Expert Puts the Accent on Curative Potential in NSCLC Landscape

Tremendous progress in lung cancer treatments and outcomes makes thoracic oncology a bright spot in the cancer care firmament these days, but Mark A. Socinski, MD, clearly remembers when that was not the case.

When Socinski was completing his fellowship at Dana-Farber Cancer Institute in Boston, Massachusetts, in the late 1980s, the prevailing attitude was gloomy. “None of the other trainees wanted to go into lung cancer and the major medical journals ran editorials debating whether lung cancer was a treatable disease or whether patients should go straight to hospice,” he said. “But I viewed specializing in lung cancer as an opportunity matched to a mentor and that’s what drew me to the field.”

That mentor was Arthur T. Skarin, MD, a physician at Dana-Farber for 40 years before his retirement in 2010. Skarin, 87, died September 4, 2022; he pioneered the development of multimodal therapy for lung cancer, which resulted in survival improvements for patients with stage III disease.¹

Since his fellowship days, Socinski has become internationally known for his research into the molecular drivers of lung cancer and his contributions to the refinement of multidisciplinary care. He oversees a broad range of cancer specialties as executive medical director of AdventHealth Cancer Institute in Orlando, Florida.

“Dr Socinski is passionate about both scientific discovery and patient care and he is renowned for his thoughtful, methodical approach to research questions, which has led him to be considered one of the premier lung cancer experts in the nation,” Rogerio C. Lilenbaum, MD, said. “He’s also an excellent teacher and has mentored numerous physicians who are now considered experts in lung cancer in their own right.”

Socinski will bring that passion for education and mentoring to his longtime role as cochair of the 20th Annual Winter Lung Cancer Conference^®. Physicians’ Education Resource®, LLC (PER^®) is hosting the 3-day event February 3 to 5, 2023, as a hybrid meeting featuring live, interactive presentations in Hollywood, Florida, along with a virtual option.

Lilenbaum, who is senior vice president, chief physician executive, and director of the Anderson Family Cancer Institute at Jupiter Medical Center in Jupiter, Florida, will join Socinski as a cochair of the meeting. Also serving as a cochair is Julie R. Brahmer, MD, MSc, FASCO, director of the thoracic oncology program, professor of oncology, and the Marilyn Meyerhoff Professor in Thoracic Oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland.

Importance of Molecular Testing

When Socinski sat down recently with OncologyLive^® to discuss trends in lung cancer therapeutics, he was interested in reflecting on where clinical practice has been and on what lies ahead. “Looking back over roughly 30 years or so, I wouldn’t have believed the advances that we’ve made in lung cancer,” he said, referencing statistics first reported in 2021. “The United States as a country had the greatest annual reduction in cancer mortality that had ever been seen. And that reduction of cancer mortality was largely led by lung cancer and melanoma.”²

For Socinski, the single greatest advance in lung cancer has been an increased understanding of the disease’s biological underpinnings. “We talk about non–small cell lung cancer [NSCLC] as if it’s 1 disease, but now we know there are 20, 30, maybe even more different diseases [in the NSCLC category], so that EGFR-mutated lung cancer is different than ALK fusion lung cancer, which is different than [NSCLC] with high PD-L1 expression,” he said. “Being able to divide the [NSCLC] pie leads to more of a personalized approach. That’s why lung cancer has become the poster child for both targeted therapy and immunotherapy.”

Socinski has been instrumental in developing clinical trials that help determine how to slice that molecular pie. In 2012, he participated in a National Cancer Institute Thoracic Malignancy Steering Committee workshop in which experts set forth the principles of designing a master protocol for testing therapies in molecularly selected populations with NSCLC.³

The protocols led to the Lung-MAP umbrella study (S1400; NCT02154490), a public-private partnership launched in 2014. Approximately 1800 patients with squamous NSCLC participated in the original study and the protocol has since been expanded to include all advanced NSCLCs.^3-5

“Not every treatment or every new drug that we develop is going to work in everybody,” Socinski said. “But it’s probably going to work well in 10% of the patients or 2% of the patients, or 20% of the patients. We just have to be able to find those patients at diagnosis, and that’s where comprehensive genomic testing comes in.”

