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Long-term survival with nivolumab in refractory metastatic renal cell carcinoma

In patients with metastatic renal cell carcinoma (RCC) who have progressed on antiangiogenic therapy, subsequent immunotherapy with nivolumab is an established treatment option, but long-term survival outcomes have not been previously reported. In extended follow-up of a phase III trial (Checkmate 025), among approximately 800 patients with metastatic RCC and disease progression on at least one previous vascular endothelial growth factor (VEGFR) inhibitor, nivolumab improved both five-year overall (26 versus 18 percent) and progression-free (5 versus 1 percent) survival compared with everolimus [1]. For patients with metastatic RCC refractory to VEGFR inhibitor therapy, we continue to offer nivolumab as an option for subsequent therapy.


Nivolumab plus ipilimumab in pleural mesothelioma

Chemotherapy has long been the mainstay of treatment for unresectable pleural mesothelioma. Now, in preliminary results of a phase III trial including over 600 patients with advanced, treatment-naive mesothelioma, immunotherapy with nivolumab plus ipilimumab improved overall survival compared with a platinum agent plus pemetrexed (18 versus 14 months), with greatest benefit for those with nonepithelioid histologies [2]. Grade >=3 treatment-related adverse events occurred in approximately one-third of patients in both groups, but more patients discontinued treatment due to toxicity in the immunotherapy group. For those with unresectable pleural mesothelioma and nonepithelioid histologies, we now suggest initial treatment with nivolumab plus ipilimumab rather than chemotherapy. Nivolumab plus ipilimumab is also an appropriate option for those with epithelioid histology cancers who prefer to avoid chemotherapy.


Timing of RT following radical prostatectomy for high-risk prostate cancer

Randomized trials have shown benefit for postoperative adjuvant radiation therapy (RT) compared with observation after radical prostatectomy for high-risk prostate cancer, but they did not adequately address whether early salvage RT at the time of a rising PSA is as effective as immediate adjuvant RT. Three trials in slightly different patient populations have now compared the two approaches, and all found similar cancer-specific outcomes, but approximately 50 percent of men who delayed RT were able to avoid it altogether, reducing treatment-related genitourinary toxicity [3-5]. A preplanned meta-analysis of all three trials also found no evidence that adjuvant RT improved event-free survival compared with early salvage RT [6]. For most men with node-negative resected prostate cancer who have extraprostatic extension, seminal vesicle invasion, or positive resection margins and an undetectable PSA level, we suggest early salvage rather than immediate adjuvant RT. Whether there are specific high-risk groups who might have a better outcome with adjuvant RT because of the risk of early disease progression remains unclear.


Early studies of preoperative immunotherapy in locoregionally advanced oral cavity squamous cell cancer

Surgery is the preferred initial treatment for most patients with locoregionally advanced oral cavity squamous cell cancer (OCSCC). Two small phase II trials evaluated the feasibility of preoperative immunotherapy [7,8]. Immunotherapy was well tolerated and associated with pathologic tumor response in approximately half. Further study is necessary to determine whether preoperative immunotherapy can improve quality of life, progression-free survival, or overall survival. Until then, preoperative immunotherapy is not indicated for locoregionally advanced OCSCC outside of a clinical trial.


Postoperative radiotherapy in N2 NSCLC

The approach to radiotherapy in non-small cell lung cancer (NSCLC) is controversial, particularly among those with mediastinal involvement (N2 disease). In the Lung ART trial, among over 500 patients with completely resected NSCLC with pathologically proven N2 disease, those assigned to postoperative radiotherapy (PORT) experienced similar rates of relapse and survival at three years as those not receiving PORT, with higher rates of cardiopulmonary toxicity [9]. For patients with N2 disease who have been treated surgically, some experts offer PORT only to those at the highest risk of recurrence, while others do not offer PORT, given the results of this trial. However, for the majority of patients with known N2 disease, chemoradiation is the preferred approach over surgery.


1. Motzer RJ, Escudier B, George S, et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer 2020.


2. Baas P, Scherpereel A, Nowak A, et al. First-line nivolumab + ipilimumab versus chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. J Thorac Oncol 2020; 15S: WCLC Presidential Symposium #2908.


3. Parker CC, Clarke NW, Cook AD, et al. Timing of radiotherapy after radical prostatectomy (RADICALS-RT): a randomised, controlled phase 3 trial. Lancet 2020; 396:1413.


4. Kneebone A, Fraser-Browne C, Duchesne GM, et al. Adjuvant radiotherapy versus early salvage radiotherapy following radical prostatectomy (TROG 08.03/ANZUP RAVES): a randomised, controlled, phase 3, non-inferiority trial. Lancet Oncol 2020; 21:1331.


5. Sargos P, Chabaud S, Latorzeff I, et al. Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial. Lancet Oncol 2020; 21:1341.


6. Vale CL, Fisher D, Kneebone A, et al. Adjuvant or early salvage radiotherapy for the treatment of localised and locally advanced prostate cancer: a prospectively planned systematic review and meta-analysis of aggregate data. Lancet 2020; 396:1422.


7. Schoenfeld JD, Hanna GJ, Jo VY, et al. Neoadjuvant Nivolumab or Nivolumab Plus Ipilimumab in Untreated Oral Cavity Squamous Cell Carcinoma: A Phase 2 Open-Label Randomized Clinical Trial. JAMA Oncol 2020; 6:1563.


8. Uppaluri R, Campbell KM, Egloff AM, et al. Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase II Trial. Clin Cancer Res 2020; 26:5140.


9. Le Pechoux C, Pourel N, Barlesi F, et al. An international randomized trial, comparing post-operative conformal radiotherapy (PORT) to no PORT, in patients with completely resected non-small cell lung cancer (NSCLC) and mediastinal N2 involvement. Primary end-point analysis of Lung ART (IFCT-0503, UK NCRI, SAKK) NCT00410683. Ann Oncol 2020; 31S: ESMO #LBA3_PR.


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