FDA准 默克突破性療法: 晚期腎癌axitinib (Inlyta)/avelumab (Bavencio)

默克Avelumab與INLYTA聯合治療晚期腎癌獲突破性療法指定 2018-05-14 文章來源：新浪醫藥新聞編譯：範東東默克2017年12月下旬宣佈，美國食品和藥品監督管理局授予了avelumab與輝瑞INLYTA（axitinib，阿西替尼）聯合療法突破性療法認定，主要用於治療晚期腎細胞癌（RCC）的初治患者。"突破性療法"是美國食品和藥物管理局於2012年7月創建，源於《美國食品和藥物管理局安全及創新法案》(FDASIA)中制定的部分內容, 旨在加速開發及審查治療嚴重的或威脅生命的疾病的新藥。此前，該藥物的初步臨床證據表明，該療法可能會顯著改善一個或多個臨床重要終點。這是FDA授予默克avelumab的第二個突破性療法認定。輝瑞全球產品開發部高級副總裁兼免疫腫瘤學早期發展和轉化腫瘤學負責人、醫學博士Chris Boshoff表示："這是一種免疫療法的組合方法，治療活性可能與INLYTA等現有藥物相輔相成，有望改善晚期腎癌患者的預後，目前來看這種疾病的五年生存率仍然很低。我們期待于明年年底完成avelumab與INLYTA聯合治療的III期研究。默克生物製藥業務研究與發展部全球主管Luciano Rossetti博士表示："FDA的這一決定加強了對先進RCC的創新性一線治療的需求以及我們對推進這些患者治療的承諾。FDA在另一個難以治療的癌症中的第二項突破性療法指定也增進了我們繼續關注和研發腫瘤治療手段的信心。"RCC是最常見的腎癌形式，2017年在美國確診的新病例約有57,500例。該病嚴重且危及生命，大約20％-30％的患者首次診斷時，疾病往往已在晚期或轉移期。此次獲得批准的理由是基於名為JAVELIN Renal 100的一項全球Ib期研究，該試驗評估了avelumab聯合INLYTA治療晚期腎癌患者的安全性和有效性的臨床資料。本次Ib期研究的最新結果發表在2017年ASCO年會上。FDA早先授予avelumab突破性療法指定用於治療轉移性默克爾細胞癌（mMCC）的患者，所述患者接受過至少一種化療方案後疾病進一步惡化。被稱為JAVELIN的avelumab臨床開發專案涉及至少30個臨床專案，並涵蓋了超過15個不同腫瘤類型的7,000多名患者參與。這包括一項隨機III期開放性多中心試驗的JAVELIN Renal 101研究，該研究將avelumab與INLYTA和sunitinib聯合用作RCC的一線治療選擇。除了RCC之外，JAVELIN計畫中的癌症研究包括非小細胞肺癌、乳腺癌、頭頸部癌症、霍奇金淋巴瘤、黑素瘤、間皮瘤、MCC、卵巢癌、胃/胃食管交界癌和泌尿道上皮癌。在美國，輝瑞研製的INLYTA被批准為一種先前的全身治療失敗後用於治療晚期RCC的單一療法。

Combinations Take Hold in Kidney Cancer   Angelica Welch Published: Monday, May 07, 2018 Bradley A. McGregor, MD The recent success seen with the combinations of nivolumab (Opdivo) plus ipilimumab (Yervoy) as well as atezolizumab (Tecentriq) plus bevacizumab (Avastin) has convinced many that this is the era of combinations in kidney cancer, says Bradley A. McGregor, MD. However, the renewed interest and excitement in combinations was started by the success of the combination of lenvatinib (Lenvima) and everolimus (Afinitor), he adds.  The combination of lenvatinib and everolimus as a treatment for patients with advanced renal cell carcinoma (RCC) following prior antiangiogenic therapy was approved by the FDA in May 2016. The decision was based on a phase II trial, known as Study 205, in which the combination reduced the risk of progression or death by 63% versus everolimus alone.1 Recently, the introduction of combination immunotherapy has made a frontline impact, with the FDA approval of nivolumab and ipilimumab for intermediate- and poor-risk patients with advanced RCC. The approval was based on data in the CheckMate-214 trial, which showed that nivolumab/ipilimumab reduced the risk of death by 32% compared with sunitinib (Sutent) in patients with metastatic kidney cancer.2 Additionally, IMmotion151, which compared the combination of atezolizumab and bevacizumab with sunitinib, showed a statistically significant reduction in the risk for death or progression in patients with PD-L1–positive advanced or metastatic kidney cancer. Nonetheless, not all patients may be ideal for combinations, says McGregor, because the addition of another agent often causes a higher rate of adverse events.  In an interview during the 2018 OncLive® State of the Science Summit™ on Genitourinary Cancers, McGregor, clinical director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and an instructor in medicine at Harvard Medical School, discussed the growth of combination therapy in the treatment of patients with kidney cancer.

