ASCO 2019: Oncology Leaders Select Top Studies

Within the week, thousands of abstracts spanning a multitude of tumor types will be presented at the 2019 ASCO Annual Meeting, many of which will lead to practice-changing implications for oncologists. The studies to be unveiled are endless, and cover antibody-drug conjugates, novel targeted agents, and long-term follow-up of currently available therapies.

Ahead of the 2019 ASCO Annual Meeting, we spoke with top leaders in oncology on their thoughts for the most pivotal abstracts being presented in Chicago.

­BREAST CANCER

Erika P. Hamilton, MD

Erika P. Hamilton, MD, medical oncologist, director, Breast and Gynecologic Cancer Research Program, Sarah Cannon Research Institute

Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: Overall survival (OS) results (Abstract LBA1008)

Based on the progression-free survival (PFS) data from MONALEESA-7, frontline ribociclib (Kisqali) was approved by the FDA for use in combination with an aromatase inhibitor (AI) for the treatment of pre/perimenopausal or postmenopausal women with hormone receptor (HR)—positive/HER2-negative advanced or metastatic breast cancer. The agent was simultaneously approved in combination with fulvestrant for the treatment of postmenopausal women with HR-positive/HER2-negative advanced or metastatic breast cancer, in the frontline setting or after disease progression on endocrine therapy.

Prior data of MONALEESA-7 trial showed a median PFS with the combination of ribociclib and an AI of 27.5 months compared with 13.8 months with an AI alone (HR, 0.569; 95% CI, 0.436-0.743). At the 2019 ASCO Annual Meeting, overall survival (OS) findings will be unveiled.

“This presentation is probably my most anticipated of ASCO as we expect to see OS data for the addition of ribociclib to endocrine therapy in premenopausal women. We have all seen the dramatic PFS benefits across multiple trials, but we are really eager to see survival data as it will help us tailor whether we should uniformly be giving CDK4/6s in the first-line setting versus any setting, etc.”

SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx; Abstract 1000)

This is the primary analysis of the randomized, open-label SOPHIA trial comparing the combination of the novel antibody margetuximab and chemotherapy with trastuzumab/chemotherapy in patients with metastatic breast cancer. While OS data are maturing, results showed that the margetuximab regimen improved PFS over trastuzumab with a comparable safety profile.

“This trial tested margetuximab (an Fc-optimized monoclonal antibody against HER2) and chemotherapy versus trastuzumab plus chemotherapy in patients with 1 to 3 prior lines of HER2-[targeted] therapy. We saw the press release with a modest improvement in PFS from 4.9 to 5.8 months (HR, 0.76; P = .333). With many of our effective HER2 agents, such as pertuzumab (Perjeta) and T-DM1 (ado-trastuzumab emtansine; Kadycla) being used in the early-stage space, new HER2 agents are eagerly awaited for patients with metastatic disease.”

Pembrolizumab (P) in patients (pts) with metastatic breast cancer (MBC) with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study (Abstract 1014)

In the phase II basket study, pembrolizumab (Keytruda) was evaluated in a cohort of patients with metastatic breast cancer with high TMB, which ranged from 9 to 37 mutations/megabase. Findings have showed that the disease control rate with pembrolizumab in this cohort is 37% (95% CI, 24%-46%), and the overall response rate (ORR) is 21% (95% CI, 8%-41%). Additionally, the median PFS and median OS is 10.6 weeks and 31.6 weeks, respectively.

“TAPUR studied pembrolizumab in patients with high tumor mutational burden, and among 28 patients with breast cancer who were heavily pretreated (>90% with ≥3 prior systemic regimens) the ORR was 21% and disease control rate (DCR) was 37%. We have to try to put all this in context with the negative pembrolizumab data released in all comers as part of the KEYNOTE-119 trial in the later-line setting, and also the positive data from atezolizumab in the first-line space with IMpassion130, but again, when patients were selected for PD-L1. It may be [that] we need to continue to define our markers of response to who gets benefit—whether it be PD-L1 or TMB.”

Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): A randomized, double-blind, placebo-controlled, phase II trial (Abstract 1005)

The highly selective oral, small molecule AKT inhibitor capivasertib was evaluated in combination with fulvestrant (Faslodex) in postmenopausal women with estrogen receptor—positive and HER2-negative breast cancer following relapse or disease progression on AI. In the intent-to-treat analysis the median PFS was 10.3 months with capivasertib compared with 4.8 months for placebo (HR, 0.57; 95% CI, 0.39-0.84; one-sided P = .0017; two-sided P = .0035). The median OS was 26.0 and 20.0 months for capivasertib/fulvestrant and placebo, respectively (HR, 0.59; 95% CI, 0.34-1.05; two-sided P = .0071).

