KEYNOTE-483 and the September 2024 FDA Approval Reshaping First-Line Mesothelioma Treatment (2026)

On September 17, 2024, the U.S. Food and Drug Administration approved pembrolizumab (Keytruda) in combination with pemetrexed and platinum-based chemotherapy as a first-line treatment for adult patients with unresectable advanced or metastatic malignant pleural mesothelioma [2]. The approval was based on KEYNOTE-483 — formally designated CCTG IND.227 (ClinicalTrials.gov NCT02784171) — a phase 2/3 randomized controlled trial of 440 patients that extended median overall survival to 17.3 months in the pembrolizumab combination arm versus 16.1 months with chemotherapy alone, a hazard ratio of 0.79 with a p-value of 0.0324 [1][5]. It is the third FDA-approved systemic regimen for pleural mesothelioma since 2004, and the first since the October 2020 approval of nivolumab plus ipilimumab from CheckMate-743 [3][6].

8 Key Facts About KEYNOTE-483 and the September 2024 FDA Approval

• FDA approval date: September 17, 2024 — pembrolizumab plus pemetrexed and platinum chemotherapy for unresectable advanced or metastatic pleural mesothelioma [2]
• Trial designation: KEYNOTE-483 / CCTG IND.227, ClinicalTrials.gov NCT02784171 [5]
• Enrollment: 440 patients with previously untreated pleural mesothelioma at 51 hospitals in Canada, Italy, and France [1]
• Median overall survival: 17.3 months (pembrolizumab combination) vs 16.1 months (chemotherapy alone); hazard ratio 0.79 (95% CI 0.64–0.98); p=0.0324 [1]
• Two-year survival: 39% (combination) vs 33% (chemotherapy alone) [1]
• Three-year survival: 25% (combination) vs 17% (chemotherapy alone) [1][10]
• Objective response rate (BICR): 52% (combination) vs 29% (chemotherapy alone) [1][10]
• Third FDA-approved first-line regimen: Joins pemetrexed/cisplatin (2004) and nivolumab/ipilimumab (October 2020) [3][4][6]

What Is KEYNOTE-483 and How Was the Trial Designed?

KEYNOTE-483 was conducted by the Canadian Cancer Trials Group as CCTG IND.227, with Merck & Co. as a co-sponsor. The trial enrolled 440 patients with previously untreated, unresectable, advanced or metastatic malignant pleural mesothelioma between January 31, 2017 and September 4, 2020 [1][5]. Patients were randomized 1-to-1 between two arms.

The pembrolizumab arm (n=222) received pembrolizumab 200 mg intravenously every 3 weeks for up to 2 years, combined with pemetrexed 500 mg per square meter and cisplatin 75 mg per square meter or carboplatin AUC 5 to 6 every 3 weeks for up to 6 cycles. The chemotherapy-alone arm (n=218) received the same pemetrexed and cisplatin or carboplatin schedule without pembrolizumab [1].

Median patient age was 71 years (interquartile range 66 to 75). Three-quarters of patients were male and 79 percent were White. Histology was 77 to 78 percent epithelioid, 12 to 16 percent biphasic or mixed, and 5 to 10 percent sarcomatoid — a distribution consistent with the broader pleural mesothelioma population [1].

The primary endpoint was overall survival in all randomly assigned patients. The trial was reported at the 2023 ASCO Annual Meeting and published in The Lancet in November 2023 with data cutoff December 15, 2022 [1]. Patients who want to understand where this fits in their treatment options can review the mesothelioma clinical trials overview for the broader trial landscape.

"What stands out to families I work with is the consistency of the benefit across subgroups. Pembrolizumab plus chemotherapy extended survival regardless of histology and regardless of PD-L1 status. For families facing a 2026 diagnosis, that consistency translates into a clearer first-line conversation with the treating oncologist."

— David Foster, Executive Director of Client Services, Danziger & De Llano

What Did KEYNOTE-483 Prove About Pembrolizumab Plus Chemotherapy?

At the final analysis with 342 deaths reported, median overall survival was 17.3 months (95 percent confidence interval 14.4 to 21.3) in the pembrolizumab combination arm versus 16.1 months (95 percent confidence interval 13.1 to 18.2) with chemotherapy alone. The hazard ratio for death was 0.79 (95 percent confidence interval 0.64 to 0.98) with a p-value of 0.0324 — a 21 percent reduction in the risk of death that crossed conventional thresholds for statistical and clinical significance [1].

