Melanoma

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

Uptake of the approved extended-interval dosing regimen for pembrolizumab has been poor, according to a review of Veterans Health Administration data.

In April 2020, the Food and Drug Administration approved extended dosing for standalone pembrolizumab – 400 mg every 6 weeks instead of the standard dosing of 200 mg every 3 weeks. The shift came, in part, to reduce patient health care encounters during the early days of the COVID-19 pandemic, but also because fewer infusions save patients time and out-of-pocket costs and reduce the burden on the health care system.

The FDA deemed this move safe after pharmacologic studies and a small melanoma study found that responses and adverse events were equivalent in comparison with standard dosing.

Given the benefits, one would expect “brisk adoption” of extended-interval dosing, Garth Strohbehn, MD, an oncologist at the VA Medical Center in Ann Arbor, Mich., and colleagues wrote in a recent report in JAMA Oncology.

However, when the team reviewed data on 835 veterans from the Veterans Health Administration who began taking single-agent pembrolizumab between April 1, 2020, and July 1, 2021, only about one-third received extended-interval dosing.

Between April and January 2021, use of extended-interval dosing rose steadily to about 35% of patients but then hovered in that range through August 2021.

Among the patients, age, sex, Charlson comorbidity index, and pembrolizumab indications were well balanced between the standard-dosing and the extended-interval dosing groups.

Notably, Dr. Strohbehn and colleagues also found no difference in time-to-treatment discontinuation between patients receiving extended dosing in comparison with patients receiving standard dosing, which is “a real-world measure of clinical effectiveness,” the team said.

And there was no difference in immune-related side effects between the two regimens, as assessed by incident levothyroxine and prednisone prescriptions.

The real-world near equivalence of extended and standard dosing intervals that was demonstrated in the study is “reassuring” and helps make the case for considering it “as a best practice” for single-agent pembrolizumab, the investigators wrote.

Dr. Strohbehn remained somewhat puzzled by the low uptake of the extended-dosing option.

“I was frankly surprised by the small number of patients who received the extended-interval regimen,” Dr. Strohbehn said in an interview.

“Admittedly, there are patients who would prefer to receive standard-interval therapy, and that preference should of course be accommodated whenever possible, but in my experience, those numbers are small,” at least in the VA system, he noted.

In addition, the authors noted, there is no direct financial incentive for more frequent dosing in the VA system.

It’s possible that low uptake could stem from clinicians’ doubts about switching to an extended-interval dose, given that the FDA’s approval was based largely on a study of 44 patients with melanoma in a single-arm trial.

If that is indeed the case, the new findings – which represent the first health system–level, real-world comparative effectiveness data for standard vs. extended-interval pembrolizumab – should help address these concerns, the team said.

“This observational dataset lends further credence to [the dosing] regimens being clinically equivalent,” said Zachery Reichert, MD, PhD, a urologic oncologist at the University of Michigan, Ann Arbor, who was not involved in the study.

To address the issue, Dr. Strohbehn and his team suggested “clinical guideline promotion to overcome some of the barriers to the adoption of extended-interval pembrolizumab.”

Dr. Riechert suggested further validation of equivalent outcomes for the two regimens, more advocacy to encourage patients to ask about the 6-week option, as well as incentives from insurers to adopt it.

Dr. Strohbehn added that the situation highlights a broader issue in oncology, namely that many drugs “end up on the market with dosing regimens that haven’t necessarily been optimized.”

Across the world, investigators are conducting clinical trials “to identify the minimum dosages, frequencies, and durations patients need in order to achieve their best outcome,” Dr. Strohbehn said. In oncology, much of this effort is being led by Project Optimus, from the FDA’s Oncology Center of Excellence, he said.

The study was funded by the VA National Oncology Program. Dr. Reichert and Dr. Strohbehn have disclosed no relevant financial relationships. One investigator has received grants from Novartis, Bristol-Myers Squibb, Regeneron, and Genentech.

A version of this article first appeared on Medscape.com.

Among patients with American Joint Committee on Cancer IIIA early-stage melanoma metastases, the presence of sentinel node (SN) tumor deposits of 0.3 mm or higher is associated with a greater risk of disease progression, and these individuals may be well served by adjuvant systemic therapy. It suggests that those with smaller tumor deposits can be managed in a similar way to AJCC IB patients who are SN negative.

Those are the conclusions from a new prospective analysis of melanoma patients drawn from nine high-volume cancer centers in Australia, Europe, and North America. It was published online in the Journal of Clinical Oncology.

Classification of stage III melanoma is difficult since it comprises a heterogeneous group of patients with divergent prognoses. That complexity has resulted in four subcategories of stage III, ranging from high-risk primaries with synchronous nodal metastases (IIID) to patients with early-stage primary tumors with low burden at the SN (IIIA). The latter patients have excellent prognoses, with close to 90% 5-year survival. In fact, they have a better survival rate than some stage II patients with SN-negative, high-risk primary tumors (AJCC IIB-IIC).

Recent phase 3 trials have produced standardized protocols for treating stage III patients with intermediate to high risk (IIIB-IIID), but there is little evidence for the best approach to treat stage IIIA.

To fill that gap, the researchers examined data from 3,607 patients with low-risk primaries, defined as AJCC pT1b-pT2a. About 11.3% were AJCC IIIA and the rest were AJCC IB with no SN tumors: They served as a comparison group. The median follow-up was 34 months.

The researchers conducted a survival analysis that identified 0.3 mm as the optimal size to stratify outcomes. Among those with SN tumors 0.3 mm or higher, 5-year disease-specific survival was 80.3%. For those with smaller tumors, the rate was 94.1% (hazard ratio, 1.26; P < .0001). For distant metastasis-free survival the rates were 72.4% and 92.1% (HR, 1.27; P < .0001). Survival rates were similar between AJCC IB and low-risk AJCC IIIA patients.

The researchers found no differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients.

Other factors were associated with the presence of high-risk SN tumor size, including male sex (chi-squared, 4.97; df, 1; P = .034), and mitotic rates higher than 1/mm² (chi-squared, 4.92; df, 1; P = .035), although only mitotic rate remained a statistically significant risk factor after multivariate analysis (HR, 1.59; P = .050).

Where extracapsular spread was present, the median maximum tumor deposit size was 3.0 mm versus 0.5 mm in the absence of ECS (Kruskal-Wallis; F, 17.78; df, 1; P < .0001). High-risk nodal disease trended towards an association with N2a stage nodal metastases, compared with N1a stage disease (22.6% vs. 13.8%; chi-squared, 4.31; df, 1; P = .052).

The results of the study suggest that guidelines from the National Comprehensive Cancer Network and The National Institute for Health and Care Excellence could be missing up to one-third of patients with stage IIIA disease with high risk of distance recurrence or death, who may benefit from adjuvant systemic therapy. “We suggest that early-stage, AJCC IIIA patients with micrometastases of maximum tumor dimension [of at least] 0.3 mm should be considered for adjuvant systemic therapy or enrollment into a clinical trial, whereas patients with micrometastases of maximum tumor dimension less than 0.3 mm can be managed in a similar fashion to their SN-negative, AJCC IB counterparts,” the authors wrote.

Eight coauthors reported various conflicts of interest with pharmaceutical companies; the other coauthors reported no conflicts of interest.

Among patients with American Joint Committee on Cancer IIIA early-stage melanoma metastases, the presence of sentinel node (SN) tumor deposits of 0.3 mm or higher is associated with a greater risk of disease progression, and these individuals may be well served by adjuvant systemic therapy. It suggests that those with smaller tumor deposits can be managed in a similar way to AJCC IB patients who are SN negative.

Those are the conclusions from a new prospective analysis of melanoma patients drawn from nine high-volume cancer centers in Australia, Europe, and North America. It was published online in the Journal of Clinical Oncology.

Classification of stage III melanoma is difficult since it comprises a heterogeneous group of patients with divergent prognoses. That complexity has resulted in four subcategories of stage III, ranging from high-risk primaries with synchronous nodal metastases (IIID) to patients with early-stage primary tumors with low burden at the SN (IIIA). The latter patients have excellent prognoses, with close to 90% 5-year survival. In fact, they have a better survival rate than some stage II patients with SN-negative, high-risk primary tumors (AJCC IIB-IIC).

Recent phase 3 trials have produced standardized protocols for treating stage III patients with intermediate to high risk (IIIB-IIID), but there is little evidence for the best approach to treat stage IIIA.

To fill that gap, the researchers examined data from 3,607 patients with low-risk primaries, defined as AJCC pT1b-pT2a. About 11.3% were AJCC IIIA and the rest were AJCC IB with no SN tumors: They served as a comparison group. The median follow-up was 34 months.

The researchers conducted a survival analysis that identified 0.3 mm as the optimal size to stratify outcomes. Among those with SN tumors 0.3 mm or higher, 5-year disease-specific survival was 80.3%. For those with smaller tumors, the rate was 94.1% (hazard ratio, 1.26; P < .0001). For distant metastasis-free survival the rates were 72.4% and 92.1% (HR, 1.27; P < .0001). Survival rates were similar between AJCC IB and low-risk AJCC IIIA patients.

The researchers found no differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients.

Other factors were associated with the presence of high-risk SN tumor size, including male sex (chi-squared, 4.97; df, 1; P = .034), and mitotic rates higher than 1/mm² (chi-squared, 4.92; df, 1; P = .035), although only mitotic rate remained a statistically significant risk factor after multivariate analysis (HR, 1.59; P = .050).

