Oncology Experts Review Key Updates from the 2019 ASCO Annual Meeting

In a Twitter poll,Targeted Oncology followers shared their thoughts on where the most exciting data came from this year; many experts were in unison that lung cancer saw the most important updates this year, while data in breast and gastrointestinal (GI) cancers also demonstrated significance.

ASCO POLL: In what area do you think the most important data came from at the 2019@ASCOAnnual Meeting? Tell us in the comments what your favorite#ASCO19abstracts were and tag colleagues to hear their opinions, too!

— Targeted Oncology (@TargetedOnc)June 4, 2019

“In recent years, immunotherapy has been the focus of major developments for lung cancer at ASCO,” said Joshua Bauml, MD, assistant professor of medicine at the University of Pennsylvania. “This year, we saw major steps forward in the area of targeted therapy.”

Overall, many abstracts were presented with practice-changing data across various fields. Data from targeted therapies, immunotherapies, and PARP inhibitors stood out amongst the physicians in attendance.

"The theme of ASCO19 was ‘Caring For Every Patient, Learning From Every Patient," and I truly believe the meeting lived up to President Monica Bertagnolli," vision for the conference,” said Mark A. Lewis, MD, of Intermountain Healthcare. "There was progressive dialogue about what endpoints truly matter to patients and whether we have allowed perceived improvements in surrogate markers to unfairly represent true benefits in the length [of time] and quality [of life] of our patients."

The plenary session for the phase III POLO trial, in particular, stood out to many physicians, marking major advances for a patient population that has remained a clinical unmet need for some time.

"The POLO study in pancreatic adenocarcinoma ignited debate about the meaning of progression-free survival (PFS) versus overall survival (OS), again in terms of the ultimate endpoints of longevity and quality of life (QoL)," said Lewis. "I think the trial surfaced a small subset of patients with defects in DNA repair damage pathways on whom the effects of PARP inhibition can be more rigorously studied. The presentation also dovetailed beautifully with the recent NCCN recommendation that all patients with pancreatic adenocarcinoma should undergo BRCA testing."

Targeted Oncologyspoke with experts in attendance at the 2019 ASCO Annual Meeting to review what they believed were some of the biggest takeaways from this year's presentation across the fields of lung cancer, breast cancer, GI cancers, genitourinary (GU) cancers, melanoma, and multiple myeloma.

Lung Cancer

“ASCO 2019 produced some exciting targeted therapy signals for non—small cell lung cancer (NSCLC), including promising data in cancers withMETmutations,EGFRexon 20 insertions,RETfusions, and early data for targetingKRASG12C mutations,” said Geoffrey R. Oxnard, MD, a medical oncologist at the Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School. “We also saw encouraging data from a whole new group of antibody-based therapies targetingEGFR,ERBB3, andTROP2.”

First-in-Class Inhibitor Induced Responses inKRASG12C+ NSCLC

In a phase I study presented at the meeting, half of patients withKRASG12C—positive advanced NSCLC treated with the investigationalKRASG12C inhibitor AMG 510 achieved a response.

“Perhaps the most exciting was the first data presented on AMG 510, a small molecule inhibitor ofKRASG12C,” said Bauml. “For decades, we have tried to find a drug that can successfully targetKRAS. AMG 510 led to responses in 50% of patients withKRASG12C—mutant NSCLC and had a very favorable [adverse] effect profile. I am very excited for the next steps with this compound.”

Among the 10 evaluable patients with NSCLC, 5 had a partial response (PR) with 4 confirmed PRs. There are currently no approved targeted agents forKRASG12C, which, according to study authors, is found in 13% of lung cancers.

Two New Targeted Therapies Appear Encouraging for Difficult Drivers in NSCLC

Two newer targeted therapies in development showed encouraging activity as potential treatments for hard-to-target driver alterations, including theEGFRexon 20 insertions andRETrearrangements. Christine M. Lovly, MD, PhD, explained during the meeting that these 2 targets are not easy to build drugs against.

In patients with NSCLC harboringEGFRexon 20 insertions, TAK-788 demonstrated a confirmed objective response rate (ORR) of 43% (95% CI, 24%-63%) and a disease control rate (DCR) of 86% (95% CI, 67%-96%). Meanwhile, BLU-667 also demonstrated an ORR of 58% (95% CI, 43%-72%) for patients withRETfusion—positive advanced NSCLC, with a DCR of 96% (95% CI, 86%-99%).

