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Establishing courses of personalized care for patients with esophageal squamous cell carcinoma (ESCC) has paced behind management of other gastric cancers.

 However, progress has been made with immunotherapy approvals such as nivolumab (Opdivo) in combination with fluoropyrimidine- and platinum-based chemotherapy as well as nivolumab plus ipilimumab (Yervoy) for the first-line treatment of patients with advanced or metastatic ESCC based on data from the phase 3 CheckMate 648 trial (NCT03143153).

“As we see new approvals occur, we’re getting even more studies, so this landscape has gotten complicated regarding who to give what to,” John L. Marshall, MD, said. “In this patient population, [those with] squamous cell cancers of the esophagus with a metastatic disease, we have good, solid evidence that immunotherapy combined with chemotherapy is going to be the standard of care for first-line therapy. We have subsequent lines of therapy out there for our patients to extend that survival and improve their quality of life.”

In “My Treatment Approach: The Evolving Treatment Landscape of Esophageal Squamous Cell Carcinoma” a 4-episode 

 series, Marshall provided an overview of ESCC and discussed several key updates to the treatment landscape including putting data in the context of the treatment algorithm. Further, Marshall shared an overview of how available evidence can be applied to clinical practice to improve patient outcomes.

Below are excerpts from Marshall’s discussion in the series.

A Survey of Patient Presentation, Testing, and Diagnosis

Upper esophageal cancers tend to be squamous cell cancers, and the classic risk factors for that are alcohol, tobacco, etc. Those squamous cell cancers have been declining, at least in Western populations, although they’re still out there. You’ll still see them. If you go a little further down, to the gastroesophageal junction, you get adenocarcinomas. Those are more common in Western populations probably because of reflux and Barrett esophagus, obesity, and other problems such as that.

These are increasingly 2 different cancers, even though for many years we’ve lumped them into 1. To diagnose these cancers, as patients are coming in with dysphagia, you often [use] an endoscopy. Usually, CT scanning is part of the basic staging. The real challenges [in treating] these patients are that they often come in with significant nutrition problems, they have pain, and they require multidisciplinary care.

The location of these tumors is very difficult with regard to surgery. Chemoradiation can be effective for local control, but often it’s a big challenge to patients who have comorbidities and nutritional issues coming in. We recognize that [treating] this patient population can be challenging.

Whenever you identify a patient with squamous cell cancers of the esophagus, it’s critical to do a very solid, basic staging—with imaging, an endoscopic ultrasound, and biopsies. Once you get that tissue, you need to know more than just that it’s squamous cell cancer. Yes, you want to know differentiation and the like, but we do increasingly want to know other biomarkers. We’re testing for microsatellite instability [MSI] in every cancer and looking for immunotherapy choices. We’re looking at PD-L1 expression and we’re looking for HER2 expression. We’re also looking for rare mutations. Increasingly, we’re testing patients for broader profile, but it’s critical in upper GI [gastrointestinal] cancers to test for PD-L1, MSI, and HER2. Those are the ones that are going to be most informative for your patient.

Trends and Disparities in Treatment Approaches for Patients With Locoregional ESCC

If the patient has localized disease with no evidence of spread, maybe lymph nodes in the region, the common strategy is giving a combination of chemotherapy and radiation. The classic regimen that we use is called the CROSS regimen.... The CROSS regimen is carboplatin and paclitaxel given weekly; it’s a pretty easy regimen. You can also give platinum and fluoropyrimidine with radiation. This is long-course radiation, 5 to 6 weeks. That can have a fairly significant response, and for some patients that’s the definitive treatment.

The goal is to try to avoid a surgical approach in those patients. Of course, with chemoradiation, it’s not definitive in many patients. When possible, we sometimes will also do a surgical resection. In patients who have residual disease after that surgical resection, there are times when you give more adjuvant therapy with the advent of immunotherapy in that space in patients who’ve had curative intent chemoradiation, surgery, and residual disease followed by immunotherapy.

Esophageal cancer, squamous cell cancers of the esophagus, are seen in 50-, 60-, 70-year-old individuals. They’re seen in White individuals, in Black individuals, in other races around the world, and in other ethnicities. What we’re looking at, increasingly, is that not everyone has the same outcome.

