In Case You Missed It: Short Takes on Current Cancer Research


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It would be impossible to cover all of the important presentations from the 5,000-plus abstracts accepted for the 2018 ASCO Annual Meeting. In addition to our regular meeting coverage of the top news stories, the following highlights focus on novel investigational approaches to therapy for various cancers. They include the use of a highly selective RET inhibitor for non–small cell lung cancer (NSCLC) and medullary thyroid cancer, poly (ADP-ribose) polymerase (PARP) inhibitor/checkpoint inhibitor combination for the treatment of platinum-resistant ovarian cancer, PARP inhibitor/abiraterone (Yonsa, Zytiga) combination for metastatic castration-resistant prostate cancer, a fibroblast growth factor receptor (FGFR) inhibitor for advanced urothelial carcinoma, and antibody-drug conjugate for advanced diffuse large B-cell lymphoma (DLBCL).

More Selective RET Inhibitor

LOXO-292, an investigational, selective RET inhibitor, showed robust clinical activity across RET-altered solid tumors in the phase I LIBRETTO-001 study.1 Responses were seen even in patients with brain metastases and the RET V804M mutation known to confer resistance to multikinase inhibitors. The best responses were seen in NSCLC and thyroid cancer.

At the time of data cutoff in April 2018, 82 patients had been treated across 7 cohorts in a dose-ranging study. The study enrolled 49 patients with RET fusion and 29 patients with RET mutations. Twelve patients had brain metastases.

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The objective response rate was 77% in 39 evaluable patients with RET-fusion–positive cancers; 77% in 30 evaluable patients with NSCLC; and 78% in patients with other RET-fusion–positive cancers. Responses occurred in RET-fusion–positive cancers regardless of the tumor type. The objective response rate was 45% (1 complete response) in patients with RET-mutated medullary thyroid cancer. Disease regression occurred in most patients, irrespective of the starting dose. No response was seen in the three evaluable patients with no evidence of an activating RET mutation.

“Disease regression was observed in response to LOXO-292 in the vast majority of patients. This activity did not differ by cancer type in this patient population composed of patients with lung, thyroid, and pancreatic cancers. Antitumor activity was seen across the entire range of dose levels, including the 20 mg/d dose,” said lead author Alexander E. Drilon, MD, of Memorial Sloan Kettering Cancer Center, New York.

Most treatment-related adverse events were grade 1 in severity. There were two cases of grade 3 events—tumor-lysis syndrome and elevated alanine transaminase levels; both events resolved.

Investigators are hopeful about LOXO-292 because it is more selective against RET than previous multikinase inhibitors that also target RET, and it is active against V804M, the most common gatekeeper mutation.

Platinum-Resistant Ovarian Cancer

The combinationof the PARP inhibitor niraparib (Zejula) plus the checkpoint inhibitor pembrolizumab (Keytruda) appears to hold promise for the treatment of platinum-resistant ovarian cancer, achieving durable responses among heavily pretreated women, according to the phase II TOPACIO trial.2 “Platinum--resistant ovarian cancer represents an unmet need,” stated lead author Panagiotis Konstantinopoulos, MD, of Dana-Farber Cancer Institute, Boston.

“TOPACIO showed that the combination of niraparib plus the programmed cell death ligand 1 (PD-L1) inhibitor pembrolizumab provides clinical benefit in patients with platinum-resistant or refractory ovarian cancer, 63% of whom had received prior bevacizumab [Avastin].”

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The objective response rate was 25% in this heavily pretreated patient population of platinum-resistant ovarian cancer (up to 5 previous treatment regimens), and more than two-thirds (67%) achieved disease control. Treatment with the dual approach showed activity across the spectrum of platinum-resistant ovarian cancer. In platinum-refractory patients, the objective response rate was 24% and disease control rate was 59%. In women whose tumors were BRCA-positive, 25% achieved an objective response, and 63% achieved disease control. Among women with homologous repair deficiency (HRD)-positive tumors, the objective response rate was 25%, and 69% achieved disease control.