Where extracapsular spread was present, the median maximum tumor deposit size was 3.0 mm versus 0.5 mm in the absence of ECS (Kruskal-Wallis; F, 17.78; df, 1; P < .0001). High-risk nodal disease trended towards an association with N2a stage nodal metastases, compared with N1a stage disease (22.6% vs. 13.8%; chi-squared, 4.31; df, 1; P = .052).

The results of the study suggest that guidelines from the National Comprehensive Cancer Network and The National Institute for Health and Care Excellence could be missing up to one-third of patients with stage IIIA disease with high risk of distance recurrence or death, who may benefit from adjuvant systemic therapy. “We suggest that early-stage, AJCC IIIA patients with micrometastases of maximum tumor dimension [of at least] 0.3 mm should be considered for adjuvant systemic therapy or enrollment into a clinical trial, whereas patients with micrometastases of maximum tumor dimension less than 0.3 mm can be managed in a similar fashion to their SN-negative, AJCC IB counterparts,” the authors wrote.

Eight coauthors reported various conflicts of interest with pharmaceutical companies; the other coauthors reported no conflicts of interest.

Among patients with American Joint Committee on Cancer IIIA early-stage melanoma metastases, the presence of sentinel node (SN) tumor deposits of 0.3 mm or higher is associated with a greater risk of disease progression, and these individuals may be well served by adjuvant systemic therapy. It suggests that those with smaller tumor deposits can be managed in a similar way to AJCC IB patients who are SN negative.

Those are the conclusions from a new prospective analysis of melanoma patients drawn from nine high-volume cancer centers in Australia, Europe, and North America. It was published online in the Journal of Clinical Oncology.

Classification of stage III melanoma is difficult since it comprises a heterogeneous group of patients with divergent prognoses. That complexity has resulted in four subcategories of stage III, ranging from high-risk primaries with synchronous nodal metastases (IIID) to patients with early-stage primary tumors with low burden at the SN (IIIA). The latter patients have excellent prognoses, with close to 90% 5-year survival. In fact, they have a better survival rate than some stage II patients with SN-negative, high-risk primary tumors (AJCC IIB-IIC).

Recent phase 3 trials have produced standardized protocols for treating stage III patients with intermediate to high risk (IIIB-IIID), but there is little evidence for the best approach to treat stage IIIA.

To fill that gap, the researchers examined data from 3,607 patients with low-risk primaries, defined as AJCC pT1b-pT2a. About 11.3% were AJCC IIIA and the rest were AJCC IB with no SN tumors: They served as a comparison group. The median follow-up was 34 months.

The researchers conducted a survival analysis that identified 0.3 mm as the optimal size to stratify outcomes. Among those with SN tumors 0.3 mm or higher, 5-year disease-specific survival was 80.3%. For those with smaller tumors, the rate was 94.1% (hazard ratio, 1.26; P < .0001). For distant metastasis-free survival the rates were 72.4% and 92.1% (HR, 1.27; P < .0001). Survival rates were similar between AJCC IB and low-risk AJCC IIIA patients.

The researchers found no differences between the AJCC IB patients and low-risk (< 0.3 mm) AJCC IIIA patients.

Other factors were associated with the presence of high-risk SN tumor size, including male sex (chi-squared, 4.97; df, 1; P = .034), and mitotic rates higher than 1/mm² (chi-squared, 4.92; df, 1; P = .035), although only mitotic rate remained a statistically significant risk factor after multivariate analysis (HR, 1.59; P = .050).

Where extracapsular spread was present, the median maximum tumor deposit size was 3.0 mm versus 0.5 mm in the absence of ECS (Kruskal-Wallis; F, 17.78; df, 1; P < .0001). High-risk nodal disease trended towards an association with N2a stage nodal metastases, compared with N1a stage disease (22.6% vs. 13.8%; chi-squared, 4.31; df, 1; P = .052).

The results of the study suggest that guidelines from the National Comprehensive Cancer Network and The National Institute for Health and Care Excellence could be missing up to one-third of patients with stage IIIA disease with high risk of distance recurrence or death, who may benefit from adjuvant systemic therapy. “We suggest that early-stage, AJCC IIIA patients with micrometastases of maximum tumor dimension [of at least] 0.3 mm should be considered for adjuvant systemic therapy or enrollment into a clinical trial, whereas patients with micrometastases of maximum tumor dimension less than 0.3 mm can be managed in a similar fashion to their SN-negative, AJCC IB counterparts,” the authors wrote.

Eight coauthors reported various conflicts of interest with pharmaceutical companies; the other coauthors reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

PARIS – If results of phase 3, randomized clinical trials are the gold standard for cancer drug approvals, then single-arm trials are at best a bronze or even brass standard, with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.

In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.

“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.

“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.

In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
 

Why do single-arm trials?

The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:

• A RCT is not possible because the disease is rare or randomization would be unethical.
• The safety of the drug is established and its potential benefits outweigh its risks.
• The drug is associated with a high and durable overall or objective response rate.
• The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.

Survival endpoints won’t do

Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.

He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.

It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.

“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.

In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
 

On second thought ...

Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.

Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
 

What’s rare and safe?

The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.

He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
 

Cherry-picking patients

Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.

“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.

“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.

Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.

Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.

A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.

“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.

Diagnostic delays can lead to diagnosis at more advanced stages. “That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.

The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.

The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).

Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.

“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.

Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.

The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.

He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.

Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.

In melanoma patients with the BRAFV600 mutation, a combination of BRAF and MEK inhibitors are highly effective over the long term, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.

The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).

There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.

The new study was published online in the Journal of Clinical Oncology.

In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.

Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
 

BRAF inhibitors as second- or later-line therapy

Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.

To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.

Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.

The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.

The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.

In melanoma patients with the BRAFV600 mutation, a combination of BRAF and MEK inhibitors are highly effective over the long term, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.

The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).

There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.

The new study was published online in the Journal of Clinical Oncology.

In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.

Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
 

BRAF inhibitors as second- or later-line therapy

Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.

To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.

Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.

The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.

The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.

In melanoma patients with the BRAFV600 mutation, a combination of BRAF and MEK inhibitors are highly effective over the long term, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.

The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).

There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.

The new study was published online in the Journal of Clinical Oncology.

In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.

Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
 

BRAF inhibitors as second- or later-line therapy

Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.

To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.

Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.

The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.

The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.

Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – “It’s not just what you give, it’s when you give it,” said the investigator reporting “that the same treatment for resectable melanoma given in a different sequence can generate lower rates of melanoma recurrence.”

Sapna Patel, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center, Houston, reported the results from the SWOG S1801 trial, which showed that patients with high-risk melanoma who received pembrolizumab both before and after surgery had significantly longer event-free survival than patients who received pembrolizumab after surgery only.

At a median follow-up of almost 15 months, there was a 42% lower rate of recurrence or death.

“Compared to the same treatment given entirely in the adjuvant setting, neoadjuvant pembrolizumab followed by adjuvant pembrolizumab improves event-free survival in resectable melanoma,” Dr. Patel commented.

She suggested that the explanation for the findings was that “inhibiting the PD-1/PD-L1 immune checkpoints before surgery gives an antitumor response at local and distant sites, and this occurs before resection of the tumor bed. This approach tends to leave behind a larger number of anti-tumor T cells ... [and] these T cells can be activated and circulated systematically to recognize and attack micro-metastatic melanoma tumors.”

The findings were presented during a presidential symposium at the European Society for Medical Oncology (ESMO) Congress 2022, Paris.

“This trial provides us with more evidence of when one strategy may be preferred over the other,” commented Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was not involved with the trial.

“Neoadjuvant immunotherapy has elicited impressive complete pathologic responses, which thus far have proven to be associated with a durable response. Neoadjuvant therapy may help identify patients who will respond well to checkpoint inhibitors and allow for de-escalation of therapy,” she told this news organization when approached for comment.

“As with all neoadjuvant therapy, we don’t want the treatment to compromise the outcomes of surgery when the intent is curative, and we once again have evidence that this is not the case when it comes to immune therapy,” she said. However, she added that “we will need further survival data to really change the standard of practice in high-risk melanoma and demonstrate whether there is a superior sequence of therapy and surgery.”

 

Details of the new results

The S1801 clinical trial enrolled 345 participants with stage IIIB through stage IV melanoma considered resectable. The cohort was randomized to receive either upfront surgery followed by 18 doses of pembrolizumab 200 mg every 3 weeks for a total of 18 doses or neoadjuvant therapy with pembrolizumab 200 mg (3 doses) followed by 15 doses of adjuvant pembrolizumab.

The primary endpoint was event-free survival (EFS), defined as the time from randomization to the occurrence of one of the following: disease progression or toxicity that resulted in not receiving surgery, failure to begin adjuvant therapy within 84 days of surgery, melanoma recurrence after surgery, or death from any cause.

At a median follow-up of 14.7 months, EFS was significantly higher for patients in the neoadjuvant group, compared with those receiving adjuvant therapy only (HR, 0.58; one-sided log-rank P = .004). A total of 36 participants died in the neoadjuvant and adjuvant groups (14 and 22 patients, extrapolating to a hazard ratio of 0.63; one-sided P = .091).

“With a limited number of events, overall survival is not statistically different at this time,” Dr. Patel said. “Landmark 2-year survival was 72% in the neoadjuvant arm and 49% in the adjuvant arm.”

The authors note that the benefit of neoadjuvant therapy remained consistent across a range of factors, including patient age, sex, performance status, stage of disease, ulceration, and BRAF status. The same proportion of patients in both groups received adjuvant pembrolizumab following surgery.

