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30 juli 2019: Bron : JAMA Oncol. Published online July 11, 2019.

Afgelopen weken zijn verschillende studies met pembrolizumab bij niet-kleincellige longkanker gepubliceerd met goede resultaten. In een fase II studie waarbij de uitzaaiingen eerst zoveel mogelijk werden verwijderd of via operatie of via gerichte radiotherapie - bestraling bleek de mediane ziekteprogressievrije tijd van 6,6 maanden naar 19,1 maanden te stijgen.

Waaronder deze: Pembrolizumab After Completion of Locally Ablative Therapy for Oligometastatic Non–Small Cell Lung Cancer

This single-arm, phase II study included 45 patients with oligometastatic (<4 sites) non–small cell lung cancer who received pembrolizumab after completion of locally ablative therapy. The median progression-free survival from the start of locally ablative therapy was 19.1 months (95% CI, 9.4–28.1 months), which compared favorably with the authors’ historical comparison of 6.6 months (P=.005). No new safety signals were identified with this sequenced treatment.

In een andere studie werd de behandeling van uitgezaaide niet-kleincellige longkanker met stereotactische bestraling of immuuntherapie met pembrolizumab vergeleken, waarbij de overall overleving verdubbelde van 7,6 maanden versus 15,9 maanden voor de immuuntherapie.

Zie dit studierapport: Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non–Small Cell Lung Cancer

Key Points

Question Does stereotactic body radiotherapy enhance the effect of immune checkpoint inhibition by increasing tumor response in nonirradiated lung cancer lesions in metastatic non–small cell lung cancer?

Findings In this phase 2 clinical trial of 76 patients with recurrent metastatic non–small cell lung cancer randomized to either pembrolizumab alone or pembrolizumab after stereotactic body radiotherapy on a single tumor site, the overall response rate at 12 weeks was 18% in the control arm vs 36% in the experimental arm.

Meaning Stereotactic body radiotherapy prior to pembrolizumab was well tolerated; although a doubling of the overall response rate was observed, the results did not meet the study criteria for meaningful clinical benefit.

Hier de twee abstracten:

uly 11, 2019

Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non–Small Cell Lung CancerResults of the PEMBRO-RT Phase 2 Randomized Clinical Trial

Willemijn S. M. E. Theelen, MD¹; Heike M. U. Peulen, MD, PhD^2,3; Ferry Lalezari, MD⁴; et alVincent van der Noort, PhD⁵; Jeltje F. de Vries, PhD⁵; Joachim G. J. V. Aerts, MD, PhD⁶; Daphne W. Dumoulin, MD⁶; Idris Bahce, MD, PhD⁷; Anna-Larissa N. Niemeijer, MD⁷; Adrianus J. de Langen, MD, PhD¹; Kim Monkhorst, MD, PhD⁸; Paul Baas, MD, PhD¹

Author Affiliations

JAMA Oncol. Published online July 11, 2019. doi:10.1001/jamaoncol.2019.1478

Abstract

Importance Many patients with advanced non–small cell lung cancer (NSCLC) receiving immunotherapy show primary resistance. High-dose radiotherapy can lead to increased tumor antigen release, improved antigen presentation, and T-cell infiltration. This radiotherapy may enhance the effects of checkpoint inhibition.

Objective To assess whether stereotactic body radiotherapy on a single tumor site preceding pembrolizumab treatment enhances tumor response in patients with metastatic NSCLC.

Design, Setting, and Participants Multicenter, randomized phase 2 study (PEMBRO-RT) of 92 patients with advanced NSCLC enrolled between July 1, 2015, and March 31, 2018, regardless of programmed death–ligand 1 (PD-L1) status. Data analysis was of the intention-to-treat population.

Interventions Pembrolizumab (200 mg/kg every 3 weeks) either alone (control arm) or after radiotherapy (3 doses of 8 Gy) (experimental arm) to a single tumor site until confirmed radiographic progression, unacceptable toxic effects, investigator decision, patient withdrawal of consent, or a maximum of 24 months.

Main Outcomes and Measures Improvement in overall response rate (ORR) at 12 weeks from 20% in the control arm to 50% in the experimental arm with P < .10.

