NCTN Group Trials Supporting FDA-Approved Indications for New Oncology Agents (2014 to 2017)
Year FDA Approval Indication / Agent / Indication / Related NCTN GroupTrial # / Publication Citations for the NCTN Clinical Trials
August 2014
(FDA) / Bevacizumab / In combination withpaclitaxeland eithercisplatinortopotecanfor the treatment of persistent, recurrent, or metastatic cervical cancer / NRG:
GOG-0240
Supplemental Indication for the Agent / TewariKS,SillMW,LongHJIII, et al. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370:734-743,2014. The GOG-0240 (Paclitaxel and Cisplatin or Topotecan With or Without Bevacizumab in Treating Patients With Stage IVB, Recurrent, or Persistent Cervical Cancer) trial showed a significant survival benefit of 3.7 months (17.0v13.3 months; hazard ratio, 0.71;P= .004) with the use of bevacizumab plus chemotherapy compared with chemotherapy alone. Adding bevacizumab also significantly improved the response rates compared with chemotherapy alone (48%v36%;P= .008).
March 2015 (FDA)
August 2015 (EMA) / Anti-GD2 Antibody ch14.18
(dinutuximab / UnituxinTM) / Use in "high-risk" neuroblastoma / COG: ANBL0032
Primary Indication for the Agent
------
COG
ANBL0931
Toxicities for labeling / YuAL,GilmanAL,OzkaynakMF, et al.Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. New Engl J Med 2010; 363: 1324–1334. This trial (COG ANBL0032) providedthedataforapprovalofch14.18(dinutuximab/Unituxin™)incombination withcytokinesandisotretinoin fortreatmentofchildren with highriskneuroblastomabytheFDAandtheEMA.
Ozkayank MF, Gilman AL, Yu AL et al. A comprehensive safety trial of chimeric antibody 14.18 (ch14.18) with GM-CSF, IL-2, and isotretinoin in high-risk neuroblastoma patients following myeloablative therapy: A Children's Oncology Group study. J Clin Oncol 32:5s, 2014 (suppl; abstr 10044). This study collected FDA-required comprehensive safety/toxicity data for immunotherapy to support a new Biological License Application.
NCTN Group Trials Supporting FDA-Approved Indications for New Oncology Agents (2014 to 2017)–continued
Year FDA Approval Indication / Agent / Indication / Related NCTN GroupTrial # / Publication Citations for the NCTN Clinical Trial
December 2016
(FDA) / Bevacizumab / In combination withpaclitaxeland eithercisplatinortopotecanfor the treatment of persistent, recurrent, or metastatic cervical cancer / NRG:
GOG-0213
Supplemental Indication for the Agent / Coleman RL, Brady MF, Herzog TJ et al. Bevacizumab and paclitaxel–carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology. Available Online 21 April 2017. FDA approval was based in part on this study which demonstrated that adding bevacizumab to chemotx showed an OS difference of 5 months compared to chemotx alone (median OS: 42.6 months vs. 37.3 months; HR=0.84, 95% CI: 0.69-1.01 and HR=0.82, 95% CI: 0.68-0.996, depending on stratification factor). Median PFS was 13.8 months vs. 10.4 months; HR=0.61, 95% CI: 0.51-0.72).
February 2017
(FDA) / Lenalidomide / As maintenance therapy for patients with multiple myeloma following autologous stem cell transplant / CALGB 100104
Supplemental Indication for the Agent / McCarthy PL, Owzar K, Hofmeister CC, et al. Phase III study of lenalidomide versus placebo after HCT for multiple myeloma. New Engl J Med 2012; 366(19):1770-1781. This trial (CALGB 100104) showed that lenalidomide maintenance therapy improved median progression-free survival (41 months, vs. 23 months with placebo; hazard ratio, 0.50; P<0.001). This benefit was observed across all patient subgroups, including those based on the β2-microglobulin level, cytogenetic profile, and response after transplantation. With a median follow-up period of 45 months, more than 70% of patients in both groups were alive at 4 years.