Rates of adverse events were similar in both groups, and neoadjuvant pembrolizumab did not result in an increase in adverse events related to surgery. In the neoadjuvant group, 28 patients (21%) with submitted pathology reports were noted to have had a complete pathologic response (0% viable tumor) on local review.
 

Questions remain

Invited discussant James Larkin, PhD, FRCP, FMedSci, a clinical researcher at The Royal Marsden Hospital, London, noted that the study had “striking results” and was a landmark trial with a simple but powerful design.

However, he pointed to some questions which need to be addressed in the future. “One important question is what is the optimal duration of neoadjuvant treatment, and can we individualize it?”

Another question is just how much postoperative treatment is really needed and whether pathology help determine that. “Can surgery be safely avoided altogether?” he asked. “Another issue is the need for anti-CTL4 therapy – which patients might benefit from anti-CTL4, in addition to anti-PD-1?”

“And by extension, this paradigm provides a great platform for testing new agents, including combinations in cases where PD-1 is not sufficient to achieve a sufficient response,” said Dr. Larkin. “In the future, trials addressing these questions hand us a major opportunity to individualize and rationally de-escalate treatment.”

Also weighing in on the study, another expert pointed out that neoadjuvant therapy in this setting is already being considered as an option. “The use of immunotherapy before surgery has been reported in some trials such as the OPACIN-neo and PRADO trials,” said Anthony J. Olszanski, RPh, MD, Vice Chair of Research at the Fox Chase Cancer Center, Philadelphia. “Results have been quite exciting and have led the NCCN to list this as a potential option for some patients in the current melanoma guidelines.”

S1801 is funded by the NIH/NCI and in part by MSD through a Cooperative Research and Development Agreement with the NCI. Pembrolizumab (KEYTRUDA) is Merck’s anti-PD-1 therapy. Dr. Patel has declared multiple relationships with industry as noted in the abstract; several co-authors have also made disclosures. Dr. Olszanski has reported participating in advisory boards for BMS, Merck, and InstilBio and running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – Cell therapies have already had a huge impact on the treatment of blood cancers, but progress in solid tumors has proved more difficult. Now, in a first multicenter randomized trial to compare the two, a novel cell therapy showed a superior outcome to immunotherapy in patients with advanced melanoma.

The cell therapy used in this trial was composed of adoptive tumor infiltrating lymphocytes (TIL), which were made individually for each patient, just as chimeric antigen receptor T cells (CAR T cells) are for patients with blood cancers. However, the process involved is somewhat different, as TILs are made from lymphocytes that have infiltrated the patient’s tumor and are obtained by surgery in the tumor, whereas CAR T cells are made from circulating blood cells. 

The phase 3 trial involved 168 patients with unresectable stage IIIC-4 melanoma and showed that patients who were treated with TILs achieved a significantly improved progression-free survival (PFS) when compared with standard immunotherapy with ipilimumab (Yervoy).

The median PFS was more than doubled to 7.2 months with TILs versus 3.1 months with ipilimumab (hazard ratio, 0.50; P < .001).

“We do think that TIL could possibly become a new treatment option for patients with advanced stage melanoma,” commented lead author John Haanen, MD, PhD, research group leader at the Netherlands Cancer Institute in Amsterdam and a professor in translational immunotherapy of cancer at Leiden (the Netherlands) University Medical Center.  

He presented the findings at a presidential symposium during the European Society for Medical Oncology Annual Congress, Paris.

“The results of this trial may fuel further research of TIL in other cancer types, potentially demonstrating benefit in many other solid tumors and expanding available treatments for patients,” said Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was approached for comment by this news organization and was not involved in the research.

Immune checkpoint inhibitors and targeted therapies have become the standard of care for advanced melanoma and greatly improved patient outcomes, she said. But as about half of patients treated with these agents will not achieve a durable benefit, there remains a need for new treatment options.

“Although immunotherapy can yield impressive long-term responses, a substantial percentage of patients will have no response, or no durable response, to checkpoint inhibitors,” said Dr. Dimitrova. “TIL therapy has proven effectiveness in melanoma. However, no phase III trials have been done to date to compare its effectiveness to a standard of care regimen.”

She noted that these results are consistent with past reports of an approximately 50% response rate with an impressive 20% complete response rate in the TIL group. Data from a phase 2 trial reported last year, for example, showed an objective response rate of 36.4%.

“It will be important to determine the persistence of antitumor activity and whether there are biomarkers that could help with patient selection given the resource intensity of the therapy,” Dr. Dimitrova said. “TIL therapy will likely become a new standard of care in metastatic melanoma refractory to immune checkpoint inhibitors.” 
 

Superior to immunotherapy

In the current study, Dr. Haanen and colleagues randomly assigned 168 patients to TIL or ipilimumab (3 mg/kg every 3 weeks, maximum 4 doses). Patients were stratified for BRAFV600 mutation status, treatment line and center, and the majority (86%) were refractory to anti–PD-1 treatment.

Patients in the TIL group underwent resection of a melanoma lesion (2-3 cm) for the ex vivo outgrowth and expansion of tumor-resident T cells. Before the cultured TILs were infused back into the patients from which they were made, the patient underwent nonmyeloablative, lymphodepleting chemotherapy with cyclophosphamide plus fludarabine that was followed by high-dose interleukin-2.

The study’s primary endpoint was progression-free survival, and secondary endpoints included overall and complete response rate, overall survival, and safety.

At a median follow-up of 33 months, TIL significantly improved progression-free survival, compared with ipilimumab. The overall response rate also favored TIL, compared with ipilimumab (49% vs. 21%), with 20% versus 7% complete responses, respectively.

The median overall survival was 25.8 months for TIL and 18.9 months for ipilimumab (HR, 0.83; P = 0.39).

Grade 3 or higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients, although Dr. Haanen noted they were manageable and, in most cases, resolved by the time patients were discharged from the hospital.

“There were no new safety concerns with TIL,” said Dr. Haanen, “And these toxicities are driven by the chemotherapy and interleukin-2 that are part of the TIL regimen. There were no long-term sequelae in patients treated with TIL, and health-related quality of life was higher in patients treated with TIL.”
 

Ultra-personalized

Also commenting on the study, Anthony J. Olszanski, MD, RPh, associate professor and vice chair of clinical research, department of hematology/oncology at Fox Chase Cancer Center, Philadelphia, agreed that the treatment of patients with melanoma who do not respond to or progress after receiving treatment with immunotherapy is “challenging and represents an unmet need.”

“TIL therapy is, in some ways, ultra-personalized therapy, because we harvest immune cells from the patient’s tumor, expand them outside of the body, and then re-infuse them,” he said. “This trial, which randomized patients between TIL versus the CTLA-4 inhibitor, ipilimumab, has shown an impressive progression-free survival and overall response rate benefit and will help establish TIL therapy as a viable treatment strategy for some patients.”

The study was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society, and Capital Region of Denmark Research Foundation.

Dr. Haanen and several of the co-authors have declared multiple relationships with industry as noted in the abstract. Dr. Olszanski reports participation in advisory boards for BMS, Merck, and Instil Bio, and he reports running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – Cell therapies have already had a huge impact on the treatment of blood cancers, but progress in solid tumors has proved more difficult. Now, in a first multicenter randomized trial to compare the two, a novel cell therapy showed a superior outcome to immunotherapy in patients with advanced melanoma.

The cell therapy used in this trial was composed of adoptive tumor infiltrating lymphocytes (TIL), which were made individually for each patient, just as chimeric antigen receptor T cells (CAR T cells) are for patients with blood cancers. However, the process involved is somewhat different, as TILs are made from lymphocytes that have infiltrated the patient’s tumor and are obtained by surgery in the tumor, whereas CAR T cells are made from circulating blood cells. 

The phase 3 trial involved 168 patients with unresectable stage IIIC-4 melanoma and showed that patients who were treated with TILs achieved a significantly improved progression-free survival (PFS) when compared with standard immunotherapy with ipilimumab (Yervoy).

The median PFS was more than doubled to 7.2 months with TILs versus 3.1 months with ipilimumab (hazard ratio, 0.50; P < .001).

“We do think that TIL could possibly become a new treatment option for patients with advanced stage melanoma,” commented lead author John Haanen, MD, PhD, research group leader at the Netherlands Cancer Institute in Amsterdam and a professor in translational immunotherapy of cancer at Leiden (the Netherlands) University Medical Center.  

He presented the findings at a presidential symposium during the European Society for Medical Oncology Annual Congress, Paris.

“The results of this trial may fuel further research of TIL in other cancer types, potentially demonstrating benefit in many other solid tumors and expanding available treatments for patients,” said Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was approached for comment by this news organization and was not involved in the research.

Immune checkpoint inhibitors and targeted therapies have become the standard of care for advanced melanoma and greatly improved patient outcomes, she said. But as about half of patients treated with these agents will not achieve a durable benefit, there remains a need for new treatment options.

“Although immunotherapy can yield impressive long-term responses, a substantial percentage of patients will have no response, or no durable response, to checkpoint inhibitors,” said Dr. Dimitrova. “TIL therapy has proven effectiveness in melanoma. However, no phase III trials have been done to date to compare its effectiveness to a standard of care regimen.”

She noted that these results are consistent with past reports of an approximately 50% response rate with an impressive 20% complete response rate in the TIL group. Data from a phase 2 trial reported last year, for example, showed an objective response rate of 36.4%.

