COMMENTARY

Top 5 Advances in Lung Cancer Immunotherapy Over the Past Decade

H. Jack West, MD; Charu Aggarwal, MD, MPH

Disclosures

January 23, 2020

We've just come to the end of a remarkable decade of progress that has transformed how we treat—and, indeed, even how we view—lung cancer.

Rewind 10 years: As we entered 2010, median survival for patients with metastatic non-small cell lung cancer (NSCLC) in nearly all trials hovered around 1 year. We had just one targetable mutation, EGFR—a lone example of an actionable driver mutation with a commercially available targeted therapy. Immunotherapy studies had failed so often that attendees would leave conferences early, just as presentations on the promise of immunotherapy began. Treatments for small cell lung cancer (SCLC) and locally advanced NSCLC had been defined years earlier and seemed deeply entrenched after years of negative clinical trials. It was hard to envision a time when we might break this impasse.

Looking back on the past decade, we now recognize it as one that completely redefined thoracic oncology through a series of pivotal turning points. In a pair of columns for Medscape Oncology, one on immunotherapy and a second on molecularly targeted therapies, we'll highlight these turning points that changed clinical practice.

Here, then, are the top 5 developments in immunotherapy that we feel exerted the greatest impact on our current and future management of lung cancer.

1. Immunotherapy demonstrates a significant overall survival (OS) benefit in advanced NSCLC. Immune checkpoint inhibition of the programmed cell death 1 (PD-1) axis was initially demonstrated as effective by producing anticancer responses in previously treated patients with advanced NSCLC as well as melanoma and renal cell carcinoma, and lung cancer has continued to be at the forefront of developments of "immuno-oncology" since that time. This work subsequently led to the initial approval of nivolumab and other PD-1/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors as second-line therapy for advanced NSCLC.

The development was truly groundbreaking, ushering in a new era that continues to evolve. This initial report, presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2013, demonstrated the potential for profound benefit in a subset of patients using an entirely new form of systemic therapy. It proved that nivolumab could lead to dramatic and prolonged responses in some heavily pretreated patients, including those with any NSCLC histology and smokers—patients who had not been the main beneficiaries of prior advances in thoracic oncology in the years leading up to that point.

2. Pembrolizumab beats first-line chemotherapy in patients with NSCLC tumors with high tumor PD-L1 expression (> 50%). Immune checkpoint inhibitors had become commercially available by 2016 as second-line therapy, where they were widely used and consistently beat docetaxel.

It was in this setting that investigators presented the results of KEYNOTE-024 simultaneously at the 2016 annual congress of the European Society for Medical Oncology and in the New England Journal of Medicine. This trial—a first-line comparison of pembrolizumab versus histology-appropriate platinum doublet chemotherapy in patients with high tumor PD-L1 expression and without an EGFR mutation or ALK rearrangement—changed the management of advanced NSCLC quickly and irreversibly by demonstrating marked benefits across essentially all endpoints.

Just weeks later, the US Food and Drug Administration (FDA) approved pembrolizumab for NSCLC with high PD-L1 expression, which comprises approximately 30% of patients. Other changes that resulted from this work included the integration of tumor PD-L1 expression testing as a new standard of care in the initial patient workup, the adoption of immunotherapy without chemotherapy as a preferred first-line therapy, and the subsequent recognition that patients with an identifiable driver mutation represent a distinctly defined subset in whom targeted therapy remains the better option.

3. Chemotherapy-immunotherapy combinations prove reliably superior to chemotherapy doublets alone, regardless of tumor PD-L1 expression levels. In spring 2018, we saw highly positive results in the KEYNOTE-189 trial of first-line carboplatin-pemetrexed with or without pembrolizumab in patients with EGFR and ALK wild-type, nonsquamous NSCLC, regardless of tumor PD-L1 expression. This was followed just weeks later by the results of the remarkably similar KEYNOTE-407 trial of carboplatin-taxane (paclitaxel or nab-paclitaxel) with or without pembrolizumab in advanced squamous NSCLC, also with any (or no) degree of tumor PD-L1 expression.