A recent paper from Savitch et al looked at this. It was published in the 

 [Results] demonstrated that African American [patients] had a worse outcome than non–African American [patients]. It’s not clear that there’s a biological reason for this, but it’s likely more [about] access to treatment. Because this is a complicated disease, it does require multidisciplinary care. It takes a village. Not everybody has a good village on their side. Particularly in patients who are part of more vulnerable populations, regardless of race, make sure to step up your game as a treatment team because we can level the playing field by helping those patients.

First-line Treatment Approaches and Considerations for Patients With Metastatic ESCC

For patients who have unresectable disease or metastatic disease, which is a high proportion of the patients that we encounter, we have 2 issues. One, we have the plumbing issue of getting the patients eating and swallowing again and maintaining nutrition. If we need supplementation through PEG [percutaneous endoscopic gastrostomy] tubes or TPN [total parenteral nutrition], we do that as needed. Sometimes we place stents. Sometimes we give chemoradiation, even though there’s metastatic disease, to control that local disease. In general, first-line treatments of choice are going to be systemic treatments.

The base is chemotherapy. You can use platinum-taxane, you can use fluoropyrimidine/ platinum. There are 3-drug recipes, but they’re more toxic, they have a higher response rate, and they don’t have an overall outcome benefit. Using 2 drugs tends to be the basic right choice for most patients in the front line.

Then we look at the options for biologics. We test everybody for PD-L1 using CPS [combined positive score], and in those patients with high numbers, there’s pretty good evidence that adding anti–PD-1 therapy to chemotherapy will benefit those patients. There are rare patients with HER2-positive disease who have both HER2 and PD-1 as potential options added to the chemotherapy.

Increasingly, first-line therapy for squamous cell cancers of the esophagus is doublet chemotherapy with checkpoint inhibition, so it’s a 3-drug cocktail in total. These have the best reported outcomes so far in these patient populations. Of course, with any patient, there may be some who aren’t candidates for immunotherapy-type approaches. These are patients who have preexisting autoimmune problems that are going to increase their risk from immunotherapies. But increasingly, there aren’t many individuals who wouldn’t be candidates for immunotherapies.

Insights on Existing and Prospective Second-line Treatment Strategies

Initial lines of therapy are combinations of chemotherapy and immunotherapy. Now you move into subsequent lines of therapy, and there are other drugs: irinotecan, taxane, platinum. There are other approaches with combinations of immunotherapies that are being explored. Beyond that first line, the benefit rate doesn’t manage to stay up or stay high for very long, so we want that optimum first-line treatment of choice if we can.

When I’m thinking about treating a patient in the first line, I like to know the CPS and the PD-L1 score. I have approval regardless of the CPS score, and there are pretty good data that in squamous cell cancers, immunotherapies work. My enthusiasm for immunotherapies certainly goes up with those patients who have CPS greater than 5, or even 10. That’s what I’d start with.

These patients need a response, and in some patients, that immunotherapy also generates a durable response. After I get that initial positive benefit in the first 3 to 4 months, I might back off and—as we do in colorectal cancer—take a maintenance-like approach with immunotherapy and an oral fluoropyrimidine, or just immunotherapy single agent so that then I can rechallenge with a chemotherapy or switch to other cytotoxic drugs through the sequence beyond the first line.

If you have a patient with metastatic or locally advanced squamous cell cancers of the esophagus, you think, “What cards do I have on the table, and when do I play what?” For most patients, that first-line treatment of choice is going to be doublet chemotherapy, and there you have a carboplatin/paclitaxel approach, or fluoropyrimidine and a platinum. We have pretty good evidence that immunotherapy should be added to that in that first-line setting. Whether you then go through a maintenance phase if you have a good response and maintain the immunotherapy or not, most of us would maintain something through there. Ultimately, they’ll progress. If you haven’t used a platinum and a taxane, you certainly still have those as a rechallenge.

The other alternative therapies are limited to things such as irinotecan, or other kinds of platinum that you didn’t give, or fluoropyrimidine if you haven’t brought that in. There aren’t many choices beyond those initial lines of therapy in patients with this disease. You want to get your best bang for your buck early on, so you can get your best initial response and then hold on to that with your other drugs and rechallenge or use drugs you haven’t used in your first-line therapy.

