June 2018 Edition Vol.11, Issue 6

Game-Changing Late-Breaking Plenary Sessions at ASCO 2018

By Lynne Lederman, PhD

Use of recurrence score test may reduce over-treatment in breast cancer

Joseph A. Sparano, MD, Montefiore Medical Center, presented the results of the TAILORx phase 3 non-inferiority trial that compared chemoendocrine therapy with endocrine therapy (ET) alone in women with hormone receptor-positive, HER2-negative, node-negative breast cancer that had an intermediate prognosis based on the Oncotype DX 21-gene recurrence score (RS).1 The trial results were published concurrently.2 Adjuvant chemotherapy has been recommended for most women with localized breast cancer, however the benefit is small and most women are over-treated.

TAILORx enrolled women age 18 to 75 years with hormone-receptor positive, HER2-negative, node-negative breast cancer, which represents half the breast cancers in the US. Results were presented for women with a mid-range RS of 11 to 25 who were randomly assigned to endocrine therapy (ET) alone (Arm B, n=3399) or to ET plus chemotherapy (Arm C, n=3312).

The primary endpoint was invasive disease-free survival (IDFS). There was no significant difference for IDFS between Arm B and Arm C (HR 1.08; 95% CI 0.94, 1.24; P=.26). The secondary endpoint was distant relapse-free interval (DRFI). There was no significant difference for DRFI between Arm B and Arm C (HR 1.10; 95% CI 0.85,1.14; P=.48), either. There were also no significant differences between Arms B and C for other secondary endpoints, including relapse-free survival and overall survival (OS), indicating that ET was non-inferior to chemotherapy.

In an exploratory analysis, no benefit from chemoendocrine therapy was seen in women of any age with RS 0 to 10 or RS 11 to 25. However, women of any age with RS 26 to 100 and women under 50 years of age with RS 16 to 25 did benefit from chemotherapy in the study. The group that benefits from chemoendocrine therapy represented only 30% of patients in the trial population. Therefore, Dr. Sparano said, the impact on care is that 70% of women in the target demographic can be spared unnecessary chemotherapy.

Discussant Lisa A. Carey, MD, University of North Carolina, commented that although the RS can be used to select some patients for chemotherapy, those with RS 25 to 31 are in a gray zone. “There is a point at which chemotherapy benefit begins to accrue, but it isn’t known exactly where it is.” She said that the Oncotype DX Recurrence Score test, which has been available since 2006, cost $4500 per assay. Widely used in the US, its primary impact has been the reduction in chemotherapy use in the treatment of breast cancer. A phase 3, randomized, prospective trial is examining the role of chemotherapy in patients with node-positive, hormone receptor-positive, HER2-negative breast cancer (NCT01272037) who have an RS score <25. Results are expected in 2022.

Maintenance therapy improves overall survival in children with rhabdomyosarcoma

Gianni Bisogno, MD, University Hospital of Padova, presented results of a trial of the effect of maintenance therapy on relapse of the rare cancer rhabdomyosarcoma (RMS) in patients age 0 to 21 years on behalf of the European paediatric Soft tissue sarcoma Study Group (EpSSG).3

Patients with high-risk, non-metastatic RMS who were in remission after standard treatment were randomly assigned to observation (n=186) or vinorelbine plus low-dose cyclophosphamide for 6 months of maintenance therapy (n=185). Maintenance therapy was less toxic than standard intensive chemotherapy. The 5-year disease-free survival was not significantly higher in the maintenance group than in the observation group (77.6% vs 69.8%, respectively; [HR 0.68; 95% CI 0.45, 1.02]; P=.0613). However, 5-year OS was significantly longer in the maintenance group (86.5% vs 73.7%; [HR 0.52; 95% CI 0.32, 0.86]; P=.0111).

Dr. Bisogno said that the EpSSG has decided that maintenance therapy will be part of a new standard of treatment for RMS in Europe. He said that subsequent trials will test different types and durations of maintenance therapy.

Discussant Douglas S. Hawkins, MD, Seattle Children’s Hospital, University of Washington, Fred Hutchinson Cancer Research Center, congratulated the EpSSG team on this study, although the study did not include patients at the highest risk of recurrence, namely, those with alveolar RMS with involved regional lymph nodes or those with distant metastases. Dr. Hawkins said maintenance therapy has modest toxicity and agreed that it should be considered standard treatment for high-risk EpSSG patients who have had a complete response to standard intensive therapy. The role of maintenance for other patient populations requires further investigation. He pointed out that the type and duration of backbone therapies as well as risk stratification in the EU and US are different.

Nephrectomy not necessary in metastatic renal cell carcinoma treated with sunitinib

Arnaud Mejean, MD, Hôpital Européen Georges-Pompidou – Paris Descartes University, presented the results of CARMENA, a phase 3, non-inferiority open-label trial of cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma (mRCC; NCT00930033).4 Trial results were published in conjunction with the presentation.5 Although nephrectomy plus systemic chemotherapy has been the standard of care for patients with mRCC, it has been questioned in the era of targeted therapies.