“FAKTION looked at the AKT inhibitor capivasertib versus placebo in combination with fulvestrant for patients with hormonally driven metastatic disease who had disease progression on an aromatase inhibitor and demonstrated an almost 6 months improvement in PFS (4.8 months to 10.3 months) and I believe showed OS benefit too. Looking forward to seeing the subgroup analyses here and toxicity profile too as we mentally place it in the ‘victory bucket’ with more positive data for the PI3K/mTOR/AKT pathway after recent positive alpelisib (Piqray) results.”

Low-fat dietary pattern and long-term breast cancer incidence and mortality: The Women’s Health Initiative randomized clinical trial (Abstract 520)

Forty US sites evaluated 48,335 postmenopausal women with no prior breast cancer and a dietary fat intake ≥32% of their total energy and randomized them to a usual diet comparison group or dietary intervention group to reduce fat intake to 20% of total energy and increase intake vegetables, fruit, and grain. This diet change led to a significantly reduction in the risk of death from breast cancer.

“[This was] a very large trial assigning over 48,000 postmenopausal healthy women with no history of breast cancers to a regular or low-fat diet intervention. They saw those in the low-fat diet group were not necessarily less likely to get breast cancer (8% but not significant), but if they did develop breast cancer [they] were significantly less likely to die of their breast cancer (HR, 0.79). This is the first randomized evidence to show that a dietary change you could make once diagnosed with breast cancer may have the power to change your outcome.”

GENITOURINARY CANCERS

Toni K. Choueiri, MD

Toni Choueiri, MD, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute;

Ziad Bakouny MD, MSc, Genitourinary Oncology Postdoctoral Research Fellow, Lank Center for Genitourinary Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute

Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial (Abstract LBA2)

In this phase III study, investigators sought to determine whether enzalutamide added to androgen deprivation therapy improves OS versus ADT with standard nonsteroidal antiandrogen therapy in this patient population. The OS findings will be unveiled during the 2019 ASCO Annual Meeting.

“A plenary session talk with highly anticipated and potentially practice-changing data to be presented in the metastatic hormone-sensitive prostate cancer (mHSPC) setting. Crucially, this landmark phase III trial evaluates the addition of enzalutamide (Xtandi) to standard of care therapy for patients with mHSPC, with a primary endpoint of OS and allowing concurrent docetaxel therapy in both arms.”

EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors (Abstract LBA4505)

Previously, the antibody-drug conjugate enfortumab vedotin was granted a breakthrough therapy designation by the FDA for the treatment of patients who had already received immune checkpoint threrapy for locally advanced or metastatic urothelial cancer. The designation was based on interim results from a phase I dose-escalation/dose-expansion trial showing an ORR of 41% (95% CI, 29.3-53.2), including 3 (4%) complete responses and 26 (37%) partial responses. Results of this late-breaker abstract will showcase new data in patients previously treated with platinum-based chemotherapy and immunotherapy.

“Patients with metastatic urothelial carcinoma who progress after platinum-based chemotherapy and immune checkpoint inhibitors have a dismal prognosis with few available systemic therapy options. After the promising results of the EV-101 phase I trial evaluating enfortumab vedotin (a cytotoxic antibody-drug conjugate), we look forward to seeing the data from cohort 1 of the phase II EV-201 trial at ASCO 2019.”

Ziad Bakouny, MD, MSC

Ziad Bakouny, MD, MSC

TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations (Abstract 5005)

The PARP inhibitor olaparib (Lynparza) was found to have antitumor activity in patients with heavily pretreated mCRPC with DNA damage repair (DDR) gene defects. The responses were most prominent in those with BRCA1/2 aberrant tumors but were also observed in patients with other DDR alterations.

“In 2015, the TOPARP-A trial had shown that most responses to olaparib in metastatic castration-resistant prostate cancers occurred in patients with pathogenic DNA damage repair (DDR) alterations but patients had not been selected by DDR gene status in that trial. In this biomarker-driven phase II trial, patients with heavily pretreated mCRPC were selected based on DDR status and treated with olaparib. Response rates as high as 80% for BRCA 1/2 alterations and 57% for PALB2 alterations were reported. This trial is a strong step towards biomarker-based treatment for patients with mCRPC.”

