Targeted Therapy, Immunotherapy Propel 10 Years of Progress in NSCLC

H. Jack West, MD

With the advent of targeted therapies and immunotherapies, coupled with investigators’ growing understanding of molecular subtypes, outcomes for patients with non–small cell lung cancer (NSCLC) have seen a dramatic uptick in the last decade.

H. Jack West, MD, an associate clinical professor in medical oncology and the executive director of employer services at City of Hope Comprehensive Cancer Center in Duarte, California, stated in an interview with Targeted Therapies in Oncology™ that a significant advance in lung cancer has been the redistribution of NSCLC into different subtypes based on the extent of tumor PD-L1 expression and the presence of driver mutations in more than one-third of patients. He added that the progress seen in the last few years in advanced NSCLC is most notably via targeted therapies and immunotherapy, which are now being integrated into the curative setting.

“There are now a broad range of algorithms for managing multiple subtypes, and for many of these, survival in advanced disease is now in the range of years,” West said.

Nils H. Thoennissen, MD, an international specialist in lung cancer at Ludwig Maximilian University of Munich, Germany, said that first-line treatment of advanced or metastatic NSCLC has changed dramatically over the past decade. This includes novel immunotherapies, such as the immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4, and targeted therapies, such as tyrosine kinase inhibitors (TKIs), which have demonstrated significant benefit for several patients with NSCLC, sparing them from the toxic effects of chemotherapy.

Approaches Prior to 2012

Lung cancer is among the most lethal cancers in both men and women, with a higher death rate than colon, breast, and pancreatic cancer combined—the 3 most prevalent malignancies. NSCLC makes up 85% of all lung cancers, with squamous cell carcinoma, adenocarcinoma, and large cell carcinoma being its 3 subtypes; SCLC makes up the remaining 15%.¹

Most patients with NSCLC present at an advanced, incurable stage. Chemotherapy used to be the major form of treatment for NSCLC; however, because of tolerability issues and adverse effects, chemotherapy became less popular. With the rapid development of cellular and molecular biotechnology, treatments have become more focused on specific regulatory molecules and genes.² Thoennissen explained that mutation-specific targeted therapies became available about 15 years ago, giving patients options to avoid toxic chemotherapy. At that time, fewer than 20% of individuals would survive for 5 years after a lung cancer diagnosis, and those with advanced NSCLC typically lived only a few months. With advancements in treatments over the past several years, survival rates have improved considerably.³

Early Days of Targeted Therapy

Prior to 2012, one of the fi rst targeted therapies was the first-generation EGFR inhibitor gefitinib (Iressa), which was approved by the FDA in 2003.⁴ The agent, though, was originally approved for the treatment of all patients with advanced NSCLC, an indication which was later volunatrily withdrawn from the market after failed attempts to confirm clinical benefit in subsequent studies, before the awareness of EGFR as a biomarker. The FDA then granted approval to gefitinib in 2015 for the firstline treatment of patients with metastatic NSCLC harboring specific EGFR mutations.⁴

EGFR mutations are found in about 10% to 20% of lung cancers in the United States in individuals who have never smoked, and rates are even higher among Asian nonsmokers.⁵ Thoennissen said that gefitinib and other first-generation EGFR inhibitors established a therapeutic proof of principle for targeted therapies that also significantly improve survival.

Another prominent class of NSCLC alterations affect the ALK gene; these occur in approximately 5% to 8% of nonsquamous NSCLC cases, usually among female patients and nonsmokers.⁵ Crizotinib (Xalkori), a small molecule TKI that inhibits ALK, MET, and ROS1, was granted accelerated approval by the FDA in 2011, and full approval in 2013, for the treatment of patients with ALK-positive NSCLC. Incredibly, development for crizotinib took approximately 6 years from identifi cation of ALK aberrations to full approval by the FDA.⁶

