01/28/2018: Articles Summaries - Lung & GU Cancers

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LUNG CANCERS GU CANCERS

Summary

LUNG CANCERS
  Druvalumab after Chemoradiotherapy in Stage III Non–Small-Cell Lung Cancer
Antonia SJ et al., N Engl J Med. 2017 Nov 16;377(20):1919-1929.
PubMed ID: 28885881

Introduction:

Durvalumab is an IgG1 human monoclonal antibody against PD-L1 that showed clinical activity in solid tumors, including advanced NSCLC in preliminary studies. Based on findings that chemotherapy with RT can upregulate PD-L1 expression in tumor cells, researchers conducted the PACIFIC study to determine the efficacy of durvalumab as consolidation therapy in stage III NSCLC.

Methods:

  • Patients: Cytologically or histologically proven locally advance or unresectable stage III NSCLC, received at least 2 previous cycle of platinum-based chemotherapy concurrently with RT (cCRT) (mean dose to lung <20Gy, V20 <35% or both), no disease progression after cCRT, PS 0-1.
  • Study design: Phase III, double blind RCT
  • Intervention
    • Experimental:
      • Durvalumab 10 mg/kg IVq2w up to 12 mo.
    • Control: Placebo
    • * All patients received previous cCRT without disease progression
  • Endpoints
    • Primary: PFS, OS
    • Secondary: % alive at 12 and 18 mo., ORR, DOR, time to death or distant metastasis (TDDM), 12-mo. OS, safety, HRQOL

 

Results:

  •  713 patients randomized 2:1 to durvalumab (n=476) and placebo (n=237)
  • Baseline patient characteristics: median age 64 yrs., 70% male, 69% white, 53% stage IIIA, 51% PS 1, 54% nonsquamous, 75% former smokers, 92% previous RT (≥54 to ≤66 Gy), 99.7% concurrent CRT, 48% partial response from CRT, 22% with PD-L1 expression ≥25%, 41% with PD-L1 expression < 25%, 37% unknown PD-L1 status, 6% with EGFR mutation, 67% EGFR negative or wild-type, 55% cisplatin-based chemotherapy (cis-etop 21%)
  • PFS benefit was observed with durvalumab regardless of PD-L1 expression before CRT (HR 0.59 [0.43-0.82] in the subgroup with PD-L1 expression <25% and those with PD-L1 expression ≥25% (HR 0.41[0.26-0.65).
  • The most common site of new lesion was the lung (11.8% v 17.3%).

Table 1: Efficacy Outcomes

  • Safety
    • Most common any grade AEs with durvalumab: cough (35.4%), pneumonitis/radiation pneumonitis (33.9%), fatigue (23.8%).
    • Most common any grade AE with placebo: cough (25.2%), pneumonitis/radiation pneumonitis (24.8%), dyspnea (23.9%)
    • Most common grade 3-4 AE in both arms: pneumonitis/radiation pneumonitis (3.4% v 2.6%)
    • Most common causes of treatment discontinuation in both arms: pneumonitis and pneumonia
    • Adverse events of special interest with durvalumab: diarrhea (18.3% v 18.8%), pneumonitis (12.6% v 7.7%), rash (12.2% v 7.3%), pruritus (12.2% v 4.7%)


Table 2: Adverse events and treatment summary

Summary

 

Discussion:

  • Interim analysis of the PACIFIC trial at a median follow-up of 14.5 months revealed that in locally advanced or unresectable state III NSCLC, patients who respond to cCRT may benefit from the addition of durvalumab consolidation. Durvalumab reduced the risk of disease progression or death as well as distant metastasis-free survival by 48%. Time to death or distant metastasis showed early separation of the curves. PFS advantage was consistent for all subgroups and regardless of PD-L1 expression cut off of 25 percent. There is no data currently on the benefit in PD-L1 negative patients as they were evaluated together with patients with PD-L1 low expression.
  • Patients on placebo were 2x more likely to develop new brain mets. Treatment response and duration of response all favored durvalumab over placebo. OS data was immature at interim analysis.
  • Durvalumab had a favourable toxicity profile. Severe adverse events and deaths were comparable, although discontinuation due to adverse event, rates of any grade pneumonitis and pneumonia and immume-mediated adverse events were higher with durvalumab. Patients in the duravalumab arm received concomitant treatment, mostly glucocorticoids and endocrine therapy and received more infusions compared to the placebo arm (median 20 v 14).
  • Durvalumab extended PFS by 11 months compared to placebo and less than half of patients were still alive at 18 months. With an acceptable safety profile, adding PD-L1 consolidation has the potential to be standard of care treatment in locally advanced NSCLC after at least two cycles of platinum-based cCRT and without disease progression following cCRT, given this compelling evidence. This is the first trial to demonstrate benefit with an anti- PD-L1 therapy given as consolidation in locally advanced NSCL.

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GU CANCERS
 

Ramucirumab plus docetaxel versus placebo plus docetaxel in patients with locally advanced or metastatic urothelial carcinoma after platinum-based therapy (RANGE): A randomised, double-blind, phase 3 trial
Petrylak DP et al., Lancet. 2017 Nov 18;390(10109):2266-2277.
PubMed ID: 28916371

Introduction:

Patients with advanced urothelial carcinoma who fail first line platinum-based chemotherapy face limited treatment options upon disease progression. Tumor angiogenesis is one of the key factors leading to refractory disease. Hence, the use of VEGF inhibitors is a plausible targeted therapy in this subpopulation.

Ramucirurab, an IgG1 monoclonal antibody binds to the extracellular domain of VEGFR-2. Preclinial studies revealed synergy of ramucirumab with docetaxel. A phase II study on patients with advanced urothelial cancer refractory to platinum therapy demonstrated significant improvement in PFS (5.4 v 2.8 mos., HR 0.389; p=0.0002) compared to docetaxel alone (J Clin Oncol 2016; 34: 1500-09). Petrylak and colleagues further investigated the efficacy and safety of this combination in the same patient population in the phase III RANGE trial.

 

Methods:

  • Patients: Histologically or cytologically confirmed locally advanced, unresectable or metastatic urothelial Ca (pure or predominant transitional cell histology) with primary tumor originating from the bladder, urethra, ureter, or renal pelvis, progression ≤14 mos. after platinum-containing chemotherapy, ECOG 0-1, no untreated brain metastases; previous treatment with one immune-checkpoint inhibitor if relapsed ≤24 mos. from the end of platinum-containing regimen was allowed.
  • Study design: Phase III, double-blind RCT
  • Intervention:
    • Experimental: Ramucirumab 10 mg/kg IV
      • Docetaxel 75 mg/m2 IV (60 mg/m2 in Korea, Taiwan, and Japan)
    • Control: Placebo
      • Docetaxel 75 mg/m2 IV (60 mg/m2 in Korea, Taiwan, and Japan)
    • All chemo given on day 1 of a 21-day cycle
  • Endpoints:
    • Primary: PFS
    • Secondary: OS, ORR, DCR, DOR, safety, patient-reported outcomes, PK and immunogenicity of ramucirumab

 

Results:

  • 530 patients randomized to ramucirumab + deocetaxel (n=263) and placebo + docetaxel (n=267)
  • Baseline patient characteristics: median age 66 yrs., 55% ≥65 yrs. old, 81% male, 77% white, 52% ECOG 1, 70% Europe and the rest of the world, 77% pure transitional cell histology, 64% bladder as primary tumor site, 70% visceral disease (41% lung metastases), 56% creatinine clearance ≥ 60, 13% Hgb <10 g/dL, 34% Bellmunt risk factor 1, 61% no previous adjuvant therapy, 64% previous cisplatin-based chemotherapy

  • QOL measures were comparable at baseline and were unchanged over time. No difference in QOL was observed between both arms.
  • After the first ramucirumab administration, the geometric mean trough concentrations before doses two, three, and five were 15 μg/mL, 23 μg/mL, and 34 μg/mL, respectively
  • Anti-ramucirumab antibodies: 19 (10%) had positive samples at baseline, three (2%) had treatment-emergent anti-ramucirumab antibodies.