April 2017
(FDA) / Midostaurin / For the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive (FLT3+), as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation / CALGB 10603
Primary Indication for the Agent / Stone RM et al - Presented at the Plenary Session of the American Society of Hematology (ASH) Annual Meeting in 2015 - J Clin Oncol 29: 2011 (suppl; abstr TPS199). Manuscript is under review at a peer-review journal. Approval was based on a randomized, double-blind, placebo-controlled trial in 717 patients with previously untreated FLT3+ AML. This trial randomized patients to either placebo or midostaurin 50 mg orally twice daily on days 8-21 of each cycle of induction and consolidation chemotherapy followed by continuous daily midostaurin for up to 12 cycles. The trial demonstrated a statistically significant improvement in overall survival (OS) for patients receiving midostaurin compared with those on the placebo-containing arm (HR 0.77, p=0.016).
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Selected Accomplishments of NCTN Program Released in First 3 Years of Program – Sorted by Cancer Type & Year
Cancer Type / Year of Publication (Presentation) of Primary Results / NCTNTrial # / Experimental Agent or Regimen / Brief Description of Result / Publication or Abstract Reference
Brain Cancer Glioma / 2016 / NRG RTOG-9802 / Chemotherapy with Radiation Therapy / A total of 251 eligible patients were enrolled from 1998 through 2002 in this phase 3 trial. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival. / Buckner JC, Shaw EG, Pugh SL, et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma.
N Engl J Med. 2016 Apr 7;374(14):1344-1355. PubMed PMID: 27050206
Brain Metastases / 2016 / Alliance N0574 / Whole Brain Radiation Therapy / This was a randomized phase 3 trial of whole brain radiation therapy (WBRT) in addition to radiosurgery vs radiosurgery alone in patients with 1-3 brain metastases. This study showed that addition of WBRT was associated with significant declines in immediate recall, memory, and verbal fluency. Importantly, addition of WBRT did not improve overall survival despite better brain control. This study led to recommendations for treatment with stereotactic radiosurgery and close monitoring without adding WBRT to better preserve cognitive function in patients with newly diagnosed brain metastases. / Brown PD, Jaeckle K, Ballman KV, et al. Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial.
JAMA. 2016 Jul 26;316(4):401-9. PubMed PMID: 27458945
Breast Cancer / 2015 / CCTG MA.20 / Radiation Therapy / Among women with node-positive or high-risk node-negative breast cancer, the addition of regional nodal irradiation to whole-breast irradiation did not improve overall survival but reduced the rate of breast-cancer recurrence. At 10-year follow-up, there was no significant between-group difference in survival, with a rate of 82.8% in the nodal-irradiation group and 81.8% in the control group. Rates of disease-free survival were 82.0% in the nodal-irradiation group 77.0% in control group. / Whelan TJ, Olivotto IA, Parulekar WR, et al. Regional Nodal Irradiation in Early-Stage
Breast Cancer.
N Engl J Med 2015; 373:307-316. PubMed PMID: 26200977
Breast Cancer / 2015 / ECOG-ACRIN PACCT-1 (TailoRx) / Oncotype DX® Recurrence Score® Determinant of Treatment / Initial results from this prospectively conducted global trial following more than 10,000 women with early stage breast cancer to determine whether the Oncotype DX® Recurrence Score® or RS (a 21-gene expression assay that scores risk by assigning a # between 0 and 100) can predict likelihood of chemotx benefit. In cohort of women who received hormone tx alone based on a RS of 10 or lower, 99% were free of breast cancer recurrence after 5 years. This finding provides evidence other women in the future may effectively use hormonal tx alone if their RS is between 0 and 10. Further follow-up of trial is ongoing to determine whether chemotherapy may also be effectively spared in patients who have a mid-range RS between 11 25. / Sparano JA, Gray RJ, Makower DF, et al. Prospective Validation of a 21-Gene Expression Assay in Breast Cancer.
N Engl J Med. 2015 Nov 19; 373(21):2005-14. PubMed PMID: 26412349
Selected Accomplishments of NCTN Program Released in First 3 Years of Program – Sorted by Cancer & Yr (cont.)