As with all our solid tumors, we use CT scanning, endoscopy, patient symptoms, and sometimes cancer markers to determine if a patient is benefiting from the treatment. It comes down to performance status and CT scanning as the primary way that we’re watching out for patient response and benefit. We always must keep in the back of our [mind] that, sometimes with immunotherapy, we can see an early uptick. I don’t think that’s a very common phenomenon, so we’re looking for tumor regressions or stable disease and improved outcomes. When that begins to turn, it’s usually straightforward to see that, and you know you need to switch treatments.

We’re all working as hard as we can to try to identify new therapies and new approaches for our patients with esophageal cancers, particularly the squamous cell type. This is where it’s important for us to do the broad molecular profiling, not just the 3 that you have to do: MSI, PD-L1, and HER2. We’re looking at new approaches around the other targets and new patterns that may emerge. Certainly, combos of chemotherapy and immunotherapy and combos of immunotherapy are being done. Unlike with some of our GI [gastrointestinal] cancers, where we get into third and fourth lines, with this disease we rarely get past the second line. Begin looking for novel approaches early on in your patients so you have something in your hip pocket if it’s out there for that patient.

John L. Marshall, MD, is chief of the Division of Hematology/Oncology at MedStar Georgetown University Hospital, a professor of medicine and oncology at the Georgetown Lombardi Comprehensive Cancer Center, and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers in Washington, DC.

Rogers JE, Sewastjanow-Silva M, Waters RE, Ajani JA. Esophageal cancer: emerging therapeutics. 

. 2022;26(2):107-117. doi:10.1080/14728222.2022.2036718

FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. FDA. Updated May 31, 2022. Accessed September 19, 2022. bit.ly/3MEZtit

Savitch SL, Grenda TR, Scott W, et al. Racial disparities in rates of surgery for esophageal cancer: a study from the National Cancer Database. 

. 2021;25(3):581-592. doi:10.1007/ s11605-020-04653-z

Articles

John L. Marshall, MD, provides an overview of esophageal squamous cell carcinoma and discusses several key updates to the treatment landscape, including putting data in the context of the treatment algorithm. 

Marshall Provides Insight on Evolving Treatment Patterns in ESCC

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.

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 

. 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.

 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.”

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 

 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.

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.

“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.

 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: 

 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 

 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.”

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.

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; 

 = .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; 

Shortly after publishing these results in the 

 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.

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.

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.

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.

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.

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.

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.

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 

 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.

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; 

 = .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.

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

Updates have recently been published for 3 key lung cancer trials in the adjuvant setting (

 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).

 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.

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 

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).

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 

-mutant NSCLC regardless of whether they received adjuvant chemotherapy.

 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).

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.

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).

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.

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 

 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.

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.

 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/m

 plus carboplatin once every 3 weeks or solvent-based paclitaxel at 200 mg/m

 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; 

 = .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; 

 < .001). Nab-paclitaxel was as effective as solventbased paclitaxel in patients with nonsquamous histology, with an ORR of 26% vs 25%, respectively (

This noninferior performance led the FDA to approve the use of nab-paclitaxel in NSCLC regardless of histology.

 “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 

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; 

 = .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; 

These findings prompted the FDA to approve the 4-pronged regimen for the first-line treatment of patients with metastatic nonsquamous NSCLC without 

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 

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.”

In memoriam: Arthur T. Skarin, MD, physician-scientist instrumental in building Dana-Farber’s adult oncology program. News release. Dana-Farber Cancer Institute. September 8, 2022. Accessed September 11, 2022. https://bit.ly/3eIEX4X

Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. 

. 2021;71(1):7-33. doi:10.3322/caac.21654

Malik SM, Pazdur R, Abrams JS, et al. Consensus report of a joint NCI thoracic malignancies steering committee: FDA workshop on strategies for integrating biomarkers into clinical development of new therapies for lung cancer leading to the inception of “master protocols” in lung cancer. 

. 2014;9(10):1443-1448. doi:10.1097/JTO.0000000000000314

Redman MW, Papadimitrakopoulou VA, Minichiello K, et al. Biomarker-driven therapies for previously treated squamous non-small-cell lung cancer (Lung-MAP SWOG S1400): a biomarker-driven master protocol. 