Targeted Therapy in the Past Decade

The past decade has seen significant progress in precision medicine in NSCLC with the growth of targeted therapies and the identification of new targetable driver mutations. Targeted medications offer patients more therapeutic options with greater safety and efficacy.² New drugs come in successive generations, with each generation usually showing improved efficacy. Although drug resistance has emerged within targeted therapies, this is driving further research into newer and better drugs, as well as placing increasing importance on the necessity of molecular testing for all patients with NSCLC at diagnosis and at disease progression.^2,5 Guidelines currently recommend testing for approximately 10 different drivers upon molecular testing.⁷

“Molecular testing is a true quantum leap in how we deliver cancer care and what we can expect from our clinical outcomes,” West said. “Biomarker testing has undergone a complete transformation over the past decade, as there are now such a broad range of actionable molecular targets with associated targeted therapies that comprehensive molecular testing with next-generation sequencing is now a standard of care and is gaining overwhelming momentum as it can check for so many clinically relevant markers simultaneously.”

“Nearly all patients with NSCLC today...have a choice of therapeutic options. Patients with NSCLC who respond to targeted therapies or immunotherapies now routinely survive 3 to 4 years, with some surviving substantially longer,” said Thoennissen. The past decade has seen a second generation of EGFR inhibitors, including afatinib (Gilotrif) and dacomitinib (Vizimpro), which have bolstered performance by irreversibly inhibiting EGFR (TIMELINE).

A third-generation EGFR inhibitor, osimertinib (Tagrisso), that has also been approved by the FDA is effective against many resistant NSCLC tumors. It differs from previously developed agents because it was designed to target tumor-promoting forms of EGFR, including the T790M drug resistance mutation, but¡ not the normal protein.⁸ This selectivity led to even longer survival for people with advanced disease, according to Thoennissen. In the phase 3 AURA3 trial (NCT02151981), treatment with osimertinib led to a median progression-free survival (PFS) of 10.1 months compared with 4.4 months with platinum chemotherapy in patients with EGFR T790M mutation–positive advanced NSCLC who had progressed on a first-line EGFR TKI (HR, 0.30; 95% CI, 0.23-0.41; P < .001).⁹

Most of these EGFR inhibitors work best against the most common EGFR mutations, exon 19 deletions, and exon 21 L858R substitution mutations.^2,5 In more recent years, agents have also been developed to target less common mutations, such as EGFR exon 20 insertion mutations, which account for up to 10% of cases and are associated with a worse prognosis than other EGFR mutations.¹⁰ To date, 2 agents have already been approved by the FDA to target this very specific patient population: amivantamab (Rybrevant) and mobocertinib (Exkivity). In initial results from the phase 1 CHRYSALIS trial (NCT02609776), amivantamab demonstrated an overall response rate (ORR) of 40% (95% CI, 29%-51%) and a median duration of response (DOR) of 11.1 months (95% CI, 6.9-not reached).¹¹ In the EXCLAIM study (NCT02716116), mobocertinib led to an ORR of 28% and a median DOR of 17.5 months.¹²

The last decade has also seen more potent and selective inhibitors for ALK, such as second- generation alectinib (Alecensa), which was approved by the FDA in 2015 for patients with ALK-positive NSCLC that progressed on crizotinib, and third-generation agents such as lorlatinib (Lorbrena).¹³ Thoennissen has seen these new ALK-targeted therapies increase PFS from 10 months to over 30 months.

Newer Targets

c-MET is a proto-oncogene encoding the receptor tyrosine kinase protein with the hepatocyte growth factor ligand. Characteristic anomalies generating enhanced MET signaling activation include MET gene amplification and exon 14 skipping mutations. Three percent of NSCLC cases have an isolated MET exon 14 mutation, and in 15% to 20% of EGFR mutation–positive NSCLC cases, it is an acquired EGFR TKI resistance pathway. It has been demonstrated that crizotinib and cabozantinib (Cabometyx) have some action against MET.¹⁴ Newer agents for MET have since been developed, with capmatinib (Tabrecta) and tepotinib (Tepmetko) now approved by the FDA for the treatment of patients with MET exon 14 skipping mutations.