Increasing the uptake of molecular testing in patients with lung cancer is one of Socinski’s professional priorities. “We now have 9 biomarkers for which the FDA has approved targeted therapies. Every patient with lung cancer should have all 9 of those biomarkers tested,” he said. “Not doing that testing is like saying you don’t have to test for hormone receptor or HER2 status in breast cancer.”

Socinski finds the results of a MYLUNG Consortium study presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting to be a call to action.⁶ That study, based on chart reviews within US Oncology Network practices between 2018 and 2020, found that only 46% of patients with metastatic NSCLC initiating first-line therapy were tested for all of 5 key biomarkers: ALK, BRAF, EGFR, and ROS1 alterations, and PD-L1 status. Overall, 37% of patients underwent next-generation sequencing. “Less than 50% of patients, and they only looked at a panel of 5 biomarkers, not the full 9 for which targeted therapies exist,” he said. “That, to me, is not good.”

Lilenbaum was even more blunt. “The description of the EGFR mutation was published in 2004. The mere fact that we still debate whether patients should be tested or how to test them, or why the rates of testing are not what they should be, is quite honestly embarrassing,” he said. “If you are going to treat a patient with lung cancer, you cannot do so in a manner that is consistent with current standards if you do not have information about the molecular profile of that tumor.”

The Therapeutic Stage Migration of Lung Cancer

In assessing the state of lung cancer care today, Socinski marvels at the improvements in outcomes for patients with advanced disease. “I’ve counseled countless patients that they have a treatable disease, but they don’t have a curable disease,” he said. “And I think that’s changing. There are patients who we heretofore thought were not curable who may be cured.”

Part of achieving that goal involves what Socinski calls a “therapeutic stage migration” of research efforts so that oncologists can identify and treat patients with earlier-stage disease.

“We’ve spent a good part of the past decade focusing on metastatic disease or locally advanced disease. Now we’re seeing that focus shift to earlystage disease,” he said. “That’s important because, despite all the important and meaningful improvements we have seen in advanced disease, the cure rates will not change unless we’re able to improve the care of early-stage disease.”

Key Neoadjuvant Trial Updates

As part of the increased focus on earlier-stage disease, Socinski singled out several neoadjuvant trials with data reported this year as being of immediate relevance to practicing oncologists.

The CheckMate 816 study (NCT02998528) compared neoadjuvant therapy with nivolumab (Opdivo), a PD-1 inhibitor, plus platinum-doublet chemotherapy with chemotherapy alone in patients with resectable stage IB-IIIA NSCLC. The primary end points of this open-label phase 3 trial were event-free survival (EFS) and pathological complete response (pCR), with overall safety (OS) as an important secondary end point.⁷

The median EFS in the combination arm was 31.6 months (95% CI, 30.2-not reached) vs 20.8 months for chemotherapy alone (95% CI, 14.0-26.7), which translated into an HR for disease progression, recurrence, or death of 0.63 (97.38% CI, 0.43-0.91; P = .005). Nearly 1 in 4 patients in the nivolumab arm achieved a pCR (24.0%; 95% CI, 18.0%-31.0%) compared with 2.2% (95% CI, 0.6%5.6%) of those who received chemotherapy alone (OR, 13.94; P < .001). OS data remain immature.⁷

Shortly after publishing these results in the New England Journal of Medicine in May 2022,⁷ the authors presented post hoc data on the association of pathological regression with EFS at the 2022 ASCO Annual Meeting. Brahmer, the Winter Lung cochair, is among the investigators.⁸

The goal was to study the association between pCR and survival, as well as the degree of pathological regression that may be predictive of EFS for neoadjuvant immunotherapy. The investigators assessed EFS based on the depth of pathological regression measured by percentage of residual viable tumor (%RVT) in each patient’s primary tumor only. They then examined the predictive ability of %RVT on EFS at 2 years.

