ESMO Congress 2019: Quick Takes From Key Clinical Trials

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The ESMO Congress continues to grow as a pivotal platform for research in clinical oncology. At the ESMO Congress 2019, important findings were showcased in more than 2,200 studies, including 93 late-breaking abstracts. The ASCO Post summarized much of that news in separate articles over several issues. Here, we present briefer summaries of additional newsworthy research.

SPARTAN: Apalutamide in Castration-Resistant Prostate Cancer

The addition of apalutamide to backbone therapy with androgen-deprivation therapy reduced the risk of death by 25% vs placebo/androgen-deprivation therapy in patients with nonmetastatic castration-resistant prostate cancer, according to updated findings of the phase III SPARTAN trial.1 At a median 41 months of follow-up, median overall survival was not reached in either arm, but it numerically favored apalutamide. The P value was slightly lower than the prespecified P value, so the difference between the two treatment arms did not reach statistical significance.

SPARTAN evaluated the safety and efficacy of apalutamide vs placebo in 1,207 patients with nonmetastatic castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level, despite receiving continuous androgen-deprivation therapy. At enrollment, the PSA doubling time was ≤ 10 months.

Patients were randomly assigned 2:1 to receive 240 mg of apalutamide daily with androgen-deprivation therapy (n = 806) or placebo with androgen-deprivation therapy (n = 401). Patients who experienced disease progression on study were allowed to receive abiraterone acetate plus prednisone.

In the updated analysis, the 4-year overall survival rates for the apalutamide and placebo arms were 72.1% and 64.7%, respectively. The survival benefit of apalutamide was observed across all prespecified patient subgroups and was consistent despite crossover from the placebo arm.

Additionally, longer follow-up showed that apalutamide lengthened the time to chemotherapy and progression-free survival 2, and improved safety vs the control arm. Apalutamide reduced the risk of metastasis or death by 72% in patients with nonmetastatic castration-resistant prostate cancer. The median metastasis-free survival was 40.5 months in the apalutamide arm vs 16.2 months in the placebo arm (P < .0001).

Apalutamide’s safety profile was found to be consistent with prior reports. The treatment discontinuation rate due to disease progression was 34% in the apalutamide group compared with 74% in the placebo group.

Matthew Smith, MD

Matthew Smith, MD

“Collectively, these results further support apalutamide as a standard-of-care option for men with high-risk, nonmetastatic castration-resistant prostate cancer,” said Matthew Smith, MD, Director of the Genitourinary Malignancies Program, Massachusetts General Hospital Cancer Center, Boston.

KEYNOTE-119: Pembrolizumab in Triple-Negative Breast Cancer

After gaining some success as a treatment for metastatic triple-negative breast cancer, pembrolizumab failed to improve overall survival vs chemotherapy in the second or third line, in the primary analysis of KEYNOTE-119, although a benefit emerged in patients with high expression of the programmed cell death ligand 1 (PD-L1).2 “Pembrolizumab did show a clear trend in improved efficacy with PD-L1 enrichment,” said Javier Cortes, MD, of IOB Institute of Oncology, Quiron Group, Madrid and Barcelona, and Vall d’Hebron Institute of Oncology in Barcelona.

Javier Cortes, MD

Javier Cortes, MD

KEYNOTE-119 enrolled 622 patients with previously treated metastatic triple-negative breast cancer, randomly assigning them to pembrolizumab at 200 mg every 2 weeks or investigator’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine. Overall superiority of pembrolizumab would be formally tested in all patients only if superiority was shown in patients with a Combined Positive Score (CPS) ≥ 1—which it was not: In the CPS ≥ 1 subset, median overall survival was 10.7 months with pembrolizumab vs 10.2 months with chemotherapy (hazard ratio [HR] = 0.86; P = .073), and in the intent-to-treat population, 9.9 months vs 10.8 months, respectively (HR = 0.97; 95% confidence interval [CI] = 0.82–1.15).

