1-in-4 NSCLC Patients Alive at 5 Years After Pembrolizumab

Liam Davenport

June 01, 2019

CHICAGO — Almost one quarter of patients with previously untreated nonsmall-cell lung cancer (NSCLC) will survive for up to 5 years with pembrolizumab (Keytruda, Merck), and the rates are even more impressive in patients whose tumors have high expression of programmed death ligand 1 (PD-L1).

These results, presented here at the American Society of Clinical Oncology annual meeting (abstract LBA9105) were from KEYNOTE-001, now the longest running efficacy and safety follow-up of pembrolizumab in advanced NSCLC.

Approached for comment, David Graham, MD, Levine Cancer Institute in Charlotte, North Carolina, said this highlights that "with the use of immunotherapy in appropriate patients, we have to start thinking of how we deal with our patients in different ways than we used to."

"In previous years, we would see a person with metastatic NSCLC and unfortunately have to paint a pretty gloomy picture, where the chances of being alive 5 years down the road would have been 5% or sometimes even less," he said.

"Now, as we look at this data, with patients appropriately treated with pembrolizumab, 1-in-4 of them, or more, are going to be around 5 years from now — and that completely changes our mindset," Graham told Medscape Medical News.

The study initially involved 550 patients without EGFR or ALK gene mutations, of whom just over 100 were treatment-naïve at enrollment.

At the meeting, Edward B. Garon, MD, MS, David Geffen School of Medicine at the University of California, Los Angeles, in Santa Monica, presented data on 100 patients who were still alive after a median of 60 months, of whom 60 had received pembrolizumab for at least 2 years.

After 5 years, 23% of treatment-naïve patients were still alive, as were 16% of those who had been previously treated.

This rose to almost 30% of treatment-naïve patients and 25% of previously treated patients with PD-L1 expression of 50% or more.

For patients with PD-L1 expression levels of 1% to 49% who had been previously treated, 13% were alive at 5 years, as were 16% of those with expression < 50% who were treatment-naïve.

In a press conference, Garon said that, in general, NSCLC is a disease in which patients have been considered to be "very unlikely" to live for 5 years after diagnosis.

The 15% 5-year overall survival rate with pembrolizumab is therefore "certainly encouraging," and the 25% survival seen in patients with PD-L1 expression ≥ 50% was "particularly impressive."

With the safety data showing no unanticipated late toxicity, Garon believes that, "in total, the data confirm that pembrolizumab has potential to improve long-term outcomes for both treatment-naïve and previously treated patients with NSCLC."

Garon told Medscape Medical News that patients who received prior treatment will have had their disease for up to 2 years before starting pembrolizumab.

Consequently, "their clock started from a different point from the people who received it as their initial therapy," meaning that "the data was similarly impressive" in the two groups.

Garon explained, however, that "the reality is that, today at least in the United States, there is probably more pembrolizumab used in a front-line setting than in the previously treated setting."

"The reason for that is that it's still unclear whether or not it is beneficial to add chemotherapy to pembrolizumab among patients who have high PD-L1 expression," although studies to answer that question are ongoing.

Garon continued: "Among patients who have 1% to 49% expression, for instance, that group frankly is not, in the US, often getting second-line single agent pembrolizumab."

"Most of those patients are receiving a PD-1 or PD-L1 inhibitor along with chemotherapy," he added.

Study Details

KEYNOTE-001 was a phase 1b study that initially enrolled 550 patients with locally advanced NSCLC, of whom 101 had not been previously treated and the remaining 449 had received at least one prior therapy.

Patients initially received 2 mg/kg of their body weight of pembrolizumab every 3 weeks or 10 mg/kg every 2 or 3 weeks. They were then switched to a single dose of 200 mg regardless of body weight every 3 weeks, which is the regimen typically used in clinical practice.

For the current analysis, the team gathered data up to November 5, 2018, on all patients who remained in the study.

After a median follow-up of 60.6 months, 100 (18%) patients were still alive, including 23 from the treatment-naïve group and 69 of those previously treated.

Among the survivors, 60 had received at least 2 years of treatment, including 14 from the treatment-naïve and 46 from the previously treated groups, with 46 still alive at the cutoff date.

Garon said that, in the treatment-naïve group, median overall survival was 35.4 months in those with PD-L1 expression ≥ 50% and 19.5% in those with expression between 1% and 49%.

This translated into a 5-year overall survival rate of 29.6% for patients with PD-L1 expression ≥ 50% and 15.7% for expression of 1% - 49%.

Among previously treated patients, median overall survival was 15.4 months for those with PD-L1 expression ≥ 50%, 8.5 months in those with expression of 1% - 49%, and 8.6 months in those with expression < 1%.

This equated to a 5-year overall survival rate of 25.0% for patients with PD-L1 expression ≥ 50%, 12.6% for expression of 1% - 49%, and 3.5% for expression < 1%.

Looking specifically at patients who were treated with pembrolizumab for at least 2 years, Garon said that 5-year overall survival was 78.6% in treatment-naïve patients and 75.8% in those who were previously treated.

The objective response rate was 86% in treatment-naïve patients and 91% in those previously treated, at an ongoing response rate at the cutoff date of 58% and 71%, respectively.

The median duration of response was 52.0 months in treatment-naïve patients and was not reached in those who had been previously treated.

Immune-related adverse events were seen in 92 (17%) of patients, the most common being hypothyroidism, in around 9%. The most serious side effect was pneumonitis, although that was seen in less than 5% of patients.

Garon pointed out that, crucially, the rate of adverse events did not increase appreciably between the 3- and 5-year analyses, and few were grades 3 - 5.

Discussing the findings, Richard L. Schilsky, MD, senior vice president and chief medical officer of ASCO, who moderated the press briefing, noted that, while response rates were "fairly high" in patients treated with pembrolizumab for at least 2 years, the majority were not complete responses.

Garon said it is "somewhat unclear" what is going on in those lesions that have improved but have not completely gone away.

He added that, in some patients, they have been able to biopsy the lesions, finding that some have active cancer, while others have scar tissue or granuloma.

It is therefore "very hard" to determine whether what is being seen on scans is "living disease," he commented.

If it is living disease, it may indicate that, "somehow, the immune system and cancer have sort of fought themselves to a draw, and the cancer has been contained."

Garon said: "I think that that's going to be an area that will be an interesting one for future research."

This study received funding from Merck Sharp & Dohme Corp. Garon reports consulting or advisory roles with Dracen; and research funding (institutional) from Merck, Genentech, AstraZeneca, Novartis, Lilly, Bristol-Myers Squibb, Mirati Therapeutics, Dynavax, Iovance Biotherapeutics, and Neon Therapeutics. His coauthors disclosed numerous relevant financial relationships, which are listed in the abstract.

2019 American Society of Clinical Oncology (ASCO) Annual Meeting: Abstract LBA9015. Presented June 2, 2019.

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