FEATURED ASCO 2018 ABSTRACTS

  • Abstract 102: RET inhibitor LOXO-292, solid tumors
  • Abstract 106: PARP inhibitor niraparib + checkpoint inhibitor pembrolizumab, recurrent ovarian cancer
  • Abstract 5003: PARP inhibitor olaparib + antiandrogen agent abiraterone, prostate cancer
  • Abstract 4503: FGFR inhibitor erdafitinib, urothelial cancer
  • Abstract 7507: Antibody-drug conjugate polatuzumab vedotin + bendamustine + rituximab, diffuse large B-cell lymphomas

“Clinical activity was observed across multiple patient subtypes, including BRCA-wild type and PD-L1–positive and –negative patients,” Dr. Konstantinopoulos said. “Responses were not limited to HRD-positive patients. Adding pembrolizumab to niraparib in BRCA wild-type and HRD-negative patients led to similar objective response rates as with PARP inhibition in BRCA-mutated patients.”

Among all patients, the median duration of response was 9.3 months. “This compares well with the duration of response with olaparib [Lynparza; another PARP inhibitor] in BRCA-mutated platinum-resistant patients,” Dr. Konstantinopoulos said.

The doses of each agent used in the phase II trial follow: niraparib at 200 mg and pembrolizumab at 200 mg. The study enrolled 60 patients who were considered platinum-resistant or -refractory. More than three-quarters were BRCA wild-type, and 57% were PD-L1–positive. Almost two-thirds had previously received bevacizumab. There were no new safety signals related to either drug.

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Formal discussant Charles Drake, MD, PhD, of the Herbert Irving Comprehensive Cancer Center, New York, said: “These results of a single-arm trial are surprising. The BRCA-ness and HRD status don’t seem to matter with the combination of a PARP inhibitor and a checkpoint inhibitor. This is intriguing and needs to be studied further in a randomized trial.”

“In this population, the historical objective response rate is 11% with pembrolizumab and 5% with a PARP inhibitor, so the objective response rates of 20% to 25% seen in this combination trial indeed appear to be improved,” Dr. Drake noted.

PARP Inhibitor Plus Abiraterone in Prostate Cancer

The combinationof the PARP inhibitor olaparib plus abiraterone (an antiandrogen agent) reduced the risk of disease progression or death by 35% compared with abiraterone alone in pretreated patients with metastatic castration-resistant prostate cancer.3 The median progression-free survival was 13.8 months with the combination compared with 8.2 months for single-agent abiraterone (P = .034).

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“Olaparib plus abiraterone provided a significant progression-free survival benefit to metastatic castration-resistant prostate cancer patients who had previously received docetaxel compared with abiraterone alone. The benefit was seen independent of homologous recombination repair [HRR] status,” said lead author Noel Clarke, MBBS, ChM, FRCS, Professor of Urologic Oncology at the Christie NHS Foundation Trust, Manchester, UK. “These findings of a phase II trial support initiation of a phase III trial.”

The study enrolled 142 patients previously treated with docetaxel for metastatic castration-resistant prostate cancer, up to 2 prior lines of chemotherapy, and no second-generation hormonal agents. They were randomized 1:1 to receive oral abiraterone plus olaparib (an all-oral regimen) or abiraterone plus placebo.

At baseline, patients in the combination arm were slightly older (median age, 70 vs 67 years, respectively), had a higher mean prostate-specific antigen concentration (86mg/L vs 47 mg/L, respectively), and a higher disease burden. In the combination arm, 45% of patients had up to 4 bone metastases, and 55% had between 5 and 9 metastases compared with 65% and 35%, respectively, in the control arm.