Patients with higher biomarker expression did, however, demonstrate a benefit from pembrolizumab. In an exploratory analysis, median overall survival in the CPS ≥ 10 group for pembrolizumab vs chemotherapy was 12.7 months vs 11.6 months (HR = 0.78; P = .057), and in the CPS ≥ 20 subset, it was 12.5 months and 4.9 months, respectively (HR = 0.58; 95% CI = 0.38–0.88), Dr. Cortes reported. Response rates were higher and more durable with pembrolizumab, and the drug was better tolerated, he added.

KATE2: T-DM1 Plus ­Atezolizumab in HER2-Positive Advanced Breast Cancer

Leisha A. Emens, MD, PhD

Leisha A. Emens, MD, PhD


Final overall survival data were presented for the KATE2 trial, which evaluated trastuzumab emtansine (T-DM1) plus atezolizumab or placebo in 202 patients with previously treated HER2-positive advanced breast cancer.3 A possible benefit was shown in 40% or so of patients with PD-L1–positive tumors, although the short follow-up lacked statistical power, reported Leisha A. Emens, MD, PhD, of the University of Pittsburgh.

The investigators previously reported no statistically significant difference in progression-free survival for the atezolizumab/T-DM1 combination in the intent-to-treat population (median, 8.2 months vs 6.8 months; HR = 0.82; P = .3332), but median progression-free survival was numerically longer in patients with PD-L1–positive disease (8.5 vs 4.1 months; HR = 0.60; 95% CI = 0.32–1.11), Dr. Emens said.

After a median follow-up of about 19 months, median overall survival was not reached in either arm, although it numerically favored T-DM1 plus atezolizumab (HR = 0.74; 95% CI = 0.42–1.30). “Although the number of events is small, the data suggest an overall survival benefit with atezolizumab and T-DM1 in the PD-L1 immunohistochemistry–positive patients: a 1-year survival rate of 94% vs 88%, respectively,” Dr. Emens said.


TROPHY-U-01: ­Sacituzumab ­Govitecan in Metastatic ­Urothelial Cancer

The antibody-drug conjugate sacituzumab govitecan showed clinical activity, with an overall response rate of 29%, in patients with heavily pretreated metastatic urothelial carcinoma, according to findings from the single-arm phase II TROPHY-U-01 trial.4 There were two complete responses, six partial responses, and two additional unconfirmed partial responses. In patients with liver metastases (n = 23), the objective response rate was 25%. In this study, sacituzumab govitecan was found to have a manageable and predictable safety profile.

“The TROPHY-U-01 study confirms the previously presented clinical activity of sacituzumab govitecan in heavily pretreated patients with advanced urothelial carcinoma,” said Scott T. Tagawa, MD, Associate Professor at Weill Cornell Medicine and Associate Attending Physician, New York-Presbyterian–Weill Cornell Medical Center. “These data, combined with the prior available data, demonstrate that sacituzumab govitecan has the potential to change the landscape of advanced urothelial carcinoma.”

Scott T. Tagawa, MD

Scott T. Tagawa, MD

In the open-label, phase II TROPHY-U-01 trial, sacituzumab govitecan was evaluated in two cohorts: patients with metastatic urothelial cancer who experienced disease progression after platinum-based therapy and checkpoint inhibition (n = 100; cohort 1) and those who were ineligible for platinum-based therapy and had disease progression after prior checkpoint inhibitor treatment (n = 40; cohort 2).

Dr. Tagawa presented preliminary data from cohort 1 on 35 patients. Patients received sacituzumab govitecan at 10 mg/kg on days 1 and 8 every 3 weeks, with treatment continued until unacceptable toxicity or disease progression. The 35 patients included in the interim analysis received at least one cycle of sacituzumab govitecan and had at least one on-treatment response assessment. The median age was 64 years (range, 43–90 years), with 20% of patients 75 years of age or older.

In these heavily pretreated patients (median number of prior therapies was three), at a median follow-up of 4.1 months, 74% of patients experienced a reduction in tumor size. The median time to onset response was 1.5 months (range, 1.2–2.8 months). Although preliminary, responses were higher in patients younger than age 75 (n = 8), in those with at least three prior anticancer regimens (n = 8), and in patients with 0 to 1 Bellmunt risk factors (n = 10). As of the data cutoff, 8 of the 10 responders have an ongoing response.