“It will be important to determine the persistence of antitumor activity and whether there are biomarkers that could help with patient selection given the resource intensity of the therapy,” Dr. Dimitrova said. “TIL therapy will likely become a new standard of care in metastatic melanoma refractory to immune checkpoint inhibitors.” 
 

Superior to immunotherapy

In the current study, Dr. Haanen and colleagues randomly assigned 168 patients to TIL or ipilimumab (3 mg/kg every 3 weeks, maximum 4 doses). Patients were stratified for BRAFV600 mutation status, treatment line and center, and the majority (86%) were refractory to anti–PD-1 treatment.

Patients in the TIL group underwent resection of a melanoma lesion (2-3 cm) for the ex vivo outgrowth and expansion of tumor-resident T cells. Before the cultured TILs were infused back into the patients from which they were made, the patient underwent nonmyeloablative, lymphodepleting chemotherapy with cyclophosphamide plus fludarabine that was followed by high-dose interleukin-2.

The study’s primary endpoint was progression-free survival, and secondary endpoints included overall and complete response rate, overall survival, and safety.

At a median follow-up of 33 months, TIL significantly improved progression-free survival, compared with ipilimumab. The overall response rate also favored TIL, compared with ipilimumab (49% vs. 21%), with 20% versus 7% complete responses, respectively.

The median overall survival was 25.8 months for TIL and 18.9 months for ipilimumab (HR, 0.83; P = 0.39).

Grade 3 or higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients, although Dr. Haanen noted they were manageable and, in most cases, resolved by the time patients were discharged from the hospital.

“There were no new safety concerns with TIL,” said Dr. Haanen, “And these toxicities are driven by the chemotherapy and interleukin-2 that are part of the TIL regimen. There were no long-term sequelae in patients treated with TIL, and health-related quality of life was higher in patients treated with TIL.”
 

Ultra-personalized

Also commenting on the study, Anthony J. Olszanski, MD, RPh, associate professor and vice chair of clinical research, department of hematology/oncology at Fox Chase Cancer Center, Philadelphia, agreed that the treatment of patients with melanoma who do not respond to or progress after receiving treatment with immunotherapy is “challenging and represents an unmet need.”

“TIL therapy is, in some ways, ultra-personalized therapy, because we harvest immune cells from the patient’s tumor, expand them outside of the body, and then re-infuse them,” he said. “This trial, which randomized patients between TIL versus the CTLA-4 inhibitor, ipilimumab, has shown an impressive progression-free survival and overall response rate benefit and will help establish TIL therapy as a viable treatment strategy for some patients.”

The study was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society, and Capital Region of Denmark Research Foundation.

Dr. Haanen and several of the co-authors have declared multiple relationships with industry as noted in the abstract. Dr. Olszanski reports participation in advisory boards for BMS, Merck, and Instil Bio, and he reports running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – Cell therapies have already had a huge impact on the treatment of blood cancers, but progress in solid tumors has proved more difficult. Now, in a first multicenter randomized trial to compare the two, a novel cell therapy showed a superior outcome to immunotherapy in patients with advanced melanoma.

The cell therapy used in this trial was composed of adoptive tumor infiltrating lymphocytes (TIL), which were made individually for each patient, just as chimeric antigen receptor T cells (CAR T cells) are for patients with blood cancers. However, the process involved is somewhat different, as TILs are made from lymphocytes that have infiltrated the patient’s tumor and are obtained by surgery in the tumor, whereas CAR T cells are made from circulating blood cells. 

The phase 3 trial involved 168 patients with unresectable stage IIIC-4 melanoma and showed that patients who were treated with TILs achieved a significantly improved progression-free survival (PFS) when compared with standard immunotherapy with ipilimumab (Yervoy).

The median PFS was more than doubled to 7.2 months with TILs versus 3.1 months with ipilimumab (hazard ratio, 0.50; P < .001).

“We do think that TIL could possibly become a new treatment option for patients with advanced stage melanoma,” commented lead author John Haanen, MD, PhD, research group leader at the Netherlands Cancer Institute in Amsterdam and a professor in translational immunotherapy of cancer at Leiden (the Netherlands) University Medical Center.  

He presented the findings at a presidential symposium during the European Society for Medical Oncology Annual Congress, Paris.

“The results of this trial may fuel further research of TIL in other cancer types, potentially demonstrating benefit in many other solid tumors and expanding available treatments for patients,” said Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center. She was approached for comment by this news organization and was not involved in the research.

Immune checkpoint inhibitors and targeted therapies have become the standard of care for advanced melanoma and greatly improved patient outcomes, she said. But as about half of patients treated with these agents will not achieve a durable benefit, there remains a need for new treatment options.

“Although immunotherapy can yield impressive long-term responses, a substantial percentage of patients will have no response, or no durable response, to checkpoint inhibitors,” said Dr. Dimitrova. “TIL therapy has proven effectiveness in melanoma. However, no phase III trials have been done to date to compare its effectiveness to a standard of care regimen.”

She noted that these results are consistent with past reports of an approximately 50% response rate with an impressive 20% complete response rate in the TIL group. Data from a phase 2 trial reported last year, for example, showed an objective response rate of 36.4%.

“It will be important to determine the persistence of antitumor activity and whether there are biomarkers that could help with patient selection given the resource intensity of the therapy,” Dr. Dimitrova said. “TIL therapy will likely become a new standard of care in metastatic melanoma refractory to immune checkpoint inhibitors.” 
 

Superior to immunotherapy

In the current study, Dr. Haanen and colleagues randomly assigned 168 patients to TIL or ipilimumab (3 mg/kg every 3 weeks, maximum 4 doses). Patients were stratified for BRAFV600 mutation status, treatment line and center, and the majority (86%) were refractory to anti–PD-1 treatment.

Patients in the TIL group underwent resection of a melanoma lesion (2-3 cm) for the ex vivo outgrowth and expansion of tumor-resident T cells. Before the cultured TILs were infused back into the patients from which they were made, the patient underwent nonmyeloablative, lymphodepleting chemotherapy with cyclophosphamide plus fludarabine that was followed by high-dose interleukin-2.

The study’s primary endpoint was progression-free survival, and secondary endpoints included overall and complete response rate, overall survival, and safety.

At a median follow-up of 33 months, TIL significantly improved progression-free survival, compared with ipilimumab. The overall response rate also favored TIL, compared with ipilimumab (49% vs. 21%), with 20% versus 7% complete responses, respectively.

The median overall survival was 25.8 months for TIL and 18.9 months for ipilimumab (HR, 0.83; P = 0.39).

Grade 3 or higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients, although Dr. Haanen noted they were manageable and, in most cases, resolved by the time patients were discharged from the hospital.

“There were no new safety concerns with TIL,” said Dr. Haanen, “And these toxicities are driven by the chemotherapy and interleukin-2 that are part of the TIL regimen. There were no long-term sequelae in patients treated with TIL, and health-related quality of life was higher in patients treated with TIL.”
 

Ultra-personalized

Also commenting on the study, Anthony J. Olszanski, MD, RPh, associate professor and vice chair of clinical research, department of hematology/oncology at Fox Chase Cancer Center, Philadelphia, agreed that the treatment of patients with melanoma who do not respond to or progress after receiving treatment with immunotherapy is “challenging and represents an unmet need.”

“TIL therapy is, in some ways, ultra-personalized therapy, because we harvest immune cells from the patient’s tumor, expand them outside of the body, and then re-infuse them,” he said. “This trial, which randomized patients between TIL versus the CTLA-4 inhibitor, ipilimumab, has shown an impressive progression-free survival and overall response rate benefit and will help establish TIL therapy as a viable treatment strategy for some patients.”

The study was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society, and Capital Region of Denmark Research Foundation.

Dr. Haanen and several of the co-authors have declared multiple relationships with industry as noted in the abstract. Dr. Olszanski reports participation in advisory boards for BMS, Merck, and Instil Bio, and he reports running trials for them.

A version of this article first appeared on Medscape.com.

PARIS – Air pollution has been recognized as a risk factor for lung cancer for about 2 decades, and investigators in the UK have now identified a potential mechanism whereby the air we breathe may trigger driver mutations already present in normal lung cells to cause cancer.

Think of it as “smoking gun–level” evidence that may explain why many nonsmokers still develop non–small cell lung cancer, said Charles Swanton, PhD, from the Francis Crick Institute and Cancer Research UK Chief Clinician, London.

“What this work shows is that air pollution is directly causing lung cancer but through a slightly unexpected pathway,” he said at a briefing prior to his presentation of the data in a presidential symposium held earlier this month in Paris at the European Society for Medical Oncology Congress 2022.

Importantly, he and his team also propose a mechanism for blocking the effects of air pollution with monoclonal antibodies directed against the inflammatory cytokine interleukein-1 beta.
 

Carcinogenesis explored

Lung cancer in never-smokers has a low mutational burden, with about 5- to 10-fold fewer mutations in a nonsmoker, compared with an ever smoker or current smoker, Dr. Swanton noted.

“The other thing to say about never-smokers is that they don’t have a clear environmental carcinogenic signature. So how do you square the circle? You’ve got the problem that you know that air pollution is associated with lung cancer – we don’t know if it causes it – but we also see that we’ve got no DNA mutations due to an environmental carcinogen,” he said during his symposium presentation.

The traditional model proposed to explain how carcinogens cause cancer holds that exposure to a carcinogen causes DNA mutations that lead to clonal expansion and tumor growth.

“But there are some major problems with this model,” Dr. Swanton said.