Among the 136 patients who had HRR testing, 21 had HRR mutations. Among mutated patients, the median progression-free survival was 17.8 months with the combination therapy vs 6.5 months with abiraterone alone. Among HRR wild-type patients, the median progression-free survival was 15 months in the combination arm vs 9.7 months in the abiraterone-alone arm. In a third group of 86 patients with HRR-unknown status, the median progression-free survival was 13.1 months vs 6.4 months. The median overall survival among all patients was 22.7 months with the combination vs 20.9 months with abiraterone alone.

There were more treatment-related dose interruptions, reductions, and discontinuations in the combination arm than in the control arm. The rate of serious adverse events was 34% vs 18%, respectively. Serious cardiovascular adverse events were more frequently reported with the combination.

Erdafitinib in Metastatic Urothelial Cancer

The investigational FGFR inhibitor (erdafitinib [JNJ-42756493]) achieved responses in more than 40% of patients with metastatic or unresectable urothelial carcinoma in a phase II trial.4 Responses to erdafitinib were observed in 40 of 99 patients, and an additional 39 patients had stable disease on treatment. Erdafitinib achieved responses in patients with no prior exposure to chemotherapy, as well as in those who had been previously treated. Response rates were similar irrespective of the presence of visceral metastases.

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“On the basis of these results, the U.S. Food and Drug Administration [FDA] has granted erdafitinib Breakthrough Therapy designation status,” said lead author Arlene O. Siefker-Radtke, MD, of The University of Texas MD Anderson Cancer Center, Houston.

Patients with FGFR alterations have had poor responses to immunotherapy, and those with advanced urothelial cancer whose disease progresses on treatment have poor outcomes with available therapies. FGFR alterations have been reported in 15% to 20% of metastatic urothelial carcinomas and 40% to 70% of non–muscle-invasive bladder cancers.

The phase II trial enrolled 100 patients with metastatic urothelial carcinoma whose disease progressed on previous therapy or who were ineligible for first-line platinum-based chemotherapy. Of them, 12 patients received erdafitinib in the first-line setting, and the remaining 88 patients received 1 to 3 lines of prior therapy. The tumor site was the upper urinary tract in 23 patients and the lower urinary tract in 76 patients. About 80% had visceral metastases.

The objective response rate was 40% (3% complete response, 37% partial response). Among previously treated patients, the objective response rate was 40.2%, vs 41.7% for previously untreated patients. The objective response rate was 38.5% for patients with visceral metastases vs 47.5% for those without visceral metastases. Some degree of tumor shrinkage was observed in 75 of the 99 patients. Adverse events were generally of a low grade, and few led to treatment discontinuation, Dr. Siefker-Radtke said.

Polatuzumab Vedotin Combination in DLBCL

Polatuzumab vedotin,when added to bendamustine (B) and rituximab (Rituxan; R), more than doubled the overall survival rate in patients with relapsed or refractory DLBCL; however, after short follow-up, it showed no benefit in patients with follicular lymphoma, according to the results of a randomized phase Ib/II study.5

Polatuzumab vedotin is a novel antibody-drug conjugate that targets CD79b-positive cells in patients with B-cell non-Hodgkin lymphoma. Its addition to BR in this study led to a median overall survival of 11.8 months vs 4.7 months with BR alone (P = .0008).

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“In patients with DLBCL, polatuzumab led to a marked improvement in the rate of complete response as well as significant improvements in progression-free and overall survival. These findings were quite remarkable, as relatively few trials have shown a survival benefit in this setting,” said Laurie Helen Sehn, MD, MPH, of the British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, Canada.

The preliminary findings of this study led to a Breakthrough Therapy designation for polatuzumab vedotin by the FDA for patients with relapsed or refractory DLBCL.

The study included cohorts of 80 DLBCL and 80 follicular lymphoma patients randomized to receive BR or polatuzumab plus BR for 6 cycles. The primary endpoint was complete response assessed by fluorodeoxyglucose positron-emission tomography 6 to 8 weeks after the end of treatment.