“Although admittedly each of these subgroups is small, it appears that the response rate is consistent across subgroups,” Dr. Tagawa said.

Treatment-related adverse events of any grade included alopecia (74%), neutropenia (66%), diarrhea (57%), and fatigue (54%). Grade 3 or 4 treatment-related adverse events were neutropenia (55%), leukopenia (29%), anemia (17%), febrile neutropenia (12%), decrease in lymphocyte count (9%), diarrhea (9%), urinary tract infection (11%), fatigue (6%), and abdominal pain (3%). Grade ≥ 2 rash occurred in five patients. There were no cases of grade > 2 peripheral neuropathy or interstitial lung disease. Three patients discontinued treatment due to treatment-related adverse events, and no treatment-related deaths were reported.

NEOLAP: Induction Therapy for Locally Advanced Pancreatic Cancer

In patients with locally advanced pancreatic cancer, conversion of the tumor to resectable status was associated with a significantly improved overall survival. Benefit was shown with two common regimens that were evaluated in the prospective, randomized phase II NEOLAP trial.5

Volker Kunzmann, MD

Volker Kunzmann, MD

In 168 patients with nonresectable pancreatic cancer, NEOLAP evaluated two induction regimens: nab-paclitaxel plus gemcitabine or sequential FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan). Conversation to resectability was comparable between the regimens, as were other secondary endpoints. In both arms, tumor resection was associated with significant survival benefits, according to the final results presented by Volker Kunzmann, MD, of the University Hospital Würzburg and Comprehensive Cancer Centre Mainfranken, Germany.

All patients received two cycles of nab-paclitaxel/gemcitabine induction. After that, 130 patients without progressive disease or unacceptable adverse events were randomly assigned to either four cycles of sequential unmodified sequential FOLFIRINOX (n = 66) or two additional cycles of nab-paclitaxel/gemcitabine (n = 64).

The primary endpoint, conversion rate (complete R0/R1 macroscopic tumor resection), was achieved by 45.0% of patients receiving FOLFIRINOX and 30.6% receiving nab-paclitaxel/gemcitabine (odds ratio [OR] = 0.54; P = .135). Median overall survival for the entire study population was 22.5 months after FOLFIRINOX and 17.2 months after nab-paclitaxel/gemcitabine (HR = 0.73; P = .268), with no significant differences per arm.

In patients in both arms whose tumors became resectable, median overall survival rose to 27.4 months, compared with 14.2 months for patients whose tumors did not convert (HR = 0.45; P = .0035), which was a significant benefit, according to the investigators. Approximately 50% of patients in each arm experienced an adverse event.

“Secondary tumor resection after obligatory surgical exploration was associated with a significant survival benefit and is therefore highly recommendable in patients with locally advanced pancreatic cancer,” Dr. Kunzmann said.


ENTRATA: Telaglenastat Plus Everolimus in Metastatic Renal Cell Carcinoma

The addition of the investigational agent telaglenastat to everolimus lengthened progression-free survival compared with everolimus alone in patients with heavily pretreated advanced renal cell carcinoma in the phase II ENTRATA study.6 In the randomized, double-blind trial, median progression-free survival was 3.8 months in the telaglenastat-plus-everolimus arm compared with 1.9 months in the placebo-plus-everolimus arm (P = .079). The improvement in median progression-free survival with the addition of telaglenastat met the prespecified threshold for achieving statistical significance for the primary endpoint (investigator-assessed progression-free survival).

“The ENTRATA study supports proof of concept for telaglenastat and supports glutaminase inhibition as a new therapeutic strategy for metastatic renal cell carcinoma for further study,” said study investigator Chung-Han Lee, MD, PhD, of Memorial Sloan Kettering Cancer Center (MSK), New York.

