Is IO Monotherapy the New Standard of Care in Advanced NSCLC?

Caveat: Twitter Is Not a Major Meeting or Journal

Roxanne Nelson, BSN, RN

April 11, 2018

Merck has released interim results from its phase 3 KEYNOTE-042 trial, claiming a survival benefit for the immuno-oncology (IO) agent pembrolizumab (Keytruda) when used as first-line monotherapy in locally advanced or metastatic non–small cell lung cancer (NSCLC). However, the results were not quantified.

The announcement quickly stimulated a lively discussion on twitter, initiated by H. Jack West, MD, medical director, Thoracic Oncology Program, Swedish Cancer Institute, Seattle, Washington, who raised the question, Might single-agent immunotherapy be the new standard of care?

According to the Merck press release, the pivotal study met its primary endpoint of overall survival (OS). An interim analysis conducted by the independent data monitoring committee showed that OS was significantly longer for patients treated with pembrolizumab than for those treated with platinum-based chemotherapy (carboplatin plus paclitaxel or carboplatin plus pemetrexed) in a cohort with a PD-L1 tumor proportion score (TPS) ≥1%.

In addition, part of the prespecified analysis included sequential testing of OS, which was significantly improved in patients with a TPS ≥50%, as well as in those with a TPS ≥20% and in the entire study population with a TPS ≥1%.

West expressed enthusiasm for the results in his initial tweet, stating that first-line pembrolizumab monotherapy in both squamous and nonsquamous NSCLC "beats doublet chemo in OS for not only pts w/high PD-L1 express'n threshold of 50%, but even in those w/PD-L1 1% or higher."

He went on to note that pembrolizumab may likely be preferred now in this first-line setting — not just for patients with PD-L1 expression of 50% or higher but also for those with a threshold of 1% — in either squamous or nonsquamous NSCLC. The therapeutic index was better than was seen with combination chemotherapy and immuno-oncology (IO). "I'd like to know whether IO is doing heavy lifting: can't know that if giving both at once," he stated.

However, Clive Peedell, MD, a consultant clinical oncologist in the United Kingdom, noted that he was not so sure about first-line immunotherapy in this setting. "In general, non-trial lung population probably better to give up-front chemo to >1%<50% PDL-1 patients, and 2nd line IO, because more likely to get both lines of therapy? (Chemo better tolerated in first line rather than relapsed 2nd line?)." he wrote.

West responded that he could "see that point," and added that he thought that "we shouldn't get too far ahead of ourselves making treatment plans based on press release" without seeing the actual trial data.

He added in his tweet, "Sequencing multi-lines optimally could be best long term. 'Best Rx up front' is mantra often taken as gospel, but let's see data to prove it."

Another participant in the discussion, consultant thoracic medical oncologist Sanjay Popat, MD, PhD, from the Royal Marsden Hospital, United Kingdom, pointed out that the "key question is how much of this OS benefit in >1% TPS & 20% TPS is driven by the >50%TPS sub population therein."

Key Data Waiting to Be Presented

KEYNOTE-042 is an ongoing, phase 3 trial that compared the efficacy and safety of pembrolizumab with that of platinum-doublet chemotherapy in treatment-naive patients with locally advanced or metastatic PD-L1-positive (TPS ≥1%) NSCLC. All patients lacked anaplastic lymphoma kinase translocations or epidermal growth factor receptor–sensitizing mutations.

The cohort included 1274 patients who were randomly assigned in a 1-to-1 ratio to receive either pembrolizumab (200 mg fixed dose every 3 weeks) as monotherapy or investigator's choice of platinum-based chemotherapy as follows: carboplatin AUC 5 or 6 mg/mL/min plus paclitaxel 200 mg/m2 every 3 weeks (Q3W) for a maximum of six cycles for patients with squamous NSCLC; or carboplatin AUC 5 or 6 mg/mL/min plus pemetrexed 500 mg/m2 Q3W for a maximum of six cycles, followed by optional pemetrexed 500 mg/m2 for patients with nonsquamous NSCLC.

The primary endpoint is overall survival with TPS ≥50%, ≥20%, and ≥1%, assessed sequentially. Secondary endpoints are progression-free survival and objective response rate.

"The impact of this press release will be blunted by the lack of an FDA approval for pembrolizumab monotherapy in the broader population of patients with 1% or greater PD-L1 expression but less than the current threshold of 50% for first-line pembrolizumab now," West told Medscape Medical News.

KEYNOTE-189, a randomized, phase 3 trial that compared efficacy and safety of platinum-doublet chemotherapy with/without pembrolizumab as first-line treatment in nonsquamous NSCLC, found that pembrolizumab in combination with chemotherapy resulted in significantly longer OS and progression-free survival than chemotherapy alone. The results will be presented at the upcoming American Association for Cancer Research annual meeting, which will be held in Chicago from April 14-18.

"As we see the initial report next week from the KEYNOTE-189 trial of chemo alone or with pembrolizumab first line for nonsquamous NSCLC regardless of PD-L1 expression, a central question will focus on whether the patients with advanced nonsquamous NSCLC and lower PD-L1 are better served by receiving pembrolizumab alone or with chemotherapy if both options are associated with a significant survival benefit relative to chemotherapy doublet alone," said West. "That will depend on seeing the actual efficacy and tolerability data for these options in the light of day, but in the meantime, we will be limited by what is approved by the FDA and insurers."

The KEYNOTE-042 trial is continuing to evaluate progression-free survival, which is a secondary endpoint. Results will be presented at an upcoming medical meeting and will be submitted to regulatory authorities worldwide, according to the manufacturer.

Dr West has a financial relationship with Merck, the makers of pembrolizumab, as well as Roche and Clovis Oncology. Dr Popat also has a financial relationship with Merck and multiple other pharmaceutical companies.

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