The survival benefit grew with longer follow-up. Two-year overall survival was 39 percent in the combination arm versus 33 percent in the chemotherapy-alone arm. Three-year overall survival was 25 percent versus 17 percent. Median progression-free survival was 7.1 months in both arms, with a hazard ratio of 0.80 favoring the combination. Objective response rate measured by blinded independent central review using modified RECIST was 52 percent in the combination arm versus 29 percent with chemotherapy alone, a near-doubling that was statistically significant at p less than 0.00001 [1][10].

Histology subgroup analyses found benefit across both epithelioid and non-epithelioid disease, with the largest survival effect in non-epithelioid (sarcomatoid and biphasic) patients. The benefit was observed regardless of PD-L1 expression status, and current ASCO 2025 and NCCN 2025 guidelines do not require PD-L1, tumor mutational burden, or microsatellite instability testing to guide first-line selection [1][7].

How Does Pembrolizumab Plus Chemotherapy Compare to Nivolumab Plus Ipilimumab?

The September 2024 pembrolizumab approval is best understood alongside the October 2020 approval of nivolumab plus ipilimumab based on CheckMate-743. CheckMate-743, published in The Lancet in 2021, established the first chemotherapy-free immunotherapy regimen for unresectable pleural mesothelioma [3]. Pembrolizumab plus chemotherapy is the chemotherapy-containing alternative.

The two regimens were tested in different trials with different control arms, so head-to-head comparisons are indirect. Both demonstrated overall survival improvements that justified FDA approval. Both are now incorporated into ASCO 2025 and NCCN 2025 first-line guidelines as Strong recommendations [7]. The choice between them depends on factors a treating medical oncologist weighs at the bedside.

• Histology: Both regimens benefit non-epithelioid patients; both work in epithelioid disease, though the magnitude of effect differs across the two studies.
• Patient performance status and comorbidities: Patients who cannot tolerate platinum-based chemotherapy may be better candidates for nivolumab plus ipilimumab.
• Adverse event profile: Dual checkpoint inhibition (nivolumab plus ipilimumab) has a different toxicity pattern than checkpoint inhibition plus cytotoxic chemotherapy.
• Logistics: Pembrolizumab plus chemotherapy is given every 3 weeks for up to 6 cycles of chemotherapy and up to 2 years of pembrolizumab; nivolumab plus ipilimumab has its own schedule.

The third FDA-approved option, pemetrexed plus cisplatin without immunotherapy, was approved in 2004 based on the EMPHACIS trial [4]. It remains an option for patients who cannot receive immunotherapy because of autoimmune conditions or transplant history. ASCO 2025 retains pemetrexed plus platinum, optionally with bevacizumab, as a Strong recommendation in epithelioid patients who are not immunotherapy candidates [7].

No additional standard first-line systemic FDA approvals have followed between September 17, 2024 and May 2026. Investigational agents are in late-stage development. Pegargiminase (ADI-PEG 20), studied in the ATOMIC-Meso trial for non-epithelioid mesothelioma, has a rolling Biologics License Application under FDA review with a decision anticipated in late 2026 or early 2027. The NovoTTF-100L tumor treating fields device was approved under the Humanitarian Device Exemption pathway in May 2019 and is not a standard FDA approval.

What Are the Side Effects of Pembrolizumab Plus Chemotherapy?

Adding pembrolizumab to standard chemotherapy increases the rate of higher-grade adverse events but did not substantially impair health-related quality of life in KEYNOTE-483 [1].

• Grade 3 or 4 treatment-related adverse events: 27 percent in the pembrolizumab arm (60 of 222 patients) versus 15 percent in the chemotherapy-alone arm (32 of 211 patients)
• Hospitalization for serious adverse events: 18 percent (pembrolizumab) versus 6 percent (chemotherapy alone)
• Grade 5 (fatal) treatment-related events: 2 patients in the pembrolizumab arm; 1 patient in the chemotherapy arm
• Most common adverse events (both arms): fatigue and nausea
• More frequent with pembrolizumab: diarrhea and skin-related effects

Pembrolizumab carries the immune-mediated adverse event profile common to PD-1 checkpoint inhibitors — pneumonitis, colitis, hepatitis, endocrinopathies, and skin reactions. Most are manageable with treatment interruption and corticosteroids when caught early. Patients beginning the regimen benefit from baseline screening for autoimmune conditions, hepatitis, and thyroid function, with structured monitoring throughout treatment. The diagnosis and treatment planning guide outlines what to expect from a coordinated multidisciplinary treatment team.