Telaglenastat is an oral inhibitor of glutaminase, the key enzyme for conversion of glutamine to glutamate. Preclinical studies and early phase I experience suggest synergistic anticancer activity for telaglenastat in combination with the mTOR inhibitor everolimus.

Chung-Han Lee, MD, PhD

Chung-Han Lee, MD, PhD

Patients with advanced clear cell renal cell carcinoma (n = 69) who had been treated with at least two prior lines of systemic therapy, including at least one VEGF receptor–targeted tyrosine kinase inhibitor, were randomly assigned 2:1 to telaglenastat at 800 mg twice daily plus everolimus at 10 mg/d, or placebo plus everolimus at the same dose. Patients with treated or stable brain metastases were allowed in the study.

The 69 patients enrolled in the trial had a median of three prior lines of therapy and multiple sites of metastatic disease. The median age was about 65 years; more than two-thirds of patients had an intermediate/poor MSK prognostic score. A total of 91% of the telaglenastat arm and 83% of the placebo arm received prior programmed cell death protein 1/PD-L1 inhibitor therapy.

The best tumor response in the telaglenastat/everolimus arm was partial response in 2.2% and stable disease in 56.5%. There were no objective responses in the placebo/everolimus arm, and the best response was stable disease in 47.8%. The secondary endpoint of overall survival is not yet mature.

The rate of treatment-emergent adverse events leading to treatment discontinuation was similar between the arms: 28.3% with telaglenastat/everolimus and 30.4% with placebo/everolimus; dose interruption or reduction of any drug due to adverse events occurred in 76.1% and 60.9%, respectively; grade ≥ 3 adverse events occurred in 80% and 61%, respectively. The most frequently reported grade ≥ 3 adverse events were anemia (17% in both arms) and fatigue (4% in the experimental arm vs 9%, respectively).

The global randomized double-blind, phase II CANTATA  study is evaluating telaglenastat in combination with cabozantinib vs placebo with cabozantinib in patients with advanced or metastatic renal cell carcinoma.

LIBRETTO-001: Selpercatinib in Thyroid Cancers

The highly selective RET inhibitor selpercatinib (formally LOXO-292) demonstrated robust objective response rates in patients with RET-mutant medullary thyroid cancer as well as in those with other RET fusion–positive thyroid cancers in the phase I/II LIBRETTO-001 trial.7 Findings from the trial for the primary analysis set comprising the first 55 patients enrolled with RET-mutant medullary thyroid cancer who received prior treatment with cabozantinib or vandetanib will be submitted to the U.S. Food and Drug Administration for potential approval. Submission of the new drug application for selpercatinib is expected before the end of 2019.

In this group (primary analysis set), the objective response rate was 56%, with a complete response rate of 6% and a partial response rate of 51%. A total of 5% of patients developed progressive disease. Similar efficacy was also observed in 26 pretreated patients with differentiated thyroid cancer.

At 10.6 months of follow-up, the median duration of response was not yet reached. At a median follow-up for progression-free survival of 11.1 months, median progression-free survival was not yet reached.

Lori J. Wirth, MD

Lori J. Wirth, MD

“The outcomes with selpercatinib in patients with medullary thyroid cancer who had disease progression or had previous treatment on approved multikinase inhibitors, compares favorably to multikinase inhibitors when they are used in the first-line setting, and it appears the drug is much less toxic,” said lead investigator Lori J. Wirth, MD, of Massachusetts General Hospital Cancer Center, Boston.

The LIBRETTO-001 trial enrolled 531 patients with various RET-altered cancers across doses of selpercatinib ranging from 20 mg/d to 240 mg twice daily. In addition to RET-mutant medullary thyroid cancer and RET fusion–positive thyroid cancer, the trial also included patients with RET fusion–positive non–small cell lung cancer (not reported by Dr. Wirth).

In patients with RET-mutant disease, the biochemical response rate, as measured by calcitonin levels, was 91% and as measured by carcinoembryonic antigen levels was 64%. “The biochemical responses were deep and sustained over time,” Dr. Wirth noted. “We did see that the overall response rate, duration of response, and progression-free survival were similar regardless of prior therapy and also similar regardless of RET mutation status, particularly M918T vs others,” she said.