Over the past decade, agents have also been developed and approved to treat newer targets, including MET, RET, HER2, BRAF, and KRAS. KRAS is the most common mutated oncogene in NSCLC, accounting for about 20% to 25% of all cases. Although the mutation has been known for many years, researchers previously thought of KRAS as an undruggable target as prior attempts were unsuccessful. The recent discovery of newer approaches for targeting KRAS, including direct targeting of KRAS G12C, has excitingly led to the emergence of effective KRAS inhibitors.¹⁵ Sotorasib (Lumakras) became the first FDA-approved KRAS inhibitor in 2021, with an accelerated approval for the treatment of adults with advanced NSCLC with a KRAS G12C mutation who have received at least 1 prior systemic therapy. The approval was based on findings from the phase 1/2 CodeBreaK 100 study (NCT03600883), which showed an ORR of 36% (95% CI, 28%-45%) and a median DOR of 10 months with sotorasib.¹⁶

Most recently, an accelerated approval was granted to an antibody-drug conjugate, trastuzumab deruxtecan (Enhertu), for treating patients with advanced NSCLC with activating HER2 mutations, the first agent approved for targeting HER2 in this patient population after showing benefit in HER2-positive breast cancer. In the DESTINY-Lung01 trial (NCT03505710) data that led to the approval, trastuzumab deruxtecan showed an objective response rate of 55% (95% CI, 44%-65%) and a median DOR of 9.3 months (95% CI, 5.7-14.7). The median PFS was 8.2 months (95% CI, 6.0-11.9) and the median overall survival (OS) was 17.8 months (95% CI, 13.8-22.1).¹⁷

Immunotherapy

Immunotherapy has become a key part of NSCLC management after ICIs targeting the PD-1, PD-L1, and CTLA-4 checkpoints showed considerable benefit first in melanoma and then in lung cancer. As a result, James P. Allison, PhD, and Tasuku Honjo, MD, PhD, won the Nobel Prize in Physiology or Medicine in 2018 for their work with ICIs.¹⁸ The immune system uses these immune checkpoints for maintaining self-tolerance and regulating responses to protect tissue in the body. These pathways can be dysregulated by tumor resistance mechanisms.

“When treatment is successful with PD-1/ PD-L1 checkpoint inhibitors, it can double the overall survival in advanced NSCLC compared with chemotherapy, with some patients achieving even long-term remission,” Thoennissen said.

Multiple ICIs have already been approved for use as monotherapies and in combination regimens for treating patients with NSCLC, and research is ongoing to find further ways that immunotherapy can be used to improve patient outcomes. ICIs in combination with chemotherapy and targeted therapies remain an active area of investigation.¹⁹

The phase 2/3 Lung-MAP study (NCT03851445), which combined an ICI with a VEGF inhibitor, has yielded promising results, according to a presentation during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.²⁰ Investigators reported improved OS with ramucirumab (Cyramza) and pembrolizumab (Keytruda) compared with the standard of care. Additionally, because patients with NSCLC who were previously treated with immunotherapy and chemotherapy were included in the trial, the challenge of resistance to immunotherapy was addressed.

In the phase 3 CheckMate 9LA trial (NCT03215706), the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) were combined with 2 cycles of platinum-doublet chemotherapy and compared with 4 cycles of chemotherapy alone for patients with advanced NSCLC in the frontline setting. The regimen demonstrated a median OS of 15.6 months vs 10.9 months with chemotherapy alone (HR, 0.66; 95% CI,0.55-0.80).²¹ The combination was subsequently approved by the FDA.

Adjuvant Therapy

“At present, stage IV NSCLC is usually not considered curable, but newer treatments are prolonging survival and reducing cancer symptoms well beyond what was expected just a few years ago,” said Thoennissen.