With a minimum follow-up of 21 months, EFS improved in patients who had either a pCR or a major pathological response, regardless of which treatment arm they were in. The %RVT appeared to be predictive of EFS at 2 years for patients in the combination group, but not the chemo- therapy-alone group.⁸

Patients who received nivolumab and had RVT of 0% to 5% had a 2-year EFS rate of 90%. EFS rates dropped successively as the %RVT increased, declining to 39% for those with more than 80% RVT. The investigators concluded that a strong pathological response in the primary tumor was associated with improved EFS with nivolumab plus chemotherapy. Further, the depth of the pathological regression appeared to predict improved EFS.⁸

Also garnering considerable interest was the OS and biomarker analysis from the NADIM trial (NCT03081689). This single-arm phase 2 study involved patients with resectable stage IIIA NSCLC who received neoadjuvant nivolumab plus paclitaxel and carboplatin followed by surgical resection and adjuvant nivolumab monotherapy for 1 year.⁹

At 3 years, the OS rate was 81.9% (95% CI, 66.8%-90.6%) in the intention-to-treat (ITT) population of 46 patients and 91.0% (95% CI, 74.2%-97.0%) in the per-protocol population of 37 patients who underwent tumor resection and at least 1 cycle of adjuvant therapy.⁹

Low baseline levels of circulating tumor DNA (ctDNA) were significantly associated with improved progression-free survival (PFS; HR, 0.20; 95% CI, 0.06-0.63) and OS (HR, 0.07; 95% CI, 0.01-0.39). Following neoadjuvant treatment, undetectable ctDNA levels were significantly associated with PFS (HR, 0.26; 95% CI, 0.07-0.93) and OS (HR, 0.04; 95% CI, 0.00-0.55). However, baseline PD-L1 expression of 1% or greater and tumor mutational burden of 10 or more mutations per megabase did not predict survival.⁹

Investigators concluded that neoadjuvant nivolumab plus chemotherapy resulted in “unprecedentedly high survival rates” and that ctDNA was a valid predictor of survival in this clinical setting.⁹

The regimen was further explored in the NADIM II trial (NCT03838159), a randomized phase 2 study evaluating the combination of neoadjuvant nivolumab plus paclitaxel and carboplatin vs the chemotherapy doublet alone in patients with locally advanced, potentially resectable stage IIIA-IIIB NSCLC without ALK or EGFR aberrations. Participants proceeded to surgery followed by adjuvant nivolumab for 6 months or observation, respectively. The primary end point was pCR, defined as absence of any viable tumor cell in the resected lung specimen and all regional lymph nodes in the ITT population.¹⁰

The pCR rate was 36.8% among those who received the nivolumab regimen (21 of 57 patients) vs 6.9% in the chemotherapy-alone arm (2 of 29 patients; P = .0068), according to findings presented at 2022 ASCO. Patients who did not undergo surgery (4 in the nivolumab arm, 9 in the chemotherapy-alone group) were considered nonresponders.¹⁰

The findings show that the neoadjuvant nivolumab plus chemotherapy regimen should be the standard of care in this population, investigators said.

Noteworthy Adjuvant Trial Updates

Updates have recently been published for 3 key lung cancer trials in the adjuvant setting (Table).^11-13 An interim analysis of OS data from the IMpower010 trial (NCT02486718) showed an OS trend in favor of adjuvant therapy with atezolizumab (Tecentriq), a PD-L1 inhibitor, compared with best supportive care in patients with stage II-IIIA NSCLC with PD-L1 expression of 1% or greater on tumor cells (TC).¹¹ In October 2021, the FDA approved atezolizumab following surgery and platinum-based chemotherapy for this population based on the disease-free survival (DFS) outcomes from IMpower010.¹⁴

After a median follow-up of 45.3 months, OS data were not yet mature. However, OS favored the atezolizumab group for participants with TC levels of at least 1% (HR, 0.71; 95% CI, 0.49-1.03) and 50% or higher (HR, 0.42; 95% CI, 0.23-0.78).11 “This is a very promising OS benefit for these high PD-L1 expressors, even though we don’t yet know whether this will turn out to be the final answer,” Socinski said.

