Editor’s Note: For more on clinical decision making in the era of neoadjuvant immunotherapy, read a case for adjuvant treatment of resectable non-small cell lung cancer.
After decades without progress, we have finally seen multiple randomized phase 3 clinical trials improving upon the standard of care in early-stage, resectable non-small cell lung cancer (NSCLC). This brief commentary covers the saga of neoadjuvant therapy in lung cancer, a historic underdog that has finally claimed its foothold, and it is an appropriate treatment for most patients with early-stage, resectable NSCLC.
Neoadjuvant Therapy in Lung Cancer: A Historic Underdog
It is no secret that neoadjuvant therapy has long been the underdog in lung cancer. The earliest potentially practice-changing clinical trials of neoadjuvant cisplatin-based chemotherapy were closed short of full accrual (despite their notably smaller sample sizes) when contemporaneous adjuvant studies showed improved overall survival (OS) compared to surgery alone.1 These adjuvant studies, when pooled, documented a modest OS improvement of 5% (5-15% depending on stage).2,3 This real—but underwhelming—5% OS advantage for cisplatin-based adjuvant chemotherapy further fueled the clinical dissuasion of neoadjuvant chemotherapy, leaving the routine practice of induction chemotherapy to a few staunch believers.
Then, the era of checkpoint inhibitor immunotherapy (IO) quickly took over the management of patients with metastatic lung cancer, first in the 2nd line treatment setting and shortly thereafter as front-line treatment. This fueled tremendous interest in the use of these incredibly effective drugs in the early-stage curative setting, including neoadjuvant therapy. However, in 2018, another advance for the treatment of lung cancer, the approval of durvalumab after concurrent chemoradiotherapy in patients with stage III lung cancer dealt another blow to the concept of neoadjuvant therapy and became the most adopted management approach. Hence, the pendulum swung further away from offering surgery to patients with stage III lung cancer towards definitive chemoradiation followed by IO.
Compelling Data for IO in Early-Stage Lung Cancer
As a clinical investigator trained in the era of precision medicine, the thought of treating patients with neoadjuvant IO monotherapy, without a known predictive biomarker was somewhat illogical. However, the classic ‘window of opportunity’ trial design lent a perfect opportunity for signal finding—both efficacy and biomarkers. The first study of neoadjuvant nivolumab x 2 doses, induced unanticipated amounts of tumor regression (pathologic response) and put forth many hypotheses about durable antitumor response.4 This small study was followed by the much larger LCMC3 study of atezolizumab monotherapy as well as the multi-arm NEOSTAR study, both showing dramatic tumor killing in small subsets of patients but without a consistent and easily applicable predictive biomarker.
As desirable as IO monotherapy was from a toxicity standpoint, without a predictive biomarker and with truly unprecedented efficacy signals from two single-arm chemoimmunotherapy studies, randomized studies were designed with the combination therapy approach. CheckMate 816 was the first randomized phase 3 study to be reported, showing an 11-month improvement in median event free survival (EFS) and a 14-fold increase in pathologic complete response with the addition of nivolumab to 3 cycles of platinum-based therapy.7 The chemotherapy-nivolumab regimen was approved by the US Food & Drug Administration and is the only purely neoadjuvant regimen with no standard provision of immunotherapy post resection.
We have since seen results of three perioperative IO studies, each comparing neoadjuvant chemotherapy with or without IO and adjuvant IO to neoadjuvant chemotherapy alone. KEYNOTE-671 was published this year showing pembrolizumab, when added to cisplatin and pemetrexed or cisplatin and gemcitabine, significantly improved EFS with a hazard ratio of 0.58 at 24 months.8 Similarly, as presented at the American Association for Cancer Research annual meeting, the addition of durvalumab to preoperative chemotherapy improved EFS by 32% and increased pathologic complete response from 4% to 17%.9 Finally, data presented at the 2023 American Society of Clinical Oncology Plenary Series, showed the addition of toripalimab to chemotherapy followed by adjuvant IO likewise improved EFS.10 We anticipate that each of these perioperative regimens will be approved, forcing us to decide in the clinic if a perioperative strategy offers more than a neoadjuvant only treatment approach.
Through appropriate prescription of neoadjuvant therapies, we have the opportunity to cure more patients. While neoadjuvant chemoimmunotherapy will not be appropriate for all patients, it is a window of opportunity that we should not miss for the majority of patients who are candidates for this approach.
Neoadjuvant Chemoimmunotherapy: Why Change Practice Now?
Cross-trial comparisons, between neoadjuvant chemoimmunotherapy, definitive chemoradiation with consolidation IO, and upfront surgery followed by adjuvant chemotherapy and subsequent IO are essentially impossible; the populations and endpoints are too different. Support for a neoadjuvant approach for most patients with medically operable and resectable stage II-III lung cancer can be built on two main pillars.
The first pillar is the biologic hypothesis that IO will induce a better antitumor response when administered while the tumor remains in situ. This is supported by the melanoma literature, showing a statically improved EFS with neoadjuvant and adjuvant pembrolizumab compared to adjuvant pembrolizumab alone.11 This trial clinically confirmed the hypothesis supported by many preclinical models and would likely be recapitulated in lung cancer trials (if ever conducted).
The second pillar is data driven but requires some extrapolation—neoadjuvant therapy is what is best for most patients. The CheckMate 816 data confirmed a high complete resection rate and more lung sparing surgeries (fewer pneumonectomies) following chemoimmunotherapy compared to chemotherapy alone.7 Neoadjuvant therapy allows time for preoperative smoking cessation and ‘prehabilitation’, as well as individualized assessment of treatment efficacy. While this in vivo efficacy assessment does not influence care today (the 816 regimen was neoadjuvant only), we anticipate approval of multiple regimens that prescribe both pre- and post-operative IO. For safety and cost considerations, evaluating response to preoperative therapy could and should eventually guide the adjuvant treatment phase—something that cannot be done with an adjuvant only approach.
For the naysayers who focus on the reality that not all patients who are treated with neoadjuvant therapy undergo surgery or have a complete resection, the unfortunate truth is that most patients with resected stage II-III lung cancer die of recurrent lung cancer. The US National Cancer Institute-sponsored ALCHEMIST initiative has prospectively collected clinical and pathologic data on patients who undergo upfront resection in the US. Only 53% of patients had guideline compliant lymph node dissections (i.e., adequate staging) and only 57% received any adjuvant chemotherapy.12 With more effective systemic therapy now approved in the neoadjuvant setting, these results will almost certainly improve.
There are caveats, of course. Neoadjuvant chemoimmunotherapy is not appropriate for all patients and should not be prescribed to those with incomplete predictive biomarker data (at a minimum EGFR and ALK status), to those at risk for autoimmune complications due to pre-existing comorbidities, to patients at risk of hemorrhagic or post-obstructive complications of their tumor, or to those not medically fit for surgery or with technically unresectable tumors.
The Window of Opportunity
While the obvious future direction is a comparative study of pre- versus post-operative chemoimmunotherapy, this is a study that, if done, will not have results for years. Today, we can treat our patients with EGFR/ALK-negative lung cancer with neoadjuvant chemoimmunotherapy: to ensure they receive systemic therapy and not just surgery alone and to potentially enable a lung-sparing surgery. Thoracic medical oncologists can only do so if surgeons refer patients preoperatively and the appropriate biomarker testing is done. Furthermore, medical oncologists have the obligation to question thoroughly to ensure no contraindications to chemotherapy and IO and to retest after induction therapy to ensure endocrinopathies are identified and managed before the operative date.
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