. 2020;21(12):1589-1601. doi:10.1016/ S1470-2045(20)30475-7

About Lung-MAP. Lung Cancer Master Protocol (Lung-MAP) Clinical Trials. Accessed September 11, 2022. https://bit.ly/2IGmhCz

Robert NJ, Nwokeji ED, Espirito JL, et al. Biomarker tissue journey among patients (pts) with untreated metastatic non-small cell lung cancer (mNSCLC) in the U.S. Oncology Network community practices. 

. 2021;39(suppl 15): 9004. doi:10.1200/ JCO.2021.39.15_suppl.9004

Forde PM, Spicer J, Lu S, et al; CheckMate 816 Investigators. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. 

. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170

Provencio-Pulla M, Spicer J, Taube JM, et al. Neoadjuvant nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) versus chemo for resectable (IB–IIIA) non-small cell lung cancer (NSCLC): association of pathological regression with event-free survival (EFS) in CheckMate 816. 

. 2022;40(suppl 17): LBA8511. doi:10.1200/ JCO.2022.40.17_suppl.LBA8511

Provencio M, Serna-Blasco R, Nadal E, et al. Overall survival and biomarker analysis of neoadjuvant nivolumab plus chemotherapy in operable stage IIIA non–small-cell lung cancer (NADIM phase II trial). 

. 2022;40(25):2924-2933. doi:10.1200/JCO.21.02660

Provencio-Pulla M, Nadal E, Gonzalez Larriba JL, et al. Nivolumab + chemotherapy versus chemotherapy as neoadjuvant treatment for resectable stage IIIA NSCLC: Primary endpoint results of pathological complete response (pCR) from phase II NADIM II trial. 

. 2022; 40(suppl 16): 8501. doi:10.1200/JCO.2022.40.16_suppl.8501

Felip E, Altorki N, Vallieres E, et al. IMpower010: overall survival interim analysis of a phase III study of atezolizumab vs best supportive care in resected NSCLC. Abstract presented at 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria; PL03.09. Accessed September 11, 2022. https://bit.ly/3dwlODi

Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. 

. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308

Tsuboi M, Wu Y, Grohe C, et al. Osimertinib as adjuvant therapy in patients (pts) with resected EGFR-mutated (EGFRm) stage IB-IIIA non-small cell lung cancer (NSCLC): updated results from ADAURA. 

. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/ annonc1089

FDA approves atezolizumab as adjuvant treatment for non-small cell lung cancer. FDA. October 15, 2021. Accessed September 11, 2022. https://bit.ly/3L42hGs

Wu YL, John T, Grohe C, et al. Postoperative chemotherapy use and outcomes from ADAURA: osimertinib as adjuvant therapy for resected EGFR-mutated NSCLC. 

. 2022;17(3):423-433. doi:10.1016/j.jtho.2021.10.014

FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed September 11, 2022. https://bit.ly/3TZhD3h

Socinski MA, Langer CJ, Huang JE, et al. Safety of bevacizumab in patients with non–small-cell lung cancer and brain metastases. 

. 2009;27(31):5255-5261. doi:10.1200/ JCO.2009.22.0616

Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced nonsmall-cell lung cancer: final results of a phase III trial. 

. 2012;30(17):2055-2062. doi:10.1200/JCO.2011.39.5848

Abraxane. Prescribing information. Celgene Corporation; 2012. Accessed September 12, 2022. https://bit.ly/3Lu5rn4

Socinski MA, Jotte RM, Capuzzo F, et al; IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. 

. 2018 ;378(24):2288-2301. doi:10.1056/ NEJMoa1716948

FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC. FDA. December 14, 2018. Accessed September 12, 2022. https://bit.ly/31GqGdf

. Accessed September 27, 2022. https://bit.ly/2YARfyA

Mark A. Socinski, MD, has become internationally known for his research into the molecular drivers of lung cancer and his contributions to the refinement of multidisciplinary care. 

Expert Puts the Accent on Curative Potential in NSCLC Landscape

Sequencing complexities with chemotherapy-based regimens in metastatic breast cancer (mBC) pose unique challenges for valuebased decision-making in routine practice. Selection of chemotherapy options requires risk quantification, patient preference, and clinical context of the patient being cared for, including socioeconomic factors. 