For example, normal skin contains a “patchwork of mutant clones,” but skin cancer is still uncommon, he said, and in studies in mice, 17 of 20 environmental carcinogens did not induce DNA mutations. He also noted that a common melanoma driver mutation, BRAF V600E, is not induced by exposure to a ultraviolet light.

“Any explanation for never-smoking lung cancer would have to fulfill three criteria: one, you have to explain why geographic variation exists; two, you have to prove causation; and three, you have to explain how cancers can be initiated without directly causing DNA mutations,” he said.

Normal lung tissues in nonsmoking adults can harbor pre-existing mutations, with the number of mutations increasing likely as a consequence of aging. In fact, more than 50% of normal lung biopsy tissues have been shown to harbor driver KRAS and/or EGFR mutations, Dr. Swanton said.

“In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harboring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don’t,” he said.
 

Geographical exposures

Looking at data on 447,932 participants in the UK Biobank, the investigators found that increasing exposure to ambient air particles smaller than 2.5 mcm (PM_2.5) was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­_2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And crucially, as Dr. Swanton and associates showed in mouse models, exposure of lung cells bearing somatic EGFR and KRAS mutations to PM2.5 causes recruitment of macrophages that in turn secrete IL-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.

Importantly, pollution-induced tumor formation can be blocked by antibodies directed against IL-1B, Dr. Swanton said.

He pointed to a 2017 study in The Lancet suggesting that anti-inflammatory therapy with the anti–IL-1 antibody canakinumab (Ilaris) could reduce incident lung cancer and lung cancer deaths.
 

‘Elegant first demonstration’

“This is a very meaningful demonstration, from epidemiological data to preclinical models of the role of PM_­2.5 air pollutants in the promotion of lung cancer, and it provides us with very important insights into the mechanism through which nonsmokers can get lung cancer,” commented Suzette Delaloge, MD, from the cancer interception program at Institut Goustave Roussy in Villejuif, France, the invited discussant.

“But beyond that, it also has a great impact on our vision of carcinogenesis, with this very elegant first demonstration of the alternative nonmutagenic, carcinogenetic promotion hypothesis for fine particulate matter,” she said.

Questions still to be answered include whether PM_2.5 pollutants could also be mutagenic, is the oncogenic pathway ubiquitous in tissue, which components of PM_2.5 might drive the effect, how long of an exposure is required to promote lung cancer, and why and how persons without cancer develop specific driver mutations such as EGFR, she said.

“This research is intriguing and exciting as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1B inhibitors,” said Tony Mok, MD, a lung cancer specialist at the Chinese University of Hong Kong, who was not involved in the study.

“We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative,” he said in a statement.

The study was supported by Cancer Research UK, the Lung Cancer Research Foundations, Rosetrees Trust, the Mark Foundation for Cancer Research and the Ruth Strauss Foundation. Dr. Swanton disclosed grants/research support, honoraria, and stock ownership with multiple entities. Dr. Delaloge disclosed institutional financing and research funding from multiple companies. Dr. Mok disclosed stock ownership and honoraria with multiple companies.

PARIS – Air pollution has been recognized as a risk factor for lung cancer for about 2 decades, and investigators in the UK have now identified a potential mechanism whereby the air we breathe may trigger driver mutations already present in normal lung cells to cause cancer.

Think of it as “smoking gun–level” evidence that may explain why many nonsmokers still develop non–small cell lung cancer, said Charles Swanton, PhD, from the Francis Crick Institute and Cancer Research UK Chief Clinician, London.

“What this work shows is that air pollution is directly causing lung cancer but through a slightly unexpected pathway,” he said at a briefing prior to his presentation of the data in a presidential symposium held earlier this month in Paris at the European Society for Medical Oncology Congress 2022.

Importantly, he and his team also propose a mechanism for blocking the effects of air pollution with monoclonal antibodies directed against the inflammatory cytokine interleukein-1 beta.
 

Carcinogenesis explored

Lung cancer in never-smokers has a low mutational burden, with about 5- to 10-fold fewer mutations in a nonsmoker, compared with an ever smoker or current smoker, Dr. Swanton noted.

“The other thing to say about never-smokers is that they don’t have a clear environmental carcinogenic signature. So how do you square the circle? You’ve got the problem that you know that air pollution is associated with lung cancer – we don’t know if it causes it – but we also see that we’ve got no DNA mutations due to an environmental carcinogen,” he said during his symposium presentation.

The traditional model proposed to explain how carcinogens cause cancer holds that exposure to a carcinogen causes DNA mutations that lead to clonal expansion and tumor growth.

“But there are some major problems with this model,” Dr. Swanton said.

For example, normal skin contains a “patchwork of mutant clones,” but skin cancer is still uncommon, he said, and in studies in mice, 17 of 20 environmental carcinogens did not induce DNA mutations. He also noted that a common melanoma driver mutation, BRAF V600E, is not induced by exposure to a ultraviolet light.

“Any explanation for never-smoking lung cancer would have to fulfill three criteria: one, you have to explain why geographic variation exists; two, you have to prove causation; and three, you have to explain how cancers can be initiated without directly causing DNA mutations,” he said.

Normal lung tissues in nonsmoking adults can harbor pre-existing mutations, with the number of mutations increasing likely as a consequence of aging. In fact, more than 50% of normal lung biopsy tissues have been shown to harbor driver KRAS and/or EGFR mutations, Dr. Swanton said.

“In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harboring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don’t,” he said.
 

Geographical exposures

Looking at data on 447,932 participants in the UK Biobank, the investigators found that increasing exposure to ambient air particles smaller than 2.5 mcm (PM_2.5) was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­_2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And crucially, as Dr. Swanton and associates showed in mouse models, exposure of lung cells bearing somatic EGFR and KRAS mutations to PM2.5 causes recruitment of macrophages that in turn secrete IL-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.

Importantly, pollution-induced tumor formation can be blocked by antibodies directed against IL-1B, Dr. Swanton said.

He pointed to a 2017 study in The Lancet suggesting that anti-inflammatory therapy with the anti–IL-1 antibody canakinumab (Ilaris) could reduce incident lung cancer and lung cancer deaths.
 

‘Elegant first demonstration’

“This is a very meaningful demonstration, from epidemiological data to preclinical models of the role of PM_­2.5 air pollutants in the promotion of lung cancer, and it provides us with very important insights into the mechanism through which nonsmokers can get lung cancer,” commented Suzette Delaloge, MD, from the cancer interception program at Institut Goustave Roussy in Villejuif, France, the invited discussant.

“But beyond that, it also has a great impact on our vision of carcinogenesis, with this very elegant first demonstration of the alternative nonmutagenic, carcinogenetic promotion hypothesis for fine particulate matter,” she said.

Questions still to be answered include whether PM_2.5 pollutants could also be mutagenic, is the oncogenic pathway ubiquitous in tissue, which components of PM_2.5 might drive the effect, how long of an exposure is required to promote lung cancer, and why and how persons without cancer develop specific driver mutations such as EGFR, she said.

“This research is intriguing and exciting as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1B inhibitors,” said Tony Mok, MD, a lung cancer specialist at the Chinese University of Hong Kong, who was not involved in the study.

“We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative,” he said in a statement.

The study was supported by Cancer Research UK, the Lung Cancer Research Foundations, Rosetrees Trust, the Mark Foundation for Cancer Research and the Ruth Strauss Foundation. Dr. Swanton disclosed grants/research support, honoraria, and stock ownership with multiple entities. Dr. Delaloge disclosed institutional financing and research funding from multiple companies. Dr. Mok disclosed stock ownership and honoraria with multiple companies.

PARIS – Air pollution has been recognized as a risk factor for lung cancer for about 2 decades, and investigators in the UK have now identified a potential mechanism whereby the air we breathe may trigger driver mutations already present in normal lung cells to cause cancer.

Think of it as “smoking gun–level” evidence that may explain why many nonsmokers still develop non–small cell lung cancer, said Charles Swanton, PhD, from the Francis Crick Institute and Cancer Research UK Chief Clinician, London.

“What this work shows is that air pollution is directly causing lung cancer but through a slightly unexpected pathway,” he said at a briefing prior to his presentation of the data in a presidential symposium held earlier this month in Paris at the European Society for Medical Oncology Congress 2022.

Importantly, he and his team also propose a mechanism for blocking the effects of air pollution with monoclonal antibodies directed against the inflammatory cytokine interleukein-1 beta.
 

Carcinogenesis explored

Lung cancer in never-smokers has a low mutational burden, with about 5- to 10-fold fewer mutations in a nonsmoker, compared with an ever smoker or current smoker, Dr. Swanton noted.

“The other thing to say about never-smokers is that they don’t have a clear environmental carcinogenic signature. So how do you square the circle? You’ve got the problem that you know that air pollution is associated with lung cancer – we don’t know if it causes it – but we also see that we’ve got no DNA mutations due to an environmental carcinogen,” he said during his symposium presentation.

The traditional model proposed to explain how carcinogens cause cancer holds that exposure to a carcinogen causes DNA mutations that lead to clonal expansion and tumor growth.

“But there are some major problems with this model,” Dr. Swanton said.

For example, normal skin contains a “patchwork of mutant clones,” but skin cancer is still uncommon, he said, and in studies in mice, 17 of 20 environmental carcinogens did not induce DNA mutations. He also noted that a common melanoma driver mutation, BRAF V600E, is not induced by exposure to a ultraviolet light.

“Any explanation for never-smoking lung cancer would have to fulfill three criteria: one, you have to explain why geographic variation exists; two, you have to prove causation; and three, you have to explain how cancers can be initiated without directly causing DNA mutations,” he said.