CALGB 90601 (Alliance): Randomized, double-blind, placebo-controlled phase III trial comparing gemcitabine and cisplatin with bevacizumab or placebo in patients with metastatic urothelial carcinoma (Abstract 4503)

Angiogenesis is thought to play a role in urothelial carcinoma development and progression, leading to the rationale for this phase III study. Patients who were enrolled had metastatic urothelial carcinoma, had no prior chemotherapy, and were >12 months from prior neoadjuvant or adjuvant chemotherapy. However, results showed that there was no improvement in OS with the addition of bevacizumab (Avastin), yet, there was a prolongation in PFS.

“The combination of gemcitabine and cisplatin (GC) is a standard treatment for cisplatin-eligible (good performance status and adequate renal function) patients with metastatic urothelial carcinoma. The addition of bevacizumab to this regimen had shown promising efficacy and tolerable toxicity in a phase II trial in this setting. In this randomized phase III trial, GC was compared with GC plus bevacizumab (GCB) for cisplatin-eligible patients with metastatic urothelial carcinoma. Patients treated with GCB had significantly better PFS (HR, 0.77; P = .0074) but not OS (HR, 0.87; P = .17) compared with GC. We look forward to seeing the full trial results to determine whether this regimen could be a viable option for patients with metastatic urothelial carcinoma.”

Atezolizumab (atezo) + bevacizumab (bev) versus sunitinib (sun) in pts with untreated metastatic renal cell carcinoma (mRCC) and sarcomatoid (sarc) histology: IMmotion151 (Abstract 4512); CheckMate 214 post-hoc analyses of nivolumab plus ipilimumab or sunitinib in IMDC intermediate/poor-risk patients with previously untreated advanced renal cell carcinoma with sarcomatoid features (4513); Efficacy of immune checkpoint inhibitors (ICI) & genomic characterization of sarcomatoid and/or rhabdoid (S/R) metastatic renal cell carcinoma (mRCC; Abstract 4514)

This group of studies to be presented in a poster discussion session during the 2019 ASCO Annual Meeting touches on the patient population with renal cell carcinoma (RCC) of sarcomatoid histology. In the IMmotion151 analysis, patients with metastatic RCC with sarcomatoid histology who received atezolizumab/bevacizumab had a longer PFS, OS, and higher ORR than those who were treated with sunitinib (Sutent), regardless of PD-L1 status.

In the posthoc analysis of the CheckMate-214 study, the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) showed promising efficacy and prolonged survival compared with sunitinib in patients with previously untreated, advanced clear cell RCC with sarcomatoid features.

Finally, a study of patients with sarcomatoid and/or rhabdoid metastatic RCC showed that this subgroup has a higher frequency of BAP1 genomic alterations and better outcomes with checkpoint inhibition compared with other therapeutic approaches.

“Sarcomatoid renal cell carcinoma is a differentiated and highly aggressive form of kidney cancer that has thus far had few effective systemic therapy options available. We eagerly await this poster discussion session, which reviews very promising clinical trial data and real-world evidence of efficacy of immune checkpoint inhibitors and its molecular correlates in this subgroup of patients.”

Addeo Alfredo, MD

Alfredo Addeo, MD

Alfredo Addeo, MD, consultant medical oncologist, University Hospital of Geneva, Switzerland

Phase III randomized trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C; Abstract 9001)

This phase III trial evaluated the combination of pemetrexed/carboplatin chemotherapy and gefitinib (Iressa) in treatment-naïve patients with EGFR-mutant non—small cell lung cancer (NSCLC). Findings showed that the combination did significantly prolong PFS and OS; however, there was an increase in toxicity—clinically relevant grade ≥3 adverse events occurred in 51% of patients on the combination compared with 25% of those on gefitinib alone.

“This is one more study confirming the superiority of chemotherapy plus a first-generation TKI compared to a first-generation TKI alone. There was an impressive hazard ratio of 0.45 for OS at cost of increased toxicity. In countries where osimertinib (Tagrisso) is not available, the combination, in fit patients, could really represent a valid alternative to a single first-generation TKI.”