In the DLBCL cohort, complete response was achieved in 40% of the polatuzumab-plus-BR arm vs 15% of the BR arm (P = .012). In addition to an improvement in overall survival, the higher complete response rate translated into significantly higher progression-free survival: 6.7 months with polatuzumab plus BR vs 2.0 months with BR (P < .0001).

By contrast, in the follicular lymphoma cohort, the complete response rate was high in both arms: 69% with polatuzumab plus BR and 63% with BR alone. There was also no significant difference in progression-free survival (P = .58) at this early analysis, she said.

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Whether polatuzumab vedotin will change treatment paradigms for patients with DLBCL may be answered by the ongoing phase III POLARIX study, according to Alison Moskowitz, MD, of Memorial Sloan Kettering Cancer, New York, who discussed the findings. POLARIX is comparing polatuzumab vedotin plus R-CHP (rituximab, cyclophosphamide, doxorubicin, prednisone) with R-CHOP (rituximab, cyclophosphamide, vincristine, prednisone).

“Certainly, there are patients who do very well with R-CHOP chemotherapy alone, and so we need to learn whether this is necessary for all patients or only the high-risk patients,” Dr. Moskowitz said. ■

DISCLOSURE: Dr. Drilon has served as a consultant or advisor to AstraZeneca, Blueprint Medicines, Genentech/Roche, Ignyta, Loxo, Pfizer, Takeda, and TP Therapeutics. Dr. Konstantinopoulos has served as a consultant or advisor to Merck and Vertex. Dr. Drake is a co-inventor on patents licensed from Johns Hopkins to  AZ Medimmune and Janssen, and has served on advisory boards for AZ Medimmune, Bayer, Bristol Myers Squibb, Compugen, Dendreon, Merck, Roche/Genentech, Potenza, Pfizer, Tizona, Kleo, Shattuck Labs and Harpoon Biotech. Dr. Clarke has received honoraria and travel expenses from Astellas Pharma, AstraZeneca, Bayer, Ferring, Ipsen, Janssen-Cilag, and Sanofi; has served as a consultant or advisor to Astellas Pharma, Bayer, Ferring, Janssen-Cilag, and Sanofi; has been on the speakers bureau for Astellas Pharma, and Janssen-Cilag; and has received institutional research funding from AstraZeneca. Dr. Siefker-Radtke has served as a consultant or advisor to AstraZeneca, Bristol-Myers Squibb, Eisai, EMD Serono, Genentech, Inovio Pharmaceuticals, Janssen, Lilly, Merck, and the National Comprehensive Cancer Network; has been on the speakers bureau for Genentech; has received research funding from Bristol-Myers Squibb, Janssen, Michael and Sherry Sutton Fund for Urothelial Cancer, the National Health Institutes, and Takeda; and has a patent on methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer. Dr. Sehn has served as a consultant or advisor to AbbVie, Amgen, Celgene, Gilead Sciences, Janssen, Lundbeck, Roche/Genentech, Seattle Genetics, and TG Therapeutics. Dr. Moskowitz reported no conflicts of interest.

REFERENCES

1. Drilon AE, et al: A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. 2018 ASCO Annual Meeting. Abstract 102. Presented June 2, 2018.

2. Konstantinopoulos PA, et al: TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC). 2018 ASCO Annual Meeting. Abstract 106. Presented June 3, 2018.

3. Clarke N, et al: Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer. 2018 ASCO Annual Meeting. Abstract 5003. Presented June 4, 2018.

4. Siefker-Radtke AO, et al: First results from the primary analysis population of the phase 2 study of erdafitinib (JNJ-42756493) in patients with metastatic or surgically unresectable urothelial carcinoma and FGFR alterations. 2018 ASCO Annual Meeting. Abstract 4503. Presented June 3, 2018.

5. Sehn LH, Ket al: Randomized phase 2 trial of polatuzumab vedotin with bendamustine and rituximab in relapsed/refractory FL and DLBCL. 2018 ASCO Annual Meeting. Abstract 7507. Presented June 3, 2018.


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