Cancer Type / Year of Publication (Presentation) of Primary Results / NCTN Trial # / Experimental Agent or Regimen / Brief Description of Result / Publication or Abstract ReferenceBreast Cancer / 2016 / CCTG MA.17R / Letrozole / The extension of treatment with an adjuvant aromatase inhibitor to 10 years for women with hormone-sensitive early stage breast cancer resulted in significantly higher rates of disease-free survival and a lower incidence of contralateral breast cancer than did placebo for women with early stage breast cancer, but the rate of overall survival was not higher with the aromatase inhibitor than with placebo. The 5-year DFS rate was 95% with letrozole and 91% with placebo. / Goss PE, Ingle JN, Pritchard, KI et al. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years.
N Engl J Med 2016; 375:209-219. PubMed PMID: 27264120
Breast Cancer / 2017 / NRG NSABP
B-46 &
NSABP
B-49 / Antracycline & taxane-containing regimens / This was a collaborative joint analysis of 3 large early breast cancer trials or the ABC trials (performed by NRG & US Oncology) which compared various taxane-plus-anthracycline regimens with docetaxel plus cyclophosphamide and confirmed the superiority of anthracyclines in high-risk early-stage breast cancer patients. The hazard ratio (HR) on the initial 334 events was 1.202, which exceeded the prespecified threshold for futility (> 1.18). 4-year invasive DFS was 88.2% in the docetaxel-plus-cyclophosphamide arm vs 90.7% for the taxane-plus-anthracycline arm, demonstrating that docetaxel plus cyclophosphamide × 6 is significantly inferior to the anthracycline and taxane–containing regimens. / Blum JL, Flynn PJ, Yothers G, et al. Anthracyclines in Early Breast Cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology).
J Clin Oncol.2017 Apr 11:JCO2016714147. [Epub ahead of print].
GI Cancer Rectal / 2016 / Alliance ACOSOG-Z6051 / Laparoscopic Resection / This study showed that, among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet pre-defined criterion for noninferiority for pathologic outcomes (i.e., successful resection as a composite of circumferential radial margin > 1 mm, distal margin without tumor, and completeness of total mesorectal excision). The noninferiority margin was 6%. Pending clinical oncologic outcomes, the findings do not support the use of laparoscopic resection in these patients. / Fleshman J, Branda M, Sargent DJ, et al. Effect of Laparoscopic-Assisted Resection vs Open Resection of Stage II or III Rectal Cancer on Pathologic Outcomes.
JAMA 314(13): 1346-1355. PubMed PMID: 26441179
GI Cancer Colon / 2017 / Alliance IDEA Pooled Analysis (CALGB-80702) / Short Course of Adjuvant Chemotherapy / Results from this international prospective pooled analysis evaluating duration of adjuvant therapy (3 vs 6 months) for patients with stage III colon cancer will be presented as a "Late Breaking Abstract" at the Plenary Session of ASCO in June 2017. Alliance conducted the meta-analysis and contribute results for 1 of the trials included in the pooled analysis. Results are expected to inform the standard of care for these patients. / Shi Q, Sobrero AF, Shields F, et al. Prospective pooled analysis of 6 phase 3 trials investigating duration of adj oxaliplatin-based therapy (3 vs 6 months) for patients with stage III colon cancer. The IDEA (International Duration Evaluation of Adj chemotx) collaboration. J Clin Oncol 35, 2017 (Abstr LBA1).
Selected Accomplishments of NCTN Program Released in First 3 Years of Program – Sorted by Cancer & Yr (cont.)
Cancer Type / Year of Publication (Presentation) of Primary Results / NCTNTrial # / Experimental Agent or Regimen / Brief Description of Result / Publication or Abstract Reference
GU Cancer Bladder / 2017 / SWOG S0377 / Gemcitabine instillation / Immediate, instillation of the common chemotherapy agent gemcitabine after removal of a newly diagnosed or occasionally recurring Grade I, II, superficial bladder cancer significantly reduces the risk of cancer recurrence. The S0337 trial showed a 34% reduction in risk of recurrence in patients receiving gemcitabine. / Messing E, Tangen C, Lerner S, et al. A Phase 3 Blinded Study of Immediate Post-TURBT Instillation of Gemcitabine vs Saline in Pts with Newly Diagnosed or Occasionally Recurring Grade I/II Non-Muscle Invasive Bladder Cancer:
SWOG S0337.