Of assessable patients with cabozantinib/vandetanib-naive RET-mutant medullary thyroid cancer (n = 76), the objective response rate was 59% (1% complete response and 58% partial response). With 5.5 months of follow-up, the median duration of response and median progression-free survival were not reached.

In those with RET fusion–positive thyroid cancer (n = 27), the objective response rate of 62% (all partial responses) was observed across all histologies, including those with poorly differentiated tumors. The median duration of response after a median follow-up of 9.3 months was not yet reached. At a median follow-up of 9.9 months, median progression-free survival was not reached.

The most commonly reported adverse events with selpercatinib were dry mouth, diarrhea, hypertension, and elevated liver enzymes (mostly grades 1 to 3). Overall, 1.7% of patients discontinued treatment due to adverse events.

“The data for selpercatinib show efficacy and safety in both the first-line and relapsed settings. Patients with thyroid cancer have long sought targeted therapy tailored to the molecular nature of their disease, and we are hopeful that selpercatinib may be used as the standard of care in the future,” Dr. Wirth said.

A randomized phase III trial is planned to compare selpercatinib with cabozantinib or vandetanib—investigator’s choice—in kinase inhibitor–naive RET-mutant medullary thyroid cancer.

BAROCCO: Continuous Cediranib/Olaparib for Recurrent Ovarian Cancer

Nicoletta Colombo, MD

Nicoletta Colombo, MD

The continuous administration of the antiangiogenic agent cediranib plus the inhibitor of poly (ADP-ribose) polymerase olaparib yielded a trend toward improved progression-free survival compared with standard-of-care weekly paclitaxel in 123 pretreated patients with recurrent platinum-resistant ovarian cancer in the phase II BAROCCO trial.8 Continuous dosing was also more effective than intermittent dosing of cediranib/olaparib, reported Nicoletta Colombo, MD, of the European Institute of Oncology, Milan, Italy.

“BAROCCO included a difficult-to-treat population with a high unmet need; 59% of patients had received three or more lines, and the median platinum-free interval was less than 3 months. It was also the first trial with the combination of cediranib and olaparib in this population with a control arm,” said Dr. Colombo.

Median progression-free survival was 5.7 months with this combination given continuously vs 3.1 months with weekly paclitaxel (HR = 0.76; P = .29) for continuous combination vs paclitaxel. With intermittent administration, progression-free survival with cediranib/olaparib was similar to placebo, 3.8 months.

In the 109 patients with BRCA wild-type disease, median progression-free survival was 5.8 months with continuous dosing vs 2.1 months with paclitaxel (HR = 0.63; P = .10), and 3.8 months with intermittent dosing, thus showing activity, even in patients lacking the BRCA mutation. The clinical benefit rates were 85%, 54%, and 63%, respectively, she said.

“Although not statistically significant, continuous ­administration shows a promising trend for improved progression-free survival, particularly in the BRCA wild-type population,” she said. “The interruption of cediranib for 2 days may have a detrimental effect on progression-free survival, with no benefit on toxicity.”