Normal lung tissues in nonsmoking adults can harbor pre-existing mutations, with the number of mutations increasing likely as a consequence of aging. In fact, more than 50% of normal lung biopsy tissues have been shown to harbor driver KRAS and/or EGFR mutations, Dr. Swanton said.

“In our research, these mutations alone only weakly potentiated cancer in laboratory models. However, when lung cells with these mutations were exposed to air pollutants, we saw more cancers and these occurred more quickly than when lung cells with these mutations were not exposed to pollutants, suggesting that air pollution promotes the initiation of lung cancer in cells harboring driver gene mutations. The next step is to discover why some lung cells with mutations become cancerous when exposed to pollutants while others don’t,” he said.
 

Geographical exposures

Looking at data on 447,932 participants in the UK Biobank, the investigators found that increasing exposure to ambient air particles smaller than 2.5 mcm (PM_2.5) was significantly associated with seven cancer types, including lung cancer. They also saw an association between PM­­_2.5 exposure levels and EGFR-mutated lung cancer incidence in the United Kingdom, South Korea, and Taiwan.

And crucially, as Dr. Swanton and associates showed in mouse models, exposure of lung cells bearing somatic EGFR and KRAS mutations to PM2.5 causes recruitment of macrophages that in turn secrete IL-1B, resulting in a transdifferentiation of EGFR-mutated cells into a cancer stem cell state, and tumor formation.

Importantly, pollution-induced tumor formation can be blocked by antibodies directed against IL-1B, Dr. Swanton said.

He pointed to a 2017 study in The Lancet suggesting that anti-inflammatory therapy with the anti–IL-1 antibody canakinumab (Ilaris) could reduce incident lung cancer and lung cancer deaths.
 

‘Elegant first demonstration’

“This is a very meaningful demonstration, from epidemiological data to preclinical models of the role of PM_­2.5 air pollutants in the promotion of lung cancer, and it provides us with very important insights into the mechanism through which nonsmokers can get lung cancer,” commented Suzette Delaloge, MD, from the cancer interception program at Institut Goustave Roussy in Villejuif, France, the invited discussant.

“But beyond that, it also has a great impact on our vision of carcinogenesis, with this very elegant first demonstration of the alternative nonmutagenic, carcinogenetic promotion hypothesis for fine particulate matter,” she said.

Questions still to be answered include whether PM_2.5 pollutants could also be mutagenic, is the oncogenic pathway ubiquitous in tissue, which components of PM_2.5 might drive the effect, how long of an exposure is required to promote lung cancer, and why and how persons without cancer develop specific driver mutations such as EGFR, she said.

“This research is intriguing and exciting as it means that we can ask whether, in the future, it will be possible to use lung scans to look for precancerous lesions in the lungs and try to reverse them with medicines such as interleukin-1B inhibitors,” said Tony Mok, MD, a lung cancer specialist at the Chinese University of Hong Kong, who was not involved in the study.

“We don’t yet know whether it will be possible to use highly sensitive EGFR profiling on blood or other samples to find nonsmokers who are predisposed to lung cancer and may benefit from lung scanning, so discussions are still very speculative,” he said in a statement.

The study was supported by Cancer Research UK, the Lung Cancer Research Foundations, Rosetrees Trust, the Mark Foundation for Cancer Research and the Ruth Strauss Foundation. Dr. Swanton disclosed grants/research support, honoraria, and stock ownership with multiple entities. Dr. Delaloge disclosed institutional financing and research funding from multiple companies. Dr. Mok disclosed stock ownership and honoraria with multiple companies.

Patients with melanoma who are deficient in vitamin D have significantly worse overall survival than those with higher levels, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.

Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.

The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.

Dr. Inés Gracia-Darder

Known association, but not much data

“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.

“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.

“So we assume that also has an effect on melanoma-specific survival,” she added.

That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
 

Retrospective cohort analysis

Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.

For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.

A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
 

Independent association with overall survival

Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.

Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.

Other predictive factors were having a higher Breslow index, as well as older age and gender.
 

Time to recommend vitamin D supplementation?

So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?

“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.

While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.

Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.

Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.

It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.

“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”

The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.

A version of this article first appeared on Medscape.com.

Patients with melanoma who are deficient in vitamin D have significantly worse overall survival than those with higher levels, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.

Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.

The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.

Dr. Inés Gracia-Darder

Known association, but not much data

“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.

“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.

“So we assume that also has an effect on melanoma-specific survival,” she added.

That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
 

Retrospective cohort analysis

Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.

For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.

A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
 

Independent association with overall survival

Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.

Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.

Other predictive factors were having a higher Breslow index, as well as older age and gender.
 

Time to recommend vitamin D supplementation?

So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?

“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.

While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.

Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.

Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.

It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.

“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”

The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.

A version of this article first appeared on Medscape.com.

Patients with melanoma who are deficient in vitamin D have significantly worse overall survival than those with higher levels, according to research presented at the annual congress of the European Academy of Dermatology and Venereology.

Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on.

The research adds to existing evidence that “vitamin D levels can play an important and independent role in patients’ survival outcomes,” study investigator Inés Gracia-Darder, MD, told this news organization. “The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients,” said Dr. Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain.

Dr. Inés Gracia-Darder

Known association, but not much data

“It is not a new finding,” but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival.

“Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor,” Dr. De Smedt said in an interview, indicating that it’s not just overall survival that might be affected.

“So we assume that also has an effect on melanoma-specific survival,” she added.

That assumption, however, is not supported by the data Dr. Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied.
 

Retrospective cohort analysis

Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years.

For inclusion, all patients had to have had their vitamin D levels measured after being diagnosed with melanoma; those with a 25-hydroxyvitamin D3 serum level of less than 10 ng/mL were deemed to be vitamin D deficient, whereas those with levels of 10 ng/mL and above were deemed normal or insufficient.

A measurement less than 10 ng/mL is considered vitamin D deficiency, Dr. De Smedt said. “But there is a difference between countries, and there’s also a difference between societies,” noting the cut-off used in the lab where she works is 20 ng/mL. This makes it difficult to compare studies, she said.
 

Independent association with overall survival

Seasonal variation in vitamin D levels were considered as a possible confounding factor, but Dr. Gracia-Darder noted that there was a similar distribution of measurements taken between October to March and April to September.

Univariate and multivariate analyses established vitamin D deficiency as being independently associated with overall survival with hazard ratios of 2.34 and 2.45, respectively.

Other predictive factors were having a higher Breslow index, as well as older age and gender.
 

Time to recommend vitamin D supplementation?

So should patients with melanoma have their vitamin D levels routinely checked? And what about advising them to take vitamin D supplements?

“In our practice, we analyze the vitamin D levels of our patients,” Dr. Gracia-Darder said. Patients are told to limit their exposure to the sun because of their skin cancer, so they are very likely to become vitamin D deficient.

While dietary changes or supplements might be suggested, there’s no real evidence to support upping vitamin D levels to date, so “future prospective studies are needed,” Dr. Gracia-Darder added.

Such studies have already started, including one in Italy, one in Australia, and another study that Dr. De Smedt has been involved with for the past few years.

Called the ViDMe study, it’s a multicenter, randomized, double-blind trial in which patients are being given a high-dose oral vitamin D supplement or placebo once a month for at least 1 year. About 430 patients with a first cutaneous malignant melanoma have been included in the trial, which started in December 2012.

It is hoped that the results will show that the supplementation will have had a protective effect on the risk of relapse and that there will be a correlation between vitamin D levels in the blood and vitamin D receptor immunoreactivity in the tumor.

“The study is still blinded,” Dr. De Smedt said. “We will unblind in the coming months and then at the end of the year, maybe next year, we will have the results.”

The study reported by Dr. Gracia-Darder did not receive any specific funding. Dr. Gracia-Darder disclosed that the melanoma unit where the study was performed receives many grants and funds to carry out research. She reported no other relevant financial relationships. Dr. De Smedt had no relevant financial relationships. The ViDMe study is sponsored by the Universitaire Ziekenhuizen Leuven.

A version of this article first appeared on Medscape.com.

To the Editor:

Ultra-late melanoma recurrence represents a minority of cases in which the quiescent period lasts longer than 15 years, and epidemiologic studies have reported recurrence rates of 6% to 10% during the ultra-late period.¹ Even more uncommon are cases that span many decades (eg, >30 years), but all are useful in understanding the cellular behavior leading to the reactivation of fully excised melanomas. Few cases have been reported in which recurrence occurs more than 35 years after the original diagnosis of melanoma. Unfortunately, mechanisms underlying this long stable quiescence and subsequent reactivation are poorly understood, which is why it is important to identify and document cases. We present a case of local recurrence of cutaneous melanoma on the patient’s lower back after a 49-year disease-free period.

A 78-year-old White woman presented to a private dermatology office for a full-body skin examination. She had a medical history of a cutaneous melanoma that had been removed on the lower back 49 years prior; Parkinson disease of 10 years’ duration; and an enlarged thyroid nodule with decreased thyrotropin and hyperthyroidism, atrial fibrillation, mitral valve prolapse, osteoarthritis in the knees, and actinic keratoses, all of which were chronic conditions lasting years to decades. She was taking several medications for these medical conditions. Her surgical history included a hysterectomy, hip replacement, hernia repair, cardioversion, and tonsillectomy in childhood. Her family medical history included breast cancer in her paternal grandmother and aunt; hypertension in her father; and sarcoma in her mother at 78 years of age, which initially was identified in the sacrum and metastasized to the lungs causing death. No family history of melanoma or other skin cancers was reported. Prior to the original diagnosis of melanoma at 29 years of age, she had no history of skin cancer or any other medical condition other than acne. The patient did report spending a great deal of time in the sun during high school.