He added that targeted therapies and checkpoint inhibitors have an even more profound effect if delivered earlier during NSCLC treatment when the disease may still be considered curable.²² Several trials a re exploring whether these treatments have greater benefits if applied to earlier-stage cancers. The possibility of this was seen in data from the phase 3 PACIFIC trial (NCT02125461) of consolidation with durvalumab (Imfi nzi) in patients with unresectable stage III NSCLC following chemoradiation. Durvalumab led to an OS rate at 2 years of 66.3% (95% CI, 61.7%-70.4%) compared with 55.6% (95% CI, 48.9%-61.8%) with placebo (2-sided P = .005).²³

In 2020, results from the phase 3 ADAURA trial (NCT02511106) showed that when osimertinib was given to patients with stage IB to IIIA NSCLC with EGFR-mutated tumors after surgery, disease-free survival (DFS) was significantly improved. In patients with stage II to IIIA disease specifi cally, 90% of patients were alive and disease free at 2 years compared with 44% in the placebo group (HR, 0.17; 99.06% CI, 0.11-0.26; P < .001). In the overall population, the DFS rate at 2 years was 89% with osimertinib and 52% with placebo (HR, 0.20; 99.12% CI, 0.14-0.30; P < .001).²⁴ That consequently led to the agent’s approval by the FDA in 2020 as an adjuvant treatment.

In addition, in June 2022 the FDA accepted the application for pembrolizumab as an adjuvant therapy for stage IB to IIIA NSCLC following complete surgical resection. Acceptance was based on results from the phase 3 KEYNOTE-091 trial (NCT02504372), in which the median DFS was 53.6 months with pembrolizumab vs 42.0 months with placebo (HR, 0.76; 95% CI, 0.63-0.91; P = .0014).²⁵

Findings from the open-label phase 3 CheckMate 816 trial (NCT02998528), which explored the use of nivolumab plus platinum- based chemotherapy vs chemotherapy alone prior to surgery in patients with stage IB to IIIA resectable NSCLC, were presented at the 2022 ASCO Annual Meeting.25 Median event-free survival, the primary end point of the trial, with neoadjuvant chemoimmunotherapy was 31.6 months (95% CI, 30.2-not reached) compared with 20.8 months (95% CI, 14.0-26.7) with chemotherapy alone (HR, 0.63; 97.38% CI, 0.43-0.91; P = .05).²⁶

Thoennissen expects that targeted therapies and immunotherapies will not be limited to advanced metastatic NSCLC and that they will have a strong position in early disease stages and signifi cantly impact the cure rates vs chemotherapy and/or radiation.

“We should continue to see steady gains in new targets and improvements in our targeted therapies that make these options available for an ever-larger subgroup of patients with NSCLC who can derive longer duration of benefit from additional lines of treatment. Progress will come faster as we see new results with targeted therapies and immunotherapy from trials of patients with curable NSCLC, largely recapitulating the remarkable gains we’ve achieved in stage IV over the last decade, and truly transforming our approach to resectable and locally advanced unresectable NSCLC,” West said.

_References:

_{1. Zappa C, Mousa SA. Non-small cell lung cancer: current treatment and future advances. Trans Lung Cancer Res. 2016;5(3):288-300. doi:10.21037/tlcr.2016.06.07}

_{2. Ye Z, Huang Y, Ke J, Zhu X, Leng S, Luo H. Breakthrough in targeted therapy for non-small cell lungcancer.Biomed Pharmacother. 2021;133:111079. doi:10.1016/j.biopha.2020.111079}

_{3. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):640-649. doi:10.1056/NEJMoa1916623}

_{4. Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets.Oncologist. 2003;8(4):303-306. doi:10.1634/theoncologist.8-4-303}

_{5. Imyanitov EN, IyevlevaAG, Levchenko EV. Molecular testing and targeted therapy for non-small cell lung cancer: current status and perspectives. Crit Rev Oncol Hematol. 2021;157:103194. doi:10.1016/j.critrevonc.2020.103194}

_{6. Kazandjian D, Blumenthal GM, Chen HY, et al. FDA approval summary: crizotinib for the treatment of metastatic non-small cell lung cancer with anaplastic lymphoma kinase rearrangements.Oncologist. 2014;19(10):e5-e11. doi:10.1634/theoncologist.2014-0241}

_{7. NCCN.Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 5.2022.Accessed November 2, 2022. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf}