DISCLOSURE: Dr. Smith has served as an advisor for Bayer, Janssen Oncology, Amgen, Pfizer, Lilly, and Novartis, has received travel funding from Amgen, Bayer, Janssen, and Lilly; and has received research funding from Janssen Oncology, Gilead Sciences, and Bayer. Dr. Cortes reported financial relationships with Roche, Novartis, Celgene, Eisai, Pfizer, Samsun, Cellestia, AstraZeneca, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, and Athenex, and owns stock in MedSIR. Dr. Emens reported financial relationships with AbbVie, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, eTHeRNA, Roche/Genentech, Gristone, MedImmune, Molecuvax, Macrogenics, Novartis, Peregrine, Replimune, Syndax, Vaccinex, Aduro, Corvus, EMD Serono, HeritX, Maxcyte, and Merck. Dr. Tagawa has had a consulting/advisory role with Medivation, Astellas Pharma, Dendreon, Janssen, Bayer, Genentech, Endocyte, Immunomedics, Karyopharm Therapeutics, AbbVie, Tolmar, QED, Amgen, Sanofi, Pfizer, and Clovis Oncology; has received research funding (institution) from Lilly, Sanofi, Janssen, Astellas Pharma, Progenics, Millennium, Amgen, Bristol-Myers Squibb, Dendreon, Rexahn Pharmaceuticals, Bayer, Genentech, Newlink Genetics, Inovio Pharmaceuticals, AstraZeneca, Immunomedics, Novartis, Aveo, Boehringer Ingelheim, Merck, Stem CentRx, Karyopharm Therapeutics, AbbVie, Medivation, Endocyte, Exelixis, and Clovis Oncology; and has received travel expenses from Sanofi, Immunomedics, and Amgen. Dr. Kunzmann disclosed personal financial relationships with Celgene. Dr. Lee reported financial relationships with Amgen, Eisai, Exelexis, Bristol-Myers Squibb, Calithera, and Pfizer, and has a leadership role in the Kidney Cancer Association. Dr. Wirth has served as an advisor or consultant for Ayala, Bayer HealthCare, Cue Biopharma, Eisai, Loxo Oncology, and Merck & Co. Dr. Colombo has received honoraria from or served as an advisor or consultant to Roche/Genentech, PharmaMar, AstraZeneca, Tesaro, Clovis Oncology, Pfizer, MSD Oncology, BioCad, and Takeda.


1. Smith MR, Saad F, Chowdhury S, et al: Apalutamide and overall survival in patients with nonmetastatic castration-resistant prostate cancer: Updated results from the phase III SPARTAN study. ESMO Congress 2019. Abstract 843O. Presented September 27, 2019.

2. Cortes J, Lipatov O, Im S-A, et al: KEYNOTE-119: Phase 3 study of pembrolizumab versus single-agent chemotherapy for metastatic triple-negative breast cancer. ESMO Congress 2019. Abstract LBA21. Presented September 28, 2019.

3. Emens LA, Esteva F, Beresford M, et al: Overall survival in KATE2, a phase II study of programmed death ligand 1 inhibitor atezolizumab plus trastuzumab emtansine (T-DM1) vs placebo plus T-DM1 in previously treated HER2-positive advanced breast cancer. ESMO Congress 2019. Abstract 305O. Presented September 28, 2019.

4. Tagawa STT, Balar A, Petrylak DP, et al: Initial results from TROPHY-U-01: A phase 2 open-label study of sacituzumab govitecan in patients with metastatic urothelial cancer after failure of platinum-based regimens or immunotherapy. ESMO Congress 2019. Abstract LBA55. Presented September 28, 2019.

5. Kunzmann V, Algul H, Goekkurt E, et al: Conversion rate in locally advanced pancreatic cancer after nab-paclitaxel/gemcitabine or FOLFIRINOX-based induction chemotherapy (NEOLAP): Final results of a multicenter randomized phase II AIO trial. ESMO Congress 2019. Abstract 671O. Presented September 27, 2019.

6. Motzer RJ, Lee C-H, Emamekhoo H, et al: ENTRATA: Randomized, double-blind, phase 2 study of telaglenastat (CB-839) + everolimus vs placebo + everolimus in patients with advanced/metastatic renal cell carcinoma. ESMO Congress 2019. Abstract LBA54. Presented September 28, 2019.

7. Wirth LJ, Sherman E, Drilon A, et al: Registrational results of LIBRETTO-001: A phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET-altered thyroid cancers. ESMO Congress 2019. Abstract LBA93.Presented September 29, 2019.

8. Colombo N, Nicoletto M, Panici B, et al: Italian multicenter randomized phase II study of weekly paclitaxel vs cediranib-olaparib with continuous schedule vs cediranib-olaparib with intermittent schedule in patients with platinum resistant high grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. ESMO Congress 2019. Abstract LBA58. Presented September 27, 2019.