According to results of a dynamic microsimulation of 10,000 women with mBC divided into 3 cohorts based on commonly observed baseline characteristics, investigators found that treatment sequences offered “indistinguishable differences” in the quality-adjusted life year (QALY) assessments but had notable differences in cost. “We also found that the relative difference in total costs associated with each alternative sequence was quite variable by cohort, with cohort 3 [patients with taxane- exposed/anthracycline-naïve disease] having the smallest percentage change in cost by sequence,” the study authors wrote.

Several approved agents are available for firstline treatment of patients with mBC; however, most will experience disease recurrence, and sequencing guidelines are unclear. To provide insight on appropriate treatment pathways for patients with endocrine-refractory or triple-negative mBC, investigators sought to elucidate tradeoffs in quality of life and cost.

Illuminating Costs of Sequencing Decisions

Building a model that reflected a dynamic microsimulation, 10,000 women 18 years or older in each cohort who experienced monthly events for 10 years or until death were followed to evaluate outcomes of various sequencing patterns of systemic therapies. All clinical scenarios evaluated in the model had participants either progress or demonstrate intolerance to first-line treatment. 

Investigators leveraged insights from 2 clinical experts on the study team and 6 external medical oncologists to develop a treatment portfolio that would reflect real-world clinical scenarios for the 3 treatment groups as follows: 

Unexposed to either taxane or anthracycline 

Additionally, NCCN guidelines were used to generate recommended single-agent cytotoxic therapies, which were then evaluated against data from MarketScan and by a number of external advisers at academic institutions and the Centers for Disease Control and Prevention. Investigators noted that although patients may receive combination therapies in clinical practice, the model was simplified to provide meaningful insight for monotherapy treatment pathways only. 

Input parameters for the simulations including presumptions for overall survival (OS) and progression-free survival (PFS) were based on data from the EMBRACE trial (NCT00388726), PELICAN trial (NCT00266799), and a phase 3 trial (NCT00078572). These studies evaluated eribulin mesylate vs treatment of physician’s choice, pegylated liposomal doxorubicin plus capecitabine, and lapatinib plus capecitabine vs capecitabine, respectively. The median OS for comparison was 25.14 months, assuming equal efficacy, with a median PFS in the first line of 5.96 months and a median PFS in subsequent lines of therapy of 4.02 months. 

“In our primary analyses, we treated survival as equivalent across treatments, following existing guidelines and best available evidence,” the authors wrote, adding it was assumed that all participants would not respond to or tolerate first and subsequent therapies. “In this way, each [participant] could conceivably receive all 3 treatment options within each of the 3 clinical scenarios, creating 6 potential treatment sequences for comparison within each cohort.” 

Adverse effects (AEs) of grade 3 or higher included in the simulation were neutropenia, anemia, fatigue, peripheral neuropathy, diarrhea, dyspnea, stomatitis, and hand-foot syndrome. Costs for each AE were calculated for all treatments and adjusted to 2018 costs. Additional inputs included monthly chemotherapy costs, monthly nonchemotherapy costs for first- through fourth-line therapy and palliative care, monthly indirect costs including lost income for patient and caregiver, and utility decrements. 

Overall, after 25 months, nearly all participants regardless of cohort progressed through 3 lines of treatment, with investigators reporting approximately 33% of participants had died. After 120 months, nearly all participants had died.

Cohort 1: Taxane- and Anthracycline-Unexposed Patients

For patients ineligible for first-line taxane or anthracycline and for those who are not considered candidates for retreatment, preferred treatment choices include paclitaxel, capecitabine, and docetaxel. Sequencing in this cohort examined 6 potential courses of treatment for these patients. “Results suggest that for taxane- and anthracycline-unexposed patients (cohort 1), treatment with paclitaxel followed by capecitabine followed by docetaxel corresponds to the highest expected QALY gain and lowest costs,” the study authors wrote. 

Specifically, beginning treatment with paclitaxel started costs at $686 per month vs $3233 per month if starting with capecitabine and $1765 per month if starting with docetaxel. Investigators observed the difference in QALY survival was fewer than 3 days between the best and next-best regimen, with sensitivity analysis confirming and showing both sequences that began with paclitaxel were noticeably less costly for patients.