The PACIFIC trial (NCT02125461) established consolidation therapy with durvalumab (Imfinzi), a PD-L1 inhibitor, after chemoradiotherapy as the standard of care for patients with unresectable stage III NSCLC. The 5-year OS data support use of the regimen for this population, investigators reported in the Journal of Clinical Oncology in April 2022.¹²

With a median follow-up of 34.2 months, the 5-year OS rates were 42.9% (95% CI, 38.2%-47.4%) with durvalumab and 33.4% (95% CI, 27.3%-39.6%) with placebo, whereas 5-year PFS rates were 33.1% (95% CI, 28.0%-38.2%) and 19.0% (95% CI, 13.6%-25.2%), respectively. OS remained consistent with the original PACIFIC data with a median OS of 47.5 months (95% CI, 38.1-52.9) with durvalumab vs 29.1 months (95% CI, 22.1-35.1) with placebo (stratified HR, 0.72; 95% CI 0.59- 0.89). PFS was also comparable with earlier results, with a median PFS of 16.9 months (95% CI, 13.0-23.9) with durvalumab vs 5.6 months (95% CI, 4.8-7.7) with placebo (stratified HR, 0.55; 95% CI, 0.45-0.68).¹²

In terms of targeted therapy, recent findings from prespecified and exploratory analyses confirmed the benefit of adjuvant therapy with osimertinib (Tagrisso) after resection for patients with stages IB-IIIA EGFR-mutant NSCLC regardless of whether they received adjuvant chemotherapy.¹⁵ The FDA approved the EGFR inhibitor for treating patients after resection whose tumors harbor exon 19 deletions or exon 21 L858R mutations in December 2020 based on results from the phase 3 ADAURA trial (NCT02511106).¹⁶

In the postoperative ADAURA findings, investigators observed DFS favoring osimertinib vs placebo with adjuvant chemotherapy (HR, 0.16; 95% CI, 0.10-0.26) and without adjuvant chemotherapy (HR, 0.23, 95% CI, 0.13-0.40). This was true regardless of disease stage.¹⁵

The DFS benefit was maintained in long-term follow-up results presented at the European Society for Medical Oncology Congress 2022 in September. At a median follow-up of 44.2 months with osimertinib (n = 233) and 19.6 months with placebo (n = 237), the median DFS was 65.8 months (95% CI, 54.4-not calculable [NC]) for patients who received osimertinib (n = 233) vs 21.9 months (95% CI, 16.6-27.5) for those who took the placebo (n = 237) among participants with stage II/IIIA disease (HR, 0.23; 95% CI, 0.18-0.30).¹³

In the overall population, osimertinib (n = 339) resulted in a median DFS of 65.8 months (95% CI, 61.7-NC) vs 28.1 months (95% CI, 22.1-35.0) with placebo (n = 343), translating to a 73% reduction in the risk of disease recurrence or death (HR, 0.27; 95% CI, 0.21-0.34). In this group, the median follow-up for those who received osimertinib was 44.2 months and 27.7 months for those given placebo.¹³

Making an Impact

Before taking on his current administrative role at AdventHealth Cancer Institute in 2016, Socinski was a prolific clinical investigator at several academic centers. His resume includes a 5-year stint at the University of Pittsburgh School of Medicine in Pennsylvania from 2011 to 2016. He served as a professor of medicine and cardiothoracic surgery; director of the Lung Cancer Section, Division of Hematology/Oncology; codirector of the UPMC Lung Cancer Center of Excellence; and codirector of the Lung and Thoracic Malignancies Program. Through the years he has coauthored more than 300 peer-reviewed journal articles as well as 16 book chapters and approximately 270 conference abstracts.

Several of his research accomplishments stand out as ushering in widespread changes to clinical practice in lung cancer. For example, he was the lead author on the Journal of Clinical Oncology report on the phase 2 PASSPORT trial (AVF3752g; NCT00312728) in 2009. The study examined the safety of bevacizumab (Avastin) in patients with nonsquamous NSCLC and previously treated brain metastases. The primary end point was the incidence of central nervous system (CNS) hemorrhage.¹⁷

PASSPORT found no CNS hemorrhages of grade 1 or greater severity among 106 safety-evaluable patients. “Brain metastases are so common in lung cancer and yet these patients had been excluded from the original indication,” Socinski said. “PASSPORT led to an FDA label change that enabled these patients to finally receive this important therapy.”