In this trial, patients with untreated mRCC who were amenable to nephrectomy were randomly assigned to nephrectomy followed by sunitinib (n=226) or sunitinib alone (n=224). The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), response rate, and safety.

Median follow-up was 50.9 months. The trial was stopped based on OS results at the second planned interim analysis. With non-inferiority defined as HR <1.20, OS was not significantly different between the groups (HR 0.89; 95% CI 0.71, 1.10). OS was 13.9 months in the nephrectomy followed by sunitinib group versus 18.4 months in the sunitinib alone group. The clinical benefit—defined as disease control rate or response of at least stable disease beyond 12 weeks—was significantly higher in the sunitinib alone group compared with the nephrectomy followed by sunitinib group (47.9% vs 36.6%, respectively; P=.022).

Sunitinib alone was non-inferior to nephrectomy followed by sunitinib, in patients with both intermediate- and high-risk mRCC. Dr. Mejean said, “Cytoreductive nephrectomy should no longer be considered the standard of care in mRCC.”

Daniel J. George, MD, Duke University, who discussed the presentation, said, “This is practice-changing data. Patients with profiles similar to the CARMENA population should get systemic therapy first.”

Pembrolizumab monotherapy effective as first-line therapy in PD-L1-expressing lung cancer

Gilberto Lopes, MD, MBA, Sylvester Comprehensive Cancer Center, University of Miami, presented results of the KEYNOTE-042 open-label, phase 3 study of pembrolizumab versus platinum-based chemotherapy, as first-line treatment for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) of ≥1% (NC02228094). The study randomly assigned patients without EGFR or ALK mutations to pembrolizumab monotherapy (n=637) or to platinum-based chemotherapy (n=637). The arms were balanced for baseline characteristics, including TPS.

Median OS for patients with TPS ≥50% was 20.0 months in the pembrolizumab group and 12.2 months in the chemotherapy group (HR 0.69; 95% CI 0.56, 0.85; P=.0003). For those with TPS ≥20%, median OS was 17.7 months in the pembrolizumab group and 13.0 months in the chemotherapy group (HR 0.77; 95% CI 0.64, 0.92; P=.0020). For all patients, median OS was 16.7 months in the pembrolizumab group and 12.1 months in the chemotherapy group (HR 0.81; 95% CI 0.71, 0.93; P=.0018). Median duration of response was 20.2 months in the pembrolizumab group versus 8.3 months in the chemotherapy group.

No significant PFS benefit for pembrolizumab was seen, although follow-up of patients is ongoing. Treatment-related serious adverse events were more frequent in the chemotherapy group than the pembrolizumab group (41% vs 18%, respectively).

Discussant Leena Gandhi, MD, PhD, NYU Perlmutter Cancer Center, said that at face value, pembrolizumab appears more effective and less toxic that chemotherapy for the trial population. But beyond face value, value should include the relative safety, relative benefit, and relative cost. She also stated that it is important to look outside of the treatment used as the control arm for other options for these patients, noting that all combinations and even monotherapy with immunotherapies are more expensive than chemotherapy.

The estimated cost of 12 weeks of pembrolizumab is more than 100 times that of carboplatin plus paclitaxel, although pembrolizumab monotherapy is less expensive than a course of other immunotherapy combinations. Her definition of value is “when most patients selected for therapy get meaningful and durable benefit from that therapy,” and selection of patients is what matters most.

Dr. Gandhi pointed out that the benefit for pembrolizumab was being driven by patients with TPS ≥50%. However, not all patients with this level of TPS will benefit from pembrolizumab monotherapy, so more biomarkers are still needed for NSCLC.

“PD-L1 as a biomarker has clinical utility, although imperfect, and should be used,” she said.

Tumor mutational burden (TMB) is one marker that may complement PD-L1 for selection of therapy, as retrospective analyses suggest patients with high TMB may benefit from nivolumab or combination nivolumab plus ipilimumab. However, like TPS, TMB does not select out all patients who would not benefit. She concluded, “Lung cancer is no longer one size fits all.”



  1. Sparano JA, Gray RJ, Wood, WC, et al. TAILORx: Phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negagive, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. J Clin Oncol. 36, 2018 (suppl; abstr LBA1).
  2. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. Published online June 3, 2018.
  3. Bisogno G, De Salvo GL, Bergeron C, et al. Maintenance low-dose chemotherapy in patients with high-risk (HR) rhabdomyosarcoma (RMS): A report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG). J Clin Oncol. 36, 2018 (suppl; abstr LBA2).
  4. Mejean A, Escudier B, Thezanas S, et al. CARMENA: Cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma—results of a phase III noninferiority trial. J Clin Oncol. 36, 2018 (suppl; abstr LBA3).
  5. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. Published online June 3, 2018. DOI: 10.1056/NEJMoa1803675.
  6. Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 36, 2018 (suppl; abstr LBA4).

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