The patient reported developing the original cutaneous melanoma during her second pregnancy at 29 years of age and recalled that it was excised with wide margins. There had been a mole on her back that was present for years but changed in size during pregnancy, prompting the original visit to the primary care physician for evaluation. Remarkably, the original pathology report was obtained from the patient and revealed a specimen consisting of a 3.7×1.7-cm skin ellipse averaging 0.7 cm in thickness. In the center of the specimen was a 0.6-cm, round, raised, pigmented lesion that revealed moderately frequent mitoses on microscopic evaluation. It was determined by the pathologist to be a malignant tumor, and the report stated that the surgical margins appeared clear.

Physical examination at the current presentation 49 years later revealed an even-bordered 2-mm black macule that was located approximately 1 cm from the original melanoma excision scar line (Figure). A biopsy was performed and sent to a dermatopathologist. Microscopic evaluation revealed nests, islands, and sheets of atypical epithelioid melanocytes extending through the dermis between collagen bundles. The melanocytes varied in size and shape with moderate nuclear pleomorphism present. Scattered mitotic figures and necrotic melanocytes were present, which most likely represented cutaneous satellite metastases of melanoma. Subsequent chest radiography, full-body positron emission tomography, and standard laboratory blood tests were unremarkable except for an enlarged right thyroid gland and moderate cardiomegaly. The patient was sent to a surgical oncologist for excision with wide surgical margins, and she elected not to have a sentinel lymph node biopsy. At follow-up 3, 6, 12, and 24 months later, there were no signs of recurrence based on direct clinical examination. The patient subsequently was lost to follow-up.

Recurrence rates of melanoma vary by stage and age at diagnosis, but prior studies have reported a recurrence rate of approximately 6% after 10 or more years following the initial diagnosis.² Ultra-late recurrences of approximately 4 decades or more are extremely rare. A PubMed search of articles indexed for MEDLINE using the terms melanoma and ultra-late recurrence revealed 4 reported cases with a quiescent period of 38 or more years.^3-6 All cases were metastatic melanomas in women; spanned 38, 40, 41, and 45 years from the initial melanoma diagnosis to recurrence; and all of the recurrences except one were regional or distal metastatic lesions (eg, lymph node, brain). In one case, both the original and recurrent lesions occurred on the left elbow.⁶ The original lesions occurred on the legs, elbow, and back of the neck, and there were no notable concomitant medical conditions. The patients were aged 72, 73, 73, and 84 years at recurrence.^3-6 However, generalizations from these cases are limited given the potential for selection bias (eg, men may be less likely to visit a clinic for follow-up and nevi examination) and the likelihood that many cases of ultra-late melanoma recurrence are unrecognized or unreported.

More recently, genomic analyses on melanoma lesions occurring 30 years apart confirmed that the second lesion was indeed a recurrence, although with numerous additional mutations.⁷ The specific mechanisms underlying the dormancy and subsequent reemergence of metastatic lesions are unclear, but there may be aberrations in the skin beyond histopathologic margins that represent an early phase of disease that are histologically unrecognizable and may lay dormant for many years before reemerging in response to external or immunologic changes.⁸ Alternatively, recurrences may be associated with lymphatic or hematogenous emboli, or there may be a tendency for melanomas to metastasize to inflamed or scarred tissue representing a tropism of the malignant melanocytes.⁹

It also is worth highlighting the concomitant diagnosis of Parkinson disease in our patient. In recent years, Parkinson disease has been linked to melanoma in both epidemiologic and genetic studies. For example, one large-scale study found a 50% increased risk for developing Parkinson disease in patients with melanoma (and vice versa), and this finding has been replicated in other studies.¹⁰ Moreover, patients with Parkinson disease have a 2-fold increase in their risk for developing melanoma, demonstrating that it is a bidirectional pathway. Not surprisingly, associations between melanin and neuromelanin pathways have been identified as a potential link between these diseases, and scientists are in the process of understanding the genetic components of both.¹⁰ It is unknown if specific genetic mutations contributed to both diseases in our case, but follow-up genetic testing on the recurrent melanoma specimen currently is being pursued.

The 49-year quiescent period in our case of recurrent cutaneous malignant melanoma potentially represents the longest ultra-late recurrence of melanoma in the literature to date based on a review of indexed publications. Moreover, it is relatively unique compared to other similar cases in that the recurrence was within a centimeter of the original excisional scar. Most metastases occur in locoregional lymph nodes or the lungs³; therefore, it is unusual to find one so close to the original lesion, especially one that occurred decades later. Factors associated with ultra-late recurrences are unknown, primarily because of the rarity of these cases as well as the biases and other factors that limit existing studies. However, genetic sequencing may provide information regarding these factors and related processes. Genetic sequencing specifically points to a small cell group remaining after excision of the primary tumor, which mutates while proliferating. Low antigenicity and tolerance to immunity during the quiescent period may explain the long duration of dormancy.⁶ More recently, there have been efforts to identify immunohistochemical signatures that may predict late recurrences, though the data are preliminary in nature.¹¹

Given the latency period and location of the recurrence, our case demonstrates that even fully excised melanomas may recur locally many decades later, hence patients should be aware of the importance of a lifetime of vigilance after being diagnosed with melanoma.

To the Editor:

Ultra-late melanoma recurrence represents a minority of cases in which the quiescent period lasts longer than 15 years, and epidemiologic studies have reported recurrence rates of 6% to 10% during the ultra-late period.¹ Even more uncommon are cases that span many decades (eg, >30 years), but all are useful in understanding the cellular behavior leading to the reactivation of fully excised melanomas. Few cases have been reported in which recurrence occurs more than 35 years after the original diagnosis of melanoma. Unfortunately, mechanisms underlying this long stable quiescence and subsequent reactivation are poorly understood, which is why it is important to identify and document cases. We present a case of local recurrence of cutaneous melanoma on the patient’s lower back after a 49-year disease-free period.

A 78-year-old White woman presented to a private dermatology office for a full-body skin examination. She had a medical history of a cutaneous melanoma that had been removed on the lower back 49 years prior; Parkinson disease of 10 years’ duration; and an enlarged thyroid nodule with decreased thyrotropin and hyperthyroidism, atrial fibrillation, mitral valve prolapse, osteoarthritis in the knees, and actinic keratoses, all of which were chronic conditions lasting years to decades. She was taking several medications for these medical conditions. Her surgical history included a hysterectomy, hip replacement, hernia repair, cardioversion, and tonsillectomy in childhood. Her family medical history included breast cancer in her paternal grandmother and aunt; hypertension in her father; and sarcoma in her mother at 78 years of age, which initially was identified in the sacrum and metastasized to the lungs causing death. No family history of melanoma or other skin cancers was reported. Prior to the original diagnosis of melanoma at 29 years of age, she had no history of skin cancer or any other medical condition other than acne. The patient did report spending a great deal of time in the sun during high school.

The patient reported developing the original cutaneous melanoma during her second pregnancy at 29 years of age and recalled that it was excised with wide margins. There had been a mole on her back that was present for years but changed in size during pregnancy, prompting the original visit to the primary care physician for evaluation. Remarkably, the original pathology report was obtained from the patient and revealed a specimen consisting of a 3.7×1.7-cm skin ellipse averaging 0.7 cm in thickness. In the center of the specimen was a 0.6-cm, round, raised, pigmented lesion that revealed moderately frequent mitoses on microscopic evaluation. It was determined by the pathologist to be a malignant tumor, and the report stated that the surgical margins appeared clear.

Physical examination at the current presentation 49 years later revealed an even-bordered 2-mm black macule that was located approximately 1 cm from the original melanoma excision scar line (Figure). A biopsy was performed and sent to a dermatopathologist. Microscopic evaluation revealed nests, islands, and sheets of atypical epithelioid melanocytes extending through the dermis between collagen bundles. The melanocytes varied in size and shape with moderate nuclear pleomorphism present. Scattered mitotic figures and necrotic melanocytes were present, which most likely represented cutaneous satellite metastases of melanoma. Subsequent chest radiography, full-body positron emission tomography, and standard laboratory blood tests were unremarkable except for an enlarged right thyroid gland and moderate cardiomegaly. The patient was sent to a surgical oncologist for excision with wide surgical margins, and she elected not to have a sentinel lymph node biopsy. At follow-up 3, 6, 12, and 24 months later, there were no signs of recurrence based on direct clinical examination. The patient subsequently was lost to follow-up.

Recurrence rates of melanoma vary by stage and age at diagnosis, but prior studies have reported a recurrence rate of approximately 6% after 10 or more years following the initial diagnosis.² Ultra-late recurrences of approximately 4 decades or more are extremely rare. A PubMed search of articles indexed for MEDLINE using the terms melanoma and ultra-late recurrence revealed 4 reported cases with a quiescent period of 38 or more years.^3-6 All cases were metastatic melanomas in women; spanned 38, 40, 41, and 45 years from the initial melanoma diagnosis to recurrence; and all of the recurrences except one were regional or distal metastatic lesions (eg, lymph node, brain). In one case, both the original and recurrent lesions occurred on the left elbow.⁶ The original lesions occurred on the legs, elbow, and back of the neck, and there were no notable concomitant medical conditions. The patients were aged 72, 73, 73, and 84 years at recurrence.^3-6 However, generalizations from these cases are limited given the potential for selection bias (eg, men may be less likely to visit a clinic for follow-up and nevi examination) and the likelihood that many cases of ultra-late melanoma recurrence are unrecognized or unreported.