Cohort 2: Taxane- and Anthracycline-Exposed Patients 

The 3 agents considered appropriate for patients who are ineligible for or refractory to taxane and anthracycline therapies included capecitabine, eribulin, and carboplatin. At $190 per month, carboplatin was the most cost-effective option and had the best safety profile of the 3 agents. Therefore, all sequences starting with this agent had the lowest cost. 

Investigators also noted that at low levels of QALY gain, there were smaller differences in starting with capecitabine vs carboplatin. However, all sequences starting with eribulin were of high cost, and it was noted that reference data for eribulin in the first-line metastatic setting were from patients who were heavily pretreated and refractory to capecitabine. The data, however, point to a rationale for conducting a threshold analysis to evaluate for cost effectiveness.

Cohort 3: Taxane-Exposed/ Anthracycline-Naive Patients

The final cohort of patients includes those who are considered refractory to taxane therapy only. These patients are eligible for treatment with pegylated liposomal doxorubicin, capecitabine, and eribulin. Sequencing with eribulin first did not elicit high numbers of QALYs compared with sequencing starting with pegylated liposomal doxorubicin or capecitabine. 

Furthermore, sequencing eribulin after capecitabine had an estimated cost of $8000 per month compared with $1765 per month for pegylated liposomal doxorubicin following capecitabine. Finally, the difference in starting with either pegylated liposomal doxorubicin or capecitabine resulted in similar cost-effectiveness.

Patient Preferences Play a Role in Treatment Decision-Making 

Beyond the value-based lens, patient preference should play a role. “Patients may have individual preferences about treatment (eg, avoiding certain adverse events or minimizing infusion or travel time) that can and should inform decisions. In these cases, although cost-effectiveness information can provide some guidance about the relative cost-benefit tradeoffs, open communication about adverse event risks, preferences, and shared decision-making between patients and providers should continue to influence practice, as recommended by NCCN guidelines in this setting,” they wrote. 

The study was not designed to determine out-of-pocket costs for patients for each treatment recommendation. However, according to a projection of mBC cases and costs through 2030, identifying ways to address cost-effective treatment pathways is of utmost importance. The study showed that a 54.8% increase in cases is expected from 2015 to 2030, from 158,997 cases to 246,194 cases. Estimated cost is expected to reach $152.4 billion across age groups and phases of care, up from $63.4 billion in 2015.2 Costs are expected to be higher for younger and midlife patients. 

Although the analysis did not account for emerging trends and changes in the treatment landscape, the numbers are sobering. As authors of the cost-effectiveness analysis concluded, “In this mBC setting where multiple chemotherapy options are recommended by guidelines and share similar survival and adverse event trajectories, treatment sequencing approaches that seek to minimize costs early may help improve value of care….Our study suggests that large incremental differences in endocrine-refractory or triple-negative mBC systemic treatment costs are not likely associated with better outcomes, which is informative for oncology value frameworks, pathway development, and policy.” 

Notably, the study authors added with small changes in quality-adjusted survival— differences of only days or weeks—“adverse event–driven quality-of-life differences across treatment sequences are not common or burdensome enough to move the needle on value, unless cost differences [exist] between treatments."

Wheeler SB, Rotter J, Gogate A, et al. Cost-effectiveness of pharmacologic treatment options for women with endocrine-refractory or triple-negative metastatic breast cancer. J Clin Oncol. Published online September 2, 2022. doi:10.1200/JCO.21.02473 

Gogate A, Wheeler SB, Reeder-Hayes KE, et al. Projecting the prevalence and costs of metastatic breast cancer from 2015 through 2030. JNCI Cancer Spectr. 2021;5(4):pkab063. doi:10.1093/ jncics/pkab063

Oncology Live®

Sequencing complexities with chemotherapy-based regimens in metastatic breast cancer pose unique challenges for valuebased decision-making in routine practice.

Cost Minimization Relies  on Sequencing in  Metastatic Breast Cancer

Smoking is associated with the most widely known cancer causing carcinogen across the world. However, a second, more insidious factor has been increasingly recognized for its role in promoting cancer growth: obesity. 

Authors of a 2016 manuscript from the International Agency for Research on Cancer looked at data on several different cancer types and were the first to publish findings that prominently identified obesity as an important risk factor, as well as a prognostic factor, in at least 13 types of human cancer.