"Mesothelioma families ask the same question every time a new approval lands: does this change what my oncologist will recommend? In most cases the answer is yes for patients still in the first-line window. The KEYNOTE-483 approval gives medical oncologists a second immunotherapy-containing first-line option, and the choice between regimens is now individualized at the bedside."

— David Foster, Executive Director of Client Services, Danziger & De Llano

How Are Treatment Guidelines Responding to the September 2024 Approval?

The September 2024 approval prompted updates to both major U.S. mesothelioma treatment guidelines.

The American Society of Clinical Oncology (ASCO) released its March 2025 mesothelioma guideline update — the first comprehensive revision since 2018, incorporating 110 peer-reviewed studies. The update recognizes three first-line systemic regimens for unresectable pleural mesothelioma [7]:

1. Nivolumab plus ipilimumab — preferred for all patients, particularly non-epithelioid disease (Recommendations 3.1 through 3.3, Strong)
2. Pembrolizumab plus pemetrexed and platinum — for epithelioid or non-epithelioid disease (Recommendation 3.4, Strong)
3. Pemetrexed plus platinum, optionally with bevacizumab — for epithelioid patients who are not immunotherapy candidates (Recommendation 4.1, Strong)

NCCN Version 1.2025 incorporated the September 2024 FDA pembrolizumab approval as a new first-line option in its mesothelioma treatment algorithm. PD-L1, TMB, and MSI status are not required to guide treatment selection under either guideline [7].

For patients planning treatment in 2026, the practical change is that the first-line conversation now includes three named regimens rather than the binary "chemotherapy versus dual immunotherapy" framing that was standard between October 2020 and September 2024. Specialized cancer centers and academic medical institutions experienced with all three regimens are well positioned to individualize the recommendation. Patients can locate appropriate centers through the mesothelioma treatment centers guide.

What Does Longer First-Line Survival Mean for Legal and Compensation Planning?

The September 2024 approval changed treatment expectations, not legal eligibility. Patients diagnosed with pleural mesothelioma in 2026 remain eligible to pursue compensation through three primary pathways: product liability lawsuits against asbestos manufacturers and premises owners, claims against asbestos bankruptcy trusts holding more than $30 billion in committed funds, and — for military veterans — Department of Veterans Affairs disability compensation and Dependency and Indemnity Compensation for surviving spouses [8][9].

What the approval does change is the planning horizon. A patient with a realistic expectation of 17 to 24 months on first-line therapy has more capacity to participate directly in claim filing, deposition, and settlement decisions than a patient diagnosed 10 years ago, when median first-line survival was closer to 12 months. Early consultation with a mesothelioma attorney preserves documentation, supports preferential trial setting in California (Code of Civil Procedure Section 36(a)) and other states with similar accelerated calendars, and lets the patient — not the estate — make case decisions.

The complete legal pathway from diagnosis through compensation recovery is mapped at Danziger & De Llano's mesothelioma practice page, and the firm has covered the financial planning side of treatment in the mesothelioma compensation overview at our companion site.

Where Do Patients and Families Go From Here?

Three steps make the most of the September 2024 approval window:

1. Confirm histology and PD-L1 status at diagnosis. While neither PD-L1 nor TMB testing is required for treatment selection under current guidelines, histology (epithelioid versus non-epithelioid) does influence regimen choice and prognostic conversation. The pathology report should clearly state mesothelioma subtype.
2. Get a treatment plan from a center that uses all three approved regimens. The choice between pembrolizumab plus chemotherapy, nivolumab plus ipilimumab, and pemetrexed plus platinum is individualized. A center that uses all three is better positioned to match regimen to patient than a center comfortable with only one.
3. Open the legal conversation in parallel with the medical one. Documentation of occupational, military, or product-based asbestos exposure is easiest to gather while the patient can directly recount the history. Filing early supports preferential trial setting and preserves all available trust fund and product liability avenues.

Free Mesothelioma Case Review — Speak With Our Team

If you or a family member has been diagnosed with pleural mesothelioma, our team can help you understand both the treatment options the September 2024 approval has opened and the compensation pathways available alongside them. Speak with a member of our team at (855) 699-5441 or visit Danziger & De Llano to schedule a no-cost case review.

Danziger & De Llano represents mesothelioma patients and families nationwide. Consultations are free, all attorney communication is privileged, and there is no fee unless we recover compensation.