Results Of the 92 patients enrolled, 76 were randomized to the control arm (n = 40) or the experimental arm (n = 36). Of those, the median age was 62 years (range, 35-78 years), and 44 (58%) were men. The ORR at 12 weeks was 18% in the control arm vs 36% in the experimental arm (P = .07). Median progression-free survival was 1.9 months (95% CI, 1.7-6.9 months) vs 6.6 months (95% CI, 4.0-14.6 months) (hazard ratio, 0.71; 95% CI, 0.42-1.18; P = .19), and median overall survival was 7.6 months (95% CI, 6.0-13.9 months) vs 15.9 months (95% CI, 7.1 months to not reached) (hazard ratio, 0.66; 95% CI, 0.37-1.18; P = .16). Subgroup analyses showed the largest benefit from the addition of radiotherapy in patients with PD-L1–negative tumors. No increase in treatment-related toxic effects was observed in the experimental arm.

Conclusions and Relevance Stereotactic body radiotherapy prior to pembrolizumab was well tolerated. Although a doubling of ORR was observed, the results did not meet the study’s prespecified end point criteria for meaningful clinical benefit. Positive results were largely influenced by the PD-L1–negative subgroup, which had significantly improved progression-free survival and overall survival. These results suggest that a larger trial is necessary to determine whether radiotherapy may activate noninflamed NSCLC toward a more inflamed tumor microenvironment.

Trial Registration ClinicalTrials.gov identifier: NCT02492568

En hier het abstract van eerstgenoemde studie:

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Editorial

Comment

Key Points

Question Does the addition of pembrolizumab after locally ablative therapy in oligometastatic non–small cell lung cancer improve outcomes compared with historical data?

Findings In this phase 2 single-arm study that included 45 patients with oligometastatic non–small cell lung cancer who received pembrolizumab after completing locally ablative therapy, the median progression-free survival was 19.1 months, which was longer than historical data.

Meaning The use of pembrolizumab after locally ablative therapy for oligometastatic non–small cell lung cancer was associated with a clinically and statistically significant improvement in progression-free survival compared with historical data, which suggests that this treatment should be further evaluated in a randomized clinical trial.

Abstract

Importance Patients with oligometastatic non–small cell lung cancer (NSCLC) may benefit from locally ablative therapy (LAT) such as surgery or stereotactic radiotherapy. Prior studies were conducted before the advent of immunotherapy, and a strong biological rationale for the use of immunotherapy exists in a minimal residual disease state.

Objective To evaluate whether the addition of pembrolizumab after LAT improves outcomes for patients with oligometastatic NSCLC.

Design, Setting, and Participants This single-arm phase 2 trial of pembrolizumab therapy was performed from February 1, 2015, through September 30, 2017, at an academic referral cancer center. The 51 eligible patients enrolled had oligometastatic NSCLC (≤4 metastatic sites) and had completed LAT to all known sites of disease. Data were analyzed from February 1, 2015, to August 23, 2018.

Interventions Within 4 to 12 weeks of completing LAT, patients began intravenous pembrolizumab therapy, 200 mg every 21 days, for 8 cycles, with provision to continue to 16 cycles in the absence of progressive disease or untoward toxic effects.

Main Outcomes and Measures The 2 primary efficacy end points were progression-free survival (PFS) from the start of LAT (PFS-L), which preceded enrollment in the trial, and PFS from the start of pembrolizumab therapy (PFS-P). The study was powered for comparison with historical data on the first efficacy end point. Secondary outcomes included overall survival, safety, and quality of life as measured by the Functional Assessment of Cancer Therapy–Lung instrument.

Results Of 51 patients enrolled, 45 (24 men [53%]; median age, 64 years [range, 46-82 years]) received pembrolizumab. At the time of analysis, 24 patients had progressive disease or had died. Median PFS-L was 19.1 months (95% CI, 9.4-28.7 months), significantly greater than the historical median of 6.6 months (P = .005). Median PFS-P was 18.7 months (95% CI, 10.1-27.1 months). Eleven patients died. Overall mean (SE) survival rate at 12 months was 90.9% (4.3%); at 24 months, 77.5% (6.7%). Neither programmed death ligand 1 expression nor CD8 T-cell tumor infiltration was associated with PFS-L. Pembrolizumab after LAT yielded no new safety signals and no reduction in quality of life.

Conclusions and Relevance Pembrolizumab after LAT for oligometastatic NSCLC appears to improve PFS with no reduction in quality of life.

Trial Registration ClinicalTrials.gov identifier: NCT02316002

niet-kleincellige longkanker, pembrolizumab, immuuntherapie, checkpointremmers, anti-PD medicijnen, progressievrije ziekte, debulking, overall overleving