 Six years later, that observation has become even more important in the context of the obesity epidemic, which has the United States firmly in its grip. Americans are becoming overweight at an increasingly alarming rate, creating an urgent need to understand how obesity affects cancer risk, progression, and treatment. 

Analyses by our group at Roswell Park Comprehensive Cancer Center in Buffalo, New York, have demonstrated that in lung cancer, the relationship between obesity and either carcinogenesis or cancer progression is more nuanced. Most studies that have examined this relationship use body mass index (BMI) as a measure of obesity. Notably, many investigators have observed a positive relationship between high BMI and better outcomes in patients with lung cancer, as well as a decreased risk in the incidence of lung cancer. These observations are at odds with preclinical experiments that have for years shown an association between a high-fat diet, obesity, and, ultimately, increased rates of cancer development and progression. The discrepancy between these lines of evidence is known as the obesity paradox.

Visceral Fat, Related Immunosuppression Are Drivers of Lung Cancer 

Recent investigations at Roswell Park have helped to unravel this paradox. Understanding that BMI may not accurately depict visceral obesity, which is known to be the main culprit behind many obesity-related negative health effects, for the same reason we sought to measure obesity differently in patients with lung cancer. 

As most patients with lung cancer in the United States have a PET scan performed as part of their diagnostics and treatment planning, the CT component of the PET scan was chosen to identify and measure visceral fat. Using images obtained at the third lumbar level, investigators measured visceral fat using analysis software and normalized this readout against total body fat at that level. Armed with this new measure, called the visceral fat index, investigators sought to recalibrate the relationship between visceral fat and lung cancer. Consistent with the hypothesis and the wealth of available preclinical data, we saw clear indications that patients with a high visceral fat index had a higher recurrence rate after treatment for lung cancer.

Investigations strongly suggest that this relationship is mediated by the immunosuppression that is a by-product of visceral obesity.

 Recent findings from our group suggest that in patients, as well as in preclinical models, obesity leads to a rewiring of the metabolic processes and immune cells that form the basis of these observations. We are focused specifically on understanding the role of regulatory T cells in the tumor microenvironment of patients who are obese because these suppressor cells are enhanced in both their frequency and activation status by obesity. Ongoing studies implicate these cells as an unappreciated link between obesity’s effects on metabolism and the immune response. We believe, though, that these data are just the tip of the iceberg.

Studies Are Underway With Widely Prescribed Diabetes Drug  

Although the resolution of the obesity paradox and lung cancer is exciting, the implications of these observations in the therapeutic space hold the potential for an even greater effect. In both retrospective clinical data sets and carefully controlled preclinical experiments, we have found that the anticancer effect of the widely used antidiabetic drug metformin is accentuated in the context of obesity.

Testing the notion that specific patient characteristics such as obesity may affect the relative potency of metformin on lung cancer survival, we analyzed the patient outcomes of 756 non–small cell lung cancer (NSCLC) cases with early-stage (stage I/II; n = 490) or latestage disease (stage III/IV; n = 266) who either did or did not use metformin (n = 121 and n = 635, respectively) and did not receive neoadjuvant therapy. 

Results showed that metformin use is associated with improved overall and recurrence-free survival only in patients who are overweight or obese, defined as a BMI greater than 25 kg/m

. A manuscript is in preparation. These results expand on the finding of a previous study from our group

Smoking is associated with the most widely known cancer causing carcinogen across the world. However, a second, more insidious factor has been increasingly recognized for its role in promoting cancer growth: obesity.

Vol. 23/No. 19 | Oncology Live®

Marshall Provides Insight on Evolving Treatment Patterns in ESCC

Expert Puts the Accent on Curative Potential in NSCLC Landscape

Cost Minimization Relies on Sequencing in Metastatic Breast Cancer

Investigators Seek to Resolve the “Obesity Paradox” in Lung Cancer

Novel Interventions May Reduce Phlebotomy Use in Patients With Polycythemia Vera

Novel AR-Targeted Therapies for Metastatic Hormone-Sensitive Prostate Cancer: Which One to Choose

Interventions Are Needed to Bridge Gaps Between Real-World and Clinical Trial Populations