Plenary Session - Oral Presentation at the Annual American Urological Association Meeting on May 15, 2017. PNFLBA-10: Late-Breaking Abstract.
GU Cancer Prostate / 2015 / ECOG-ACRIN E3805 / Docetaxel with Andogen Deprivation Therapy (ADT) / E3805 - Using six cycles of the combination of docetaxel and androgen deprivation (ADT) therapy as initial treatment for metastatic prostate cancer—and not waiting until progression on ADT as is typically done in current clinical practice—improved overall survival by 13.6 months compared to ADT alone. The finding suggests that physicians can immediately consider changing their clinical practice from the use of hormone therapy alone to a combination of chemotherapy and hormone therapy to improve survival. / Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal Tx in Metastatic Hormone-Sensitive Prostate Cancer.
N Engl J Med. 2015 Aug 20; 373(8):737-46. PubMed PMID: 26244877
GU Cancer Prostate / 2017 / NRG RTOG-9601 / Bicalutamide with Radiation Therapy / NRG RTOG 9601 - The addition of 24 months of antiandrogen therapy with daily bicalutamide to salvage radiation therapy resulted in significantly higher rates of long-term overall survival and lower incidences of metastatic prostate cancer and death from prostate cancer than radiation therapy plus placebo based on long term follow-up from this phase 3 trial. / Shipley WU, Seiferheld W, Lukka HR, et al. Report of NRG Oncology/RTOG 9601, a phase III trial of radiation therapy with or without bicalutamide in patients with PSA elevation following radical prostatectomy for localized carcinoma of the prostate.
N Engl J Med 2017; 376:417-428. PubMed PMID: 28146658
GU Cancer Renal / 2016 / ECOG-ACRIN E2805 / Sunitinib and Sorafenib / No preventive benefit from the use of either sunitinib or sorafenib following surgery in male and female adults with locally advanced kidney cancer. This definitive phase III trial showed no disease-free survival benefit from these widely-used drugs as adjuvant treatment in this population of patients. / Haas NS, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): A double-blind, placebo-controlled, randomised, phase 3 trial.
Lancet. 2016; 387(10032): 2008-2016. PubMed PMID: 26969090
Selected Accomplishments of NCTN Program Released in First 3 Years of Program – Sorted by Cancer & Yr (cont.)
Cancer Type / Year of Publication (Presentation) of Primary Results / NCTNTrial # / Experimental Agent or Regimen / Brief Description of Result / Publication or Abstract Reference
Gyne Cancer Ovarian / 2016 / NRG GOG-0262 / Paclitaxel / Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. / Chan JK, Brady MF, Penson RT, et al. Weekly vs. every-3-week paclitaxel and carboplatin for ovarian cancer.
N Engl J Med. 2016 Feb 25;374(8):738-48. PubMed PMID: 26933849
Gyne Cancer Ovarian / 2017 / NRG GOG-0213 / Bevacizumab / The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, the sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to therapy for these patients. / Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab & paclitaxel-carboplatin chemotherapy & secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/GOG-0213): a multicentre, open-label, randomised, phase 3 trial.
Lancet Oncol. 2017 Apr 21. pii: S1470-2045(17)30279-6. PubMed PMID: 28438473
Hematologic Leukemia / 2016 / SWOG S1203 / Idarubicin with
high-dose cytarabine; Vorinostat / Treatment with Idarubicin with high-dose cytarabine (IA) is not more effective than 7+3 in younger patients with AML. Outcomes with IA or IA plus vorinostat are similar. In patients with favorable cytogenetics, outcomes were inferior with IA or IA+V when compared to 7+3, perhaps related to use of lower doses of ara-C during consolidation. / Garcia-Manero G, Othus M, Pagel JM, et al. SWOG S1203: a randomized phase III study of standard cytarabine plus daunorubicin (7+3) therapy versus idarubicin with high dose cytarabine (IA) with or without vorinostat (IA+V) in younger patients with previously untreated acute myeloid leukemia (AML).