RELAY: A multinational, double-blind, randomized Phase 3 study of erlotinib (ERL) in combination with ramucirumab (RAM) or placebo (PL) in previously untreated patients with epidermal growth factor receptor mutation-positive (EGFRm) metastatic non-small cell lung cancer (NSCLC; Abstract 9000)

Patients with treatment-naïve EGFR-mutant NSCLC were randomized to receive erlotinib (Tarceva) and ramucirumab (Cyramza) or erlotinib/placebo in the phase III RELAY trial. Data showed that the combination demonstrated improved PFS at 19.4 months compared with 12.4 months in the erlotinib/placebo arm (HR, 0.591; 95% CI, 0.461-0.760; P <.0001). Moreover, safety was consistent with the established safety profiles of the individual compounds.

“This study strengthens further the benefit of combining an anti-VEGFR to an anti-EGFR inhibitor. The PFS is considerably high at 19.4 months, which is numerical in line with the FLAURA data. Is it time to explore osimertinib with an anti-VEGFR in the first-line setting? I’d say yes. We are going to see soon the data coming out of the BOOSTER-ETOP study where osimertinib was used in the second-line setting of patients with T790M mutations versus osimertinib plus bevacizumab. A positive endpoint would further push for trying this combination in the first-line setting.”

ECOG-ACRIN 5508: Pemetrexed, bevacizumab or the combination as maintenance therapy for advanced non-squamous NSCLC (Abstract 9002)

Here, patients with advanced nonsquamous NSCLC who received no prior systemic therapy were treated with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to 4 cycles. Then, they were randomized 1:1:1 to maintenance therapy with bevacizumab, pemetrexed, or the combination of both agents every 3 weeks until disease progression. However, results did not demonstrate a survival benefit with the combined agents compared with each drug alone.

“This is a maintenance study that showed no point in giving both bevacizumab and pemetrexed after carboplatin/paclitaxel/bevacizumab in nonsquamous NSCLC. Either single-agent pemetrexed or bevacizumab can be considered as optimal treatment. Interestingly, this abstract pairs up well with the SAKK 19/09 nonrandomized cohort study, which already showed the lack of OS benefit with the combination of pemetrexed and bevacizumab as maintenance therapy.”

Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study (Abstract 9004)

In updated efficacy results of the GEOMETRY mono-1 study, the highly potent and selective MET inhibitor capmatinib was evaluated in patients with MET exon 14 skipping mutations. Regardless of line of therapy capmatinib was given, the capmatinib was associated with deep and durable responses.

“MET mutations causing exon 14 skipping produce c-MET receptors lacking a negative regulatory site, with the result that MET exon 14 skipping mutations are oncogenic drivers. Three percent to 4% of NSCLCs harbor MET exon 14 skipping mutations; these tumors appear to be sensitive to c-MET inhibition. Hence, this study with capmatinib showed good activity within the different cohorts (MET exon 14 skipping—mutated or –amplified) and promising duration of response. I personally feel we are going to see this drug moving quickly throughout clinical trial development and reaching clinical practice very soon. We have and know the target; the drug is effective and tolerable, so it is a no-brainer.”

Phase II study of tepotinib in NSCLC patients with METex14 mutations (Abstract 9005)

The ongoing single-arm phase II study (NCT02864992) of tepotinib evaluated the agent in patients with advanced EGFR or ALK wild-type NSCLC. At the data cut-off of October 16, 2018, in patients who had a tumor biopsy or liquid biopsy, promising responses were observed alongside a favorable safety profile.

“MET exon 14 skipping mutations—reported in 3% to 4% of NSCLC patients&mdash;can be conveniently detected using liquid biopsy. In this study, the authors reported the results from a phase II study of tepotinib in NSCLC patients with MET exon 14 skipping mutations identified by liquid biopsy or tumor biopsy. Again, the c-MET inhibitor showed excellent and durable activity in both cases with a good safety profile. It looks like the options for treating patients with MET exon 14 skipping mutations patients is rapidly increasing, which is a very good news for patients and the scientific community.”

Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: Results from KEYNOTE-001 (Abstract LBA9015).

The initial results from KEYNOTE-001 were the basis for the FDA’s accelerated approval to pembrolizumab (Keytruda) as a treatment for patients with pretreated PD-L1—positive NSCLC, regardless of histology. In KEYNOTE-001, the ORR was 41% in a subgroup of 61 patients with pretreated PD-L1&shy;–positive advanced NSCLC. At the 2019 ASCO Annual Meeting, 5-year OS data from the pivotal study will be presented.

“Unfortunately, no data are available yet, but the poster discussion is on Sunday. I am quite confident the 5-year OS is going to be quite positive: I’d say 18%—let’s see.”

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