_{8. Santarpia M, Liguori A, Karachaliou N, et al. Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy. Lung Cancer (Auckl). 2017;8:109-125. doi:10.2147/LCTT.S119644}

_{9. Mok TS, Wu YL, Ahn MJ, et al; AURA3 Investigators. Osimertinib or platinum–pemetrexed in EGFR T790M–positive lung cancer. N Engl J Med. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674}

_{10. Wang F, Li C, Wu Q, LuH. EGFR exon 20 insertion mutations in non-small cell lung cancer. Transl Cancer Res. 2020;9(4):2982-2991. doi:10.21037/tcr.2020.03.10}

_{11. Park K, Haura EB, LeighlNB, et al. Amivantamab in EGFR exon 20 insertion–mutated non–small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase Istudy. J Clin Oncol. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662}

_{12. Ramalingam SS, Zhou C, Kim TM, et al. Mobocertinib (TAK-788) inEGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study. J Clin Oncol. 2021;39(suppl 15):9014. doi:10.1200/JCO.2021.39.15_suppl.9014}

_{13. Larkins E, Blumenthal GM, Chen H, et al. FDA approval: alectinib for the treatment of metastatic, ALK-positive non-small cell lung cancer following crizotinib.Clin Cancer Res. 2016;22(21):5171-5176. doi:10.1158/1078-0432.CCR-16-1293}

_{14. Puccini A, Marin-Ramos NI, Bergamo F, et al. Safety and tolerability of c-MET inhibitors in cancer. Drug Saf. 2019;42(2):211-233. doi:10.1007/s40262-018-0780-x}

_{15. Corral de la Fuente E, Olmedo Garcia ME, Gomez Rueda A, Lage Y, Garrido P. Targeting KRAS in non-small cell lung cancer.Front Oncol. 2022;11:792635. doi:10.3389/fonc.2021.792635}

_{16. Nakajima EC, Drezner N, Li X, et al. FDA approval summary: sotorasib for KRASG12C-mutated metastatic NSCLC.Clin Cancer Res. 2022;28(8):1482-1486. doi:10.1158/1078-0432.CCR-21-3074}

_{17. Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Trial Investigators. Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. 2022;386(3):241-251. doi:10.1056/NEJMoa2112431}

_{18. Huang PW, Chang JWC. Immune checkpoint inhibitors winthe 2018 Nobel Prize.Biomed J. 2019;42(5):299-306. doi:10.1016/j.bj.2019.09.002}

_{19. Cheng B, Xiong S, Li C, et al. An annual review of the remarkable advances in lung cancer clinical research in 2019. J Thor Dis.2020;12(3):1056-1069. doi:10.21037/jtd.2020.03.11}

_{20. Reckamp KL, Redman MW, Dragnev KH, et al. Phase II randomized study of ramucirumab and pembrolizumab versus standard of care in advanced non-small-cell lung cancer previously treated with immunotherapy-Lung-MAP S1800A. J Clin Oncol.2022;40(21):2295-2306. doi:10.1200/JCO.22.00912}

_{21. Paz-Ares L, Ciuleanu TE, Cobo M, et al. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase3 trial. Lancet Oncol. 2021;22(2):198-211. doi:10.1016/S1470-2045(20)30641-0}

_{22. Chen R, Manochakian R, James L, et al.Emerging therapeutic agents for advanced non-small cell lung cancer.J Hematol Oncol.2020;13(1):58. doi:10.1186/s13045-020-00881-723.Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697}

_{24. Wu YL, Tsuboi M, He J, et al; ADAURA Investigators.Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}

_{25. O’Brien M, Paz-Ares L, Marreaud S, et al; EORTC-1416-LCG/ETOP 8-15 –PEARLS/KEYNOTE-091 Investigators. Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial.Lancet Oncol. 2022;23(10):1274-1286. doi:10.1016/S1470-2045(22)00518-6}

_{26. Passiglia F, Bertaglia V, Reale ML, et al. Major breakthroughs in lung cancer adjuvant treatment: looking beyond the horizon. Cancer Treat Rev.2021;101:102308. doi:10.1016/j.ctrv.2021.102308}