More recently, genomic analyses on melanoma lesions occurring 30 years apart confirmed that the second lesion was indeed a recurrence, although with numerous additional mutations.⁷ The specific mechanisms underlying the dormancy and subsequent reemergence of metastatic lesions are unclear, but there may be aberrations in the skin beyond histopathologic margins that represent an early phase of disease that are histologically unrecognizable and may lay dormant for many years before reemerging in response to external or immunologic changes.⁸ Alternatively, recurrences may be associated with lymphatic or hematogenous emboli, or there may be a tendency for melanomas to metastasize to inflamed or scarred tissue representing a tropism of the malignant melanocytes.⁹

It also is worth highlighting the concomitant diagnosis of Parkinson disease in our patient. In recent years, Parkinson disease has been linked to melanoma in both epidemiologic and genetic studies. For example, one large-scale study found a 50% increased risk for developing Parkinson disease in patients with melanoma (and vice versa), and this finding has been replicated in other studies.¹⁰ Moreover, patients with Parkinson disease have a 2-fold increase in their risk for developing melanoma, demonstrating that it is a bidirectional pathway. Not surprisingly, associations between melanin and neuromelanin pathways have been identified as a potential link between these diseases, and scientists are in the process of understanding the genetic components of both.¹⁰ It is unknown if specific genetic mutations contributed to both diseases in our case, but follow-up genetic testing on the recurrent melanoma specimen currently is being pursued.

The 49-year quiescent period in our case of recurrent cutaneous malignant melanoma potentially represents the longest ultra-late recurrence of melanoma in the literature to date based on a review of indexed publications. Moreover, it is relatively unique compared to other similar cases in that the recurrence was within a centimeter of the original excisional scar. Most metastases occur in locoregional lymph nodes or the lungs³; therefore, it is unusual to find one so close to the original lesion, especially one that occurred decades later. Factors associated with ultra-late recurrences are unknown, primarily because of the rarity of these cases as well as the biases and other factors that limit existing studies. However, genetic sequencing may provide information regarding these factors and related processes. Genetic sequencing specifically points to a small cell group remaining after excision of the primary tumor, which mutates while proliferating. Low antigenicity and tolerance to immunity during the quiescent period may explain the long duration of dormancy.⁶ More recently, there have been efforts to identify immunohistochemical signatures that may predict late recurrences, though the data are preliminary in nature.¹¹

Given the latency period and location of the recurrence, our case demonstrates that even fully excised melanomas may recur locally many decades later, hence patients should be aware of the importance of a lifetime of vigilance after being diagnosed with melanoma.

To the Editor:

Ultra-late melanoma recurrence represents a minority of cases in which the quiescent period lasts longer than 15 years, and epidemiologic studies have reported recurrence rates of 6% to 10% during the ultra-late period.¹ Even more uncommon are cases that span many decades (eg, >30 years), but all are useful in understanding the cellular behavior leading to the reactivation of fully excised melanomas. Few cases have been reported in which recurrence occurs more than 35 years after the original diagnosis of melanoma. Unfortunately, mechanisms underlying this long stable quiescence and subsequent reactivation are poorly understood, which is why it is important to identify and document cases. We present a case of local recurrence of cutaneous melanoma on the patient’s lower back after a 49-year disease-free period.

A 78-year-old White woman presented to a private dermatology office for a full-body skin examination. She had a medical history of a cutaneous melanoma that had been removed on the lower back 49 years prior; Parkinson disease of 10 years’ duration; and an enlarged thyroid nodule with decreased thyrotropin and hyperthyroidism, atrial fibrillation, mitral valve prolapse, osteoarthritis in the knees, and actinic keratoses, all of which were chronic conditions lasting years to decades. She was taking several medications for these medical conditions. Her surgical history included a hysterectomy, hip replacement, hernia repair, cardioversion, and tonsillectomy in childhood. Her family medical history included breast cancer in her paternal grandmother and aunt; hypertension in her father; and sarcoma in her mother at 78 years of age, which initially was identified in the sacrum and metastasized to the lungs causing death. No family history of melanoma or other skin cancers was reported. Prior to the original diagnosis of melanoma at 29 years of age, she had no history of skin cancer or any other medical condition other than acne. The patient did report spending a great deal of time in the sun during high school.

The patient reported developing the original cutaneous melanoma during her second pregnancy at 29 years of age and recalled that it was excised with wide margins. There had been a mole on her back that was present for years but changed in size during pregnancy, prompting the original visit to the primary care physician for evaluation. Remarkably, the original pathology report was obtained from the patient and revealed a specimen consisting of a 3.7×1.7-cm skin ellipse averaging 0.7 cm in thickness. In the center of the specimen was a 0.6-cm, round, raised, pigmented lesion that revealed moderately frequent mitoses on microscopic evaluation. It was determined by the pathologist to be a malignant tumor, and the report stated that the surgical margins appeared clear.

Physical examination at the current presentation 49 years later revealed an even-bordered 2-mm black macule that was located approximately 1 cm from the original melanoma excision scar line (Figure). A biopsy was performed and sent to a dermatopathologist. Microscopic evaluation revealed nests, islands, and sheets of atypical epithelioid melanocytes extending through the dermis between collagen bundles. The melanocytes varied in size and shape with moderate nuclear pleomorphism present. Scattered mitotic figures and necrotic melanocytes were present, which most likely represented cutaneous satellite metastases of melanoma. Subsequent chest radiography, full-body positron emission tomography, and standard laboratory blood tests were unremarkable except for an enlarged right thyroid gland and moderate cardiomegaly. The patient was sent to a surgical oncologist for excision with wide surgical margins, and she elected not to have a sentinel lymph node biopsy. At follow-up 3, 6, 12, and 24 months later, there were no signs of recurrence based on direct clinical examination. The patient subsequently was lost to follow-up.

Recurrence rates of melanoma vary by stage and age at diagnosis, but prior studies have reported a recurrence rate of approximately 6% after 10 or more years following the initial diagnosis.² Ultra-late recurrences of approximately 4 decades or more are extremely rare. A PubMed search of articles indexed for MEDLINE using the terms melanoma and ultra-late recurrence revealed 4 reported cases with a quiescent period of 38 or more years.^3-6 All cases were metastatic melanomas in women; spanned 38, 40, 41, and 45 years from the initial melanoma diagnosis to recurrence; and all of the recurrences except one were regional or distal metastatic lesions (eg, lymph node, brain). In one case, both the original and recurrent lesions occurred on the left elbow.⁶ The original lesions occurred on the legs, elbow, and back of the neck, and there were no notable concomitant medical conditions. The patients were aged 72, 73, 73, and 84 years at recurrence.^3-6 However, generalizations from these cases are limited given the potential for selection bias (eg, men may be less likely to visit a clinic for follow-up and nevi examination) and the likelihood that many cases of ultra-late melanoma recurrence are unrecognized or unreported.

More recently, genomic analyses on melanoma lesions occurring 30 years apart confirmed that the second lesion was indeed a recurrence, although with numerous additional mutations.⁷ The specific mechanisms underlying the dormancy and subsequent reemergence of metastatic lesions are unclear, but there may be aberrations in the skin beyond histopathologic margins that represent an early phase of disease that are histologically unrecognizable and may lay dormant for many years before reemerging in response to external or immunologic changes.⁸ Alternatively, recurrences may be associated with lymphatic or hematogenous emboli, or there may be a tendency for melanomas to metastasize to inflamed or scarred tissue representing a tropism of the malignant melanocytes.⁹

It also is worth highlighting the concomitant diagnosis of Parkinson disease in our patient. In recent years, Parkinson disease has been linked to melanoma in both epidemiologic and genetic studies. For example, one large-scale study found a 50% increased risk for developing Parkinson disease in patients with melanoma (and vice versa), and this finding has been replicated in other studies.¹⁰ Moreover, patients with Parkinson disease have a 2-fold increase in their risk for developing melanoma, demonstrating that it is a bidirectional pathway. Not surprisingly, associations between melanin and neuromelanin pathways have been identified as a potential link between these diseases, and scientists are in the process of understanding the genetic components of both.¹⁰ It is unknown if specific genetic mutations contributed to both diseases in our case, but follow-up genetic testing on the recurrent melanoma specimen currently is being pursued.

The 49-year quiescent period in our case of recurrent cutaneous malignant melanoma potentially represents the longest ultra-late recurrence of melanoma in the literature to date based on a review of indexed publications. Moreover, it is relatively unique compared to other similar cases in that the recurrence was within a centimeter of the original excisional scar. Most metastases occur in locoregional lymph nodes or the lungs³; therefore, it is unusual to find one so close to the original lesion, especially one that occurred decades later. Factors associated with ultra-late recurrences are unknown, primarily because of the rarity of these cases as well as the biases and other factors that limit existing studies. However, genetic sequencing may provide information regarding these factors and related processes. Genetic sequencing specifically points to a small cell group remaining after excision of the primary tumor, which mutates while proliferating. Low antigenicity and tolerance to immunity during the quiescent period may explain the long duration of dormancy.⁶ More recently, there have been efforts to identify immunohistochemical signatures that may predict late recurrences, though the data are preliminary in nature.¹¹

Given the latency period and location of the recurrence, our case demonstrates that even fully excised melanomas may recur locally many decades later, hence patients should be aware of the importance of a lifetime of vigilance after being diagnosed with melanoma.