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Durable Responses in Metastatic NSCLC: Are We Getting Closer to a Cure?


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In the United States, the incidence-based mortality related to non–small cell lung cancer (NSCLC) has decreased by approximately 3% each year since 2008 in men; during the same period, the mortality in women decreased by 2% to 4% annually.1 Although multiple factors are likely responsible for the reduction in mortality, it is clear that the advent of several novel therapeutic options has improved the outlook for patients with NSCLC.

A Host of Novel Targeted Therapies

Presently, treatment options are personalized to individual patients based on genomic testing and PD-L1 expression testing. Targeted therapies have been approved by the U.S. Food and Drug Administration for nine different genomic driver mutations; these mutations account for nearly 40% to 50% of all cases of lung adenocarcinoma, which accounts for the majority of lung cancer. For this subset of patients, targeted therapies achieve objective responses in 25% to 90% and result in median progression-free survival of 6 to 35 months.

Suresh S. Ramalingam, MD

Suresh S. Ramalingam, MD

The advent of newer generations of tyrosine kinase inhibitors with improved target specificity and safety profile allows for patients to continue therapies for extended periods without suffering undue adverse events. Furthermore, knowledge regarding mechanisms of acquired resistance to targeted therapies has paved the way for novel approaches to overcome or delay resistance and provide further clinical benefits to patients even beyond initial therapy. Beyond the tyrosine kinase inhibition approach, a newer wave of therapies including monoclonal antibodies and antibody-drug conjugates is also associated with promising clinical benefit for certain difficult-to-treat targets such as HER2 mutation and EGFR insertion 20 mutation.2

Molecular Oncology: Guiding Treatment Choices

It is now well established that for patients with treatable driver mutations, targeted therapies provide the best results and should be standard first-line therapy for most patients (except for those who have tumors with KRAS G12C and EGFR insertion 20). For patients without a treatable driver mutation, immune checkpoint inhibitors are used routinely, either as monotherapy or as part of novel combination regimens.

For patients with high PD-L1 expression (≥ 50%), monotherapy with PD-1 or PD-L1 inhibitors provides durable benefits, with median survival exceeding 2 years, and a 5-year survival rate of more than 30%.3 The monotherapy approach is not as effective in patients with low or no PD-L1 expression; hence, the combination of PD-1 or PD-L1 inhibitors and platinum-based chemotherapy is used, with robust outcomes, though a durable benefit is observed in a smaller subset of patients compared with those who have high PD-L1 expression. More recently, the combination of PD-1 and CTLA-4 inhibition (nivolumab plus ipilimumab) has demonstrated the ability to provide long-term survival both in patients with PD-L1–positive and PD-L1–negative disease4; the 4-year survival rates are 29% and 24% for these two groups of patients respectively.

Patients Are Living Longer, but Are They Cured?

The durable progression-free survival and improved overall survival results observed with targeted therapies and immune checkpoint inhibitors in metastatic NSCLC represent a vast improvement over the median survival of just 6 to 8 months at the turn of the century.5 For patients with EGFR-mutated disease, the median survival is approximately 3 to 4 years6; for patients with ALK-positive disease, the median survival is 6 to 7 years.7

In addition, median progression-free survival of more than 2 years has been observed with several targeted agents that have just entered the clinic. The ability to provide effective control of brain metastasis with several targeted therapies has also made substantial contributions to improving survival outcomes for patients with metastatic NSCLC.

However, it is now clear that targeted therapies do not result in cure for metastatic NSCLC; it is only a matter of time before acquired resistance develops. On the other hand, it is no longer uncommon to see patients treated with immune checkpoint inhibitors present without evidence of disease several years after treatment has been discontinued. In fact, this raises the possibility that a subset, albeit a small one, of patients with NSCLC may be cured with immunotherapy. It is highly encouraging to learn that for patients who develop relapse after long-term remission with immune checkpoint inhibition, reintroduction of therapy may result in tumor responses again.

Fruits of Research Soon Ready for Harvest?

The conventional wisdom in lung cancer has been that a cure can be achieved only in early-stage disease, and the primary goal of therapy for metastatic disease is palliation and prolongation of survival. The durable outcomes achieved with immunotherapy have undoubtedly challenged this notion; indeed, in melanoma, immunotherapy has rendered a long-ago untreatable disease to one that is curable, even in an advanced stage.

Although precision therapies have advanced far in the realm of targeted therapies, personalizing immunotherapy is still at an early phase. PD-L1 expression as a biomarker guides treatment, but further innovation is necessary. Learning about the immune milieu of individual patients regarding the status of stimulatory and inhibitory signals, tumor neoantigens, and the robustness of the host immune system will be critical in advancing precision approaches that modulate the immune system. T-cell therapies that have been successful in certain hematologic malignancies are at an early phase of development in solid tumors, including lung cancer. Many highly innovative approaches to improve the efficacy of immunotherapy, specifically in the setting of overcoming resistance, are already under investigation.

Let us hope that the fruits of these lines of research will be ready for harvest soon and help us deliver cures to patients with metastatic lung cancer in the near future. 

DISCLOSURE: Dr. Ramalingam has received honoraria as an advisor or consultant to from Amgen, Astra Zeneca, Bristol Myers Squibb, Merck, Roche, Genmab, Eisai, Glaxo SmithKline, and Takeda; and has received institutional research support from Amgen, Astra Zeneca, Bristol Myers Squibb, Merck, Genmab, Glaxo SmithKline, and Takeda.

Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.

REFERENCES

1. Howlader N, Forjaz G, Mooradian MJ, et al: The effect of advances in lung-cancer treatment on population mortality. N Engl J Med 383:640-649, 2020.

2. Li BT, Smit EF, Goto Y, et al: Trastuzumab deruxtecan in HER2-mutant non-small-cell lung cancer. N Engl J Med. September 18, 2021 (early release online).

3. Garon EB, Hellmann MD, Rizvi NA, et al: Five-year overall survival for patients with advanced non-small-cell lung cancer treated with pembrolizumab: Results from the phase I KEYNOTE-001 study. J Clin Oncol 37:2518-2527, 2019.

4. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al: Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med 381:2020-2031, 2019.

5. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346:92-98, 2002.

6. Ramalingam SS, Vansteenkiste J, Planchard D, et al: Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382:41-50, 2020.

7. Mok T, Camidge DR, Gadgeel SM, et al: Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 31:1056-1064, 2020.

Dr. Ramalingam is the Roberto C. Goizueta Chair in Cancer Research and Executive Director, Winship Cancer Institute of Emory University, Atlanta.


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