These trials demonstrated clinically and significantly superior progression-free survival (PFS), OS, and response rate with the combination of chemotherapy and immunotherapy and, importantly, a rather limited increase in toxicity that did not extend beyond what we expected for these combinations. Of note, both of these trials demonstrated that the benefits deriving from the addition of pembrolizumab were comparable across the entire PD-L1 spectrum.

Combined chemotherapy-immunotherapy using histology-appropriate regimens thus became a new first-line standard of care, though whether patients with high PD-L1 should receive pembrolizumab monotherapy or chemotherapy plus pembrolizumab remains debatable. Other chemo-immunotherapy combinations have also demonstrated comparable superiority over chemotherapy alone, though none have eclipsed the KEYNOTE-189 and KEYNOTE-407 regimens in terms of efficacy or tolerability.

4. Consolidation durvalumab significantly improves survival and defines a new standard of care in stage III unresectable NSCLC. At the beginning of the past decade, chemoradiation—defined as 6-7 weeks of chemotherapy with concurrent chest radiation—had been the established standard of care for many years, though one that the oncology community desperately sought to improve upon. Several promising concepts had fallen by the wayside—consolidation gefitinib, consolidation docetaxel, and later a higher dose of chest radiation—with no benefit and even a net increase in harm with the addition of more treatment.

The PACIFIC trial broke this impasse. It randomly assigned patients with stage III unresectable NSCLC, regardless of tumor PD-L1 expression, to receive either durvalumab or placebo every 2 weeks if they demonstrated no progression after completing chemoradiation with any of a range of platinum-based combinations and concurrent chest radiotherapy.

Consolidation durvalumab initially won FDA approval by significantly improving PFS; however it was also later shown to significantly improve OS with no significant deterioration in quality of life. It now defines the clear new standard of care in a setting that had defied improvement for far too long.

5. Immune checkpoint inhibitor therapy is integrated with chemotherapy as first-line treatment in extensive-stage SCLC. Similar to stage III NSCLC, extensive-stage SCLC had been treated with cisplatin or carboplatin with etoposide for the entirety of most oncologists' careers (unless they were present when the ASCO meeting was held in a single hotel). Despite trials with many novel agents and investigational approaches over several decades, it wasn't until the IMpower133 trial demonstrated a significant OS benefit with atezolizumab and carboplatin-etoposide that first-line treatment for this disease was finally redefined. In the period since the publication of these results and the subsequent FDA approval of atezolizumab for extensive-stage SCLC, the CASPIAN trial also demonstrated very similar results with durvalumab combined with cisplatin or carboplatin plus etoposide in the same first-line setting for extensive-stage SCLC.

Critics of this new strategy cite the relatively modest median OS benefit—in the range of 2 months with chemo-immunotherapy relative to first-line chemotherapy alone—but the benefit is clinically meaningful for a subset of patients whom we have yet to prospectively define but hope to identify in the coming years. In the meantime, integrating an immune checkpoint inhibitor with first-line platinum-etoposide in extensive-stage SCLC represents the only reliable means by which all patients have the opportunity to benefit from immunotherapy.

Looking Forward

Given the progress over the past several years in immunotherapy, we should expect the field to continue evolving rapidly, not only for advanced NSCLC but hopefully by demonstrating a survival benefit in curative settings, such as early-stage NSCLC and limited-stage SCLC.

Although immunotherapy has dominated the conversation in thoracic oncology more recently, there were major advances with targeted therapies as well over the past decade. In a follow-up piece for Medscape, we will look at the top 5 developments in targeted therapies and new molecular targets in lung cancer.

H. Jack West, MD, associate clinical professor and executive director of employer services at City of Hope Comprehensive Cancer Center in Duarte, California, regularly comments on lung cancer for Medscape. Charu Aggarwal, MD, MPH, is an assistant professor in the Department of Medicine at the University of Pennsylvania and a contributor to Medscape Oncology Decision Point.

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