Abstract #901. Annual Meeting of American Society of Hematology (ASH) in Dec. 2016.
Hematologic Multiple Myeloma / 2016 / SWOG S1203 / Bortezomib / The addition of bortezomib to lenalidomide dexamethasone for induction therapy in previously untreated myeloma results in a statistically significant and clinically meaningful improvement in PFS as well as better overall survival compared to lenalidomide & dexamethasone alone. The therapy had an acceptable safety and tolerability profile despite increased neurotoxicity and represents a potential new standard of care. Median PFS was significantly improved (43 months vs 30 months). The median overall survival was also significantly improved (75 months vs 64 months). / Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial.
Lancet. 2017 Feb 4;389(10068):519-527. PubMed PMID: 28017406
Selected Accomplishments of NCTN Program Released in First 3 Years of Program – Sorted by Cancer & Yr (cont.)
Cancer Type / Year of Publication (Presentation) of Primary Results / NCTNTrial # / Experimental Agent or Regimen / Brief Description of Result / Publication or Abstract Reference
Hematologic Leukemia / 2016 / Alliance CALGB-50303 / DA-EPOCH-R (Dose-adjusted Etoposide + Prednisone + Vincristine + Cyclophosphamide + Doxorubicin + Rituximab) / There was no difference in event-free survival or overall survival between R-CHOP and DA-EPOCH-R when considering all patients. DA-EPOCH-R showed increased toxicity consistent with higher dose-intensity but not increased grade 5 toxicity. Compared to R-CHOP, more patients on DA-EPOCH-R did not complete treatment, which may reflect patterns of care or toxicity. Due to the clinical and genetic diversity of DLBCL, subset analyses are necessary to determine the effect of CNS relapse, GCB and ABC subtypes, age and IPI on outcomes of the two arms. These data do not address the efficacy of these regimens in PMBL or MYC+ DLBCL due to their low frequency, and where more dose-intense regimens appear to be important. Full molecular analyses are ongoing. / Wilson WH, sin-Ho J, Pitcher BN, et al. Phase III Randomized Study of R-CHOP Versus DA-EPOCH-R and Molecular Analysis of Untreated Diffuse Large B-Cell Lymphoma: CALGB/Alliance 50303.
Presented at 58th Annual Meeting of American Society of Hematology (ASH)
in December 2016. Abstract #469.
Imaging / 2016 / ECOG-ACRIN ACRIN-6691 / Near-infrared optical imaging (Breast Cancer) / The first multicenter trial of near-infrared optical imaging ever performed in the world, this prospectively conducted trial evaluated whether changes from baseline to mid-therapy in a Diffuse Optical Spectroscopic Imaging (DOSI)-derived imaging endpoint, the Tissue Optical Index (TOI), predict pathologic complete response (pCR) in 60 women with newly diagnosed breast cancer planning to undergo neoadjuvant chemotherapy. The trial concluded that combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction. / Tromberg BJ, Zhang Z, Leproux A, et al. Predicting responses to neoadjuvant chemotherapy in breast cancer: ACRIN 6691 trial of diffuse optical spectroscopic imaging.
Cancer Res. 2016; 76(20):5933-5944. PubMed PMID: 27527559
Melanoma / 2014 (November) / ECOG-ACRIN E1609 / Sagramostim plus high-dose ipilimumab / Treatment with the granulocyte-macrophage colony-stimulating factor (GM-CSF) sargramostim plus high-dose (10mg/kg) ipilimumab (a CTLA-4 blocking monoclonal antibody) resulted in longer overall survival & lower toxicity, but no difference in PFS in patients with unresectable metastatic (stage III or IV) melanoma, compared to treatment with ipilimumab alone. This trial result may mitigate concerns over toxicity of ipilimumab therapy administered at high dosage. These findings require confirmation in larger studies with longer follow-up. / Hodi FS, Lee S, McDermott DF, et al. Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial.
JAMA. 2014 Nov 5; 312(17):1744-53. PubMed PMID: 25369488
Selected Accomplishments of NCTN Program Released in First 3 Years of Program – Sorted by Cancer & Yr (cont.)