Table 1: Efficacy Outcomes

  • Safety
    • Most frequent any grade side effects: fatigue (43% v 46%, alopecia (24% v 35%), diarrhea (29% v 21%), decreased appetite (28% v 23%), nausea (24% v 20%)
    • Most common grade ≥3 adverse event with ramucirumab: neutropenia (15% v 14%), febrile neutropenia (10% v 6), fatigue (8% v 9%)

       

    • Use of G-CSF: 42% v 42%
    • Most frequent cause of dose adjustment (dose reduction/delay/omission): febrile neutropenia (4% in each arm)
    • Most common cause of treatment discontinuation: sepsis (2% v 0%)
    • Most common cause of treatment-related death: sepsis (2% v 0%)
    • One patient on ramucirumab died from neutropenic sepsis.

Table 2: Adverse Event and Treatment Summary

 

 Discussion:

  • In patients with advanced urothelial Ca who failed platinum-based chemotherapy, ramucirumab with docetaxel significantly delayed disease progression by 1.31 mos. and doubled 12mo. PFS compared to docetaxel alone. OS data was immature at interim analysis.
  • Combination therapy improved tumor responses and extended duration of response to therapy compared to chemotherapy alone with docetaxel. More patients on ramucirumab experienced tumor burden reduction. No improvement in QOL was observed in either treatment arm.
  • The addition of anti-VEGF targeted therapy (ramucirumab) with chemotherapy (docetaxel) did not appear to compound side effects. Most adverse events were low grade. Side effects related to anti-VEGF therapy were observed in up to 6% (grade ≥3) of patients on ramucirumab. Although rates of neutropenia were similar in both arms, sepsis occurred in 2% on ramucurimab; one patient succumbed to neutropenic sepsis.
  • The study provided evidence in favor of ramucirumab with docetaxel as a treatment option in platimun-refractory advanced urothelial Ca. However, certain issues must be addressed. In terms of baseline characteristics, slightly more patients on ramucirumab had liver metastases (30% v 26%) and Belllmunt risk score 3 (18% v 12%). Only 6% received previous immune checkpoint inhibitor therapy, median follow-up was short at 5 mos., with a median treatment duration of 12.1 wks.
  • A phase 1 study of avelumab, an anti.PD-L1 monoclonal antibody yielded 17% objective response in patients with advanced urothelial Ca after failing platinum therapy who were followed up for at least 6 mos. (Lancet Oncol, http://dx.doi.org/10.1016/S1470-2045(17)30900-2). This is comparable to ORR of 24.5% in the RANGE trial.
  • Pembrolizumab has been approved as 2nd line treatment for advanced urothelial cancer based on results from a phase III trial that demonstrated improvement in OS (10.3 vs 7.4, HR= 0.73, P = 0.002) and 21% ORR, despite shorter PFS compared to placebo (N Engl J Med 376:1015-1026, 2017). Similar results were observed for nivolumab in the 2nd line setting (Oncol 2017;18: 312-22). At least 19% achieved an objective tumor response at a median follow-up of 7 mos. and the benefit was observed regardless of PD-L1 expression.
  • Although results from the RANGE study are encouraging, further investigation on combination therapy with ramucirumab is needed before it can be recommended.
  • The cost of treatment with the addition of ramuciraumab to chemotherapy is a concern, given its marginal advantage over monotherapy. With available targeted treatment options in this setting, determining the most effective drug or combination with the best safety profile remains a challenge.

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