAURA Investigators. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med. 2020;382(1):41-50. doi: 10.1056/NEJMoa1913662.
3. Smeltzer M, Wynes M, Taylor K, et al. The International Association for the Study of Lung Cancer (IASLC) global survey on molecular testing in lung cancer. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract MA21.03.
4. Thress KS, Markovets A, Barrett JC, et al. Complete clearance of plasma EGFR mutations as a predictor of outcome on osimertinib in the AURA trial. J Clin Oncol. 2017;35(suppl 5; abstr 9018). doi: 10.1200/JCO.2017.35.15_suppl.9018.
5. de Koning HJ, van der Aalst CM, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382(6):503-513. doi: 10.1056/NEJMoa1911793.
6. Jemal A, Fedewa SA. Lung cancer screening with low-dose computed tomography in the United States-2010 to 2015. JAMA Oncol. 2017;3(9):1278-1281. doi: 10.1001/jamaoncol.2016.6416.

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