Socinski also was lead author on the registration trial that led to FDA approval of albumin-bound paclitaxel (nab-paclitaxel; Abraxane) plus carboplatin as a first-line treatment for patients with locally advanced or metastatic NSCLC in 2012.¹⁸ In the phase 3 study (NCT00540514), patients with previously untreated stage IIIB-IV NSCLC were randomly assigned to receive either nab-paclitaxel weekly at 100 mg/m² plus carboplatin once every 3 weeks or solvent-based paclitaxel at 200 mg/m² plus carboplatin, both administered every 3 weeks.

The nab-paclitaxel regimen demonstrated a significantly higher objective response rate (ORR) of 33% compared with 25% for the solvent-based paclitaxel combination (response rate ratio, 1.313; 95% CI,1.082-1.593; P = .005). In patients with squamous histology, nab-paclitaxel outperformed the solvent-based formulation 41% vs 24%, respectively; (response rate ratio, 1.680; 95% CI, 1.271-2.221; P < .001). Nab-paclitaxel was as effective as solventbased paclitaxel in patients with nonsquamous histology, with an ORR of 26% vs 25%, respectively (P = .808).¹⁸

This noninferior performance led the FDA to approve the use of nab-paclitaxel in NSCLC regardless of histology.¹⁹ “At the time we did the study, nab-paclitaxel was already approved in breast cancer, but our trial gave it a new indication in lung cancer,” Socinski said.

Then there was Socinski’s work on the IMPower trials, which looked at atezolizumab in combination with chemotherapy. In addition to serving as chair of the steering committee that guided the 4 IMPower trials, he also was lead author on the phase 3 IMpower150 study (NCT02366143) findings in the New England Journal of Medicine in 2018.²⁰

The 3-arm study randomized patients with metastatic nonsquamous NSCLC to receive atezolizumab plus carboplatin and paclitaxel (ACP), bevacizumab plus carboplatin and paclitaxel (BCP), or atezolizumab plus BCP (ABCP), followed by maintenance therapy with atezolizumab, bevacizumab, or both. The ABCP and BCP groups were compared first for efficacy.

The median OS was 19.2 months (95% CI, 17.0-23.8) with the ABCP regimen compared with 14.7 months (95% CI, 13.3-16.9) with BCP (HR, 0.78; 95% CI, 0.64-0.96; P = .02). PFS also was longer in the ABCP group than in the BCP group at 8.3 months (95% CI, 7.7-9.8) vs 6.8 months (95% CI, 6.0-7.1), respectively, which translated into an HR for disease progression or death of 0.62 (95% CI, 0.52-0.74; P < .001).²⁰

These findings prompted the FDA to approve the 4-pronged regimen for the first-line treatment of patients with metastatic nonsquamous NSCLC without EGFR or ALK alterations in December 2018.²¹

Cancer Care of the Future

Although Socinski remains an active investigator, much of his attention these days is focused on improving care delivery as he begins his sixth year of building a top-notch multidisciplinary cancer program for AdventHealth.

Those efforts are gaining recognition. AdventHealth in Orlando ranked number 30 among the nation’s top hospitals for cancer care in U.S. News & World Report’s 2022-2023 Best Hospitals Honor Roll.²²

AdventHealth “had the resources and most of the vision and they’ve let us build the cancer program the way I think it should be,” Socinski said. “I don’t think you need an academic medical center to build a cancer program. What you need is that level of expertise. We’re recruiting oncologists who have had successful careers at academic medical centers to work with outstanding general oncologists.”

In their roles as disease leaders, these specialists will continue to see patients 1 or 2 days per week and supplement general oncologists’ care with the specialized expertise needed to provide state-of-the-art care. The disease leaders devote the rest of their time to programmatic elements such as quality initiatives, accreditation efforts, and, of course, research. “We want them writing clinical trials, working with the clinical research team to make sure that infrastructure is adequate, that we offer a sufficient variety of clinical trials, and that patients are accrued to these trials,” Socinski said.

Socinski believes in bolstering both the specialist and the generalist rosters at AdventHealth. “Even though I can’t take care of every patient with lung cancer in central Florida, I can make sure we have everything in place so that no patient is left behind,” he said. “Our approach is to make sure every patient with cancer sees an expert in their disease to make sure that the I’s are dotted, the T’s are crossed, and there’s no stone left unturned. And when we do that, there’s no reason we can’t be as good as every academic medical center, every comprehensive cancer center out there.”

References

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