OncLive: Please give an overview of your presentation. McGregor: When you look at kidney cancer as a whole, from 10 years ago when sunitinib was approved to where things are now, the landscape has evolved rapidly. Combination therapy is becoming the mainstay. Everyone thinks about combination therapy coming of age with nivolumab plus ipilimumab in the CheckMate-214 trial, and atezolizumab plus bevacizumab in IMmotion151. It has actually been around much longer than that with the FDA-approved combination of lenvatinib and everolimus— using a tyrosine kinase inhibitor (TKI) and an mTOR inhibitor.  This idea of combining different agents to get a synergistic effect is certainly very appealing, and it seems to be the way of the future with increased response rates. We hope that the impressive response rates seen with axitinib (Inlyta)/avelumab (Bavencio), axitinib/pembrolizumab (Keytruda), and pembrolizumab/ lenvatinib translate into similar impressive complete response (CR) rates. The hope is that with these therapies, we are offering these patients a chance for cure.  Many of the combinations now are trying to harness immunotherapy [plus other] immune-oncology agents, VEGF inhibitors, or multiple [other] TKI inhibitors. What combinations are the furthest along? The two phase III trials that have read out are CheckMate-214 with nivolumab plus ipilimumab and IMmotion151 with atezolizumab and bevacizumab.  What was most appealing with the CheckMate-214 data were the impressive CR rates, specifically in the PD-L1–positive subgroup, at 16%. The CR rate for the PD-L1–negative group was comparable with what we see with interleukin-2.  When you look at IMmotion151, there was also an impressive CR rate at around 9% overall. The most appealing thing about this combination is the toxicity profile. It is a very well-tolerated regimen, as opposed to [nivolumab plus ipilimumab] where the data suggest the combination is [appropriate] only for intermediate- and poor-risk patients. When you look at the subset analysis of IMmotion151, you seem to have benefit across subgroups independent of their status.  We have multiple ongoing phase III trials that were inspired by phase I data. To varying degrees, all have very impressive response rates upwards of 70% to 80%. These are phase I trials, so take that with a grain of salt. Our hope is that these response rates translate into the phase III data, and hopefully improve disease control and CR rates.  Right now, the 3 TKI/immunotherapy-based trials are pembrolizumab/lenvatinib—which has only been presented and not published—and then axitinib/avelumab and axitinib/ pembrolizumab; those have both been published in the past 6 months.  At Dana-Farber Cancer Institute, we are participating in the CLEAR trial, which is pembrolizumab with lenvatinib versus lenvatinib with everolimus versus sunitinib. Additionally, there is a phase I study of nivolumab plus cabozantinib (Cabometyx) versus sunitinib. Does everyone need combinations? Combinations are great, but as we have seen from these studies, combinations come with increased toxicities. About 60% of patients who take ipilimumab plus nivolumab require steroids, and some toxicities with these immunotherapy combinations approach 70%. Therefore, the question is, "Do you need to give everyone this therapy?" We have a very interesting trial that starts with nivolumab monotherapy, and then based on response, you add ipilimumab. Perhaps not everyone needs a combination, so if you can see the same response with less therapy and avoid toxicity, that is very appealing.

Are there concerns with sequencing? That is going to be an important question. There will never be a head-to-head trial of nivolumab/ipilimumab versus pembrolizumab/ lenvatinib versus pembrolizumab/axitinib, so we are going to be stuck in this situation where we have all of these data. We are going to be left doing cross-trial comparisons and focusing on toxicity profiles. At the end of the day, it may come down to the patient. If you have a patient who has poorly controlled hypertension or cardiovascular comorbidities, perhaps you will be less likely to offer them a VEGF TKI and nivolumab/ipilimumab may be a better option. It will be a balancing game. Could combinations with cabozantinib have potential? One trial that is going to be opening shortly will be cabozantinib with atezolizumab. It will be a phase Ib trial; it has finished its escalation phase and is moving to the expansion phase, so it will be for a lot of patients with genitourinary malignancies. The study will be looking at bladder cancer, as well as frontline kidney cancer.

References

Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial [published correction appears in Lancet Oncol. 2016;17(17):e270]. Lancet Oncol. 2015;16(15):1473-1482. doi: 10.1016/S1470-2045(15)00290-9.

Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab plus ipilimumab vs sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. In: Proceedings from the 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract LBA5.