Breast Cancer

Improved OS Observed in HR+, HER2- Advanced Breast Cancer With Ribociclib Plus ET

According to findings from the phase III MONALEESA-7 trial, both peri- and premenopausal women with hormone receptor (HR)—positive HER2-negative advanced breast cancer demonstrated an estimated OS rate at 42 months of 70.2% when treated with ribociclib (Kisqali) plus endocrine therapy compared with 46.0% for placebo and endocrine therapy.

“Adding ribociclib, a CDK4/6 inhibitor, to endocrine therapy and ovarian suppression in pre-menopausal hormone receptor—positive metastatic breast cancer resulted in a 29% relative reduction in risk of death. It is very exciting to see OS data emerging from the practice-changing CDK4/6 data,” said Stephanie Graff, MD, associate director of breast cancer research at Sarah Cannon Research Institute.

In addition, Erika P. Hamilton, MD, director of breast cancer research at Sarah Cannon Research Institutesaid, “With OS now seen in the first-line setting with the addition of CDK4/6, and with endocrine therapy in combination with CDK4/6 showing a 6 month improvement in PFS when compared to chemotherapy (capecitabine) in Young-PEARL, I hope these results can be used to ensure that women receive access to CDK4/6 inhibitors up front and their use is not delayed to the second-line setting where it is also approved.”

PFS Rate in ER+ Breast Cancer Doubled With Capivasertib Plus Fulvestrant

In findings from the placebo-controlled phase II FAKTION trial, the addition of capivasertib, an AKT inhibitor, to fulvestrant demonstrated a more than doubling in PFS in patients with endocrine receptor—positive advanced breast cancer compared to the fulvestrant alone arm.

“FAKTION tested the addition of capivasertib to fulvestrant for women with hormonally driven metastatic breast cancer,” Hamilton toldTargeted Oncology.“The addition of this AKT inhibitor led to an improvement in PFS of almost 6 months (4.8 vs 10.3 months), and although not statistically significant with aPof 0.07, a trend to improved survival as well.”

“This leads to the growing body of evidence that inhibiting the PI3K/mTOR/AKT pathway in breast cancer translates to improved outcome. What I think is particularly fascinating about this abstract is that women received benefit regardless of whether they were one of the 40% that had activation in this pathway or not. This is in contrast to the body of data we have for PI3K inhibitors (such as the recently approved alpelisib [Piqray]) and underscores the importance of biomarker endpoints in trials and continued blood and tissue collection for such assays,” Hamiltonconcluded.

Patient-reported outcomes (PROs) from the phase III IMpassion130 trial of atezolizumab (atezo) plus nabpaclitaxel (nP) in metastatic triple-negative breast cancer (mTNBC). Abstract #1067

“In IMpassion130, investigators looked at the addition of atezolizumab (Tecentriq) to nab-paclitaxel (Abraxane) in first-line metastatic triple-negative breast cancer (TNBC),” said Graff. “At ASCO 2019 we received the OS update with improvement from 18 months to 25 months in persons with PD-L1—expressing TNBC, supporting the prior FDA accelerated approval. This is a clear standard-of-care option for correctly identified patients.”

“Women eligible for atezolizumab can be identified currently through the use of the SP142 assay that is done in ~12 labs throughout the United States,” Hamilton added. “Any expression in tumor immune cells qualify women to receive this drug.”

GI Cancers

PFS Increased With Olaparib as Maintenance Therapy forBRCA+ Metastatic Pancreatic Cancer

“With a GI cancer study in the plenary, it’s hard to avoid discussing it. The POLO randomized, controlled trial compared maintenance olaparib (Lynparza)versus placebo in patients with a germline BRCA1orBRCA2mutation and metastatic pancreatic cancer who initially received first-line, platinum-based chemotherapy,” said Syed Yousuf Zafar, MD, MHS, an associate professor of medicine, public policy, and population health sciences at Duke Cancer Institute.

The randomized, double-blind, placebo-controlled phase III POLO trial demonstrated that the PARP inhibitor olaparib led to significantly improved PFS in patients with germlineBRCA-mutated metastatic pancreatic cancer versus placebo.

“While OS data were not yet mature, PFS was significantly longer in the olaparib arm (7.4 months vs 3.8 months). This study is the first biomarker-driven study in pancreatic cancer,” said Zafar. “While it is ultimately useful only for the very small proportion of pancreatic cancer patients with a germlineBRCA1orBRCA2mutation, the median duration of response (DOR) for those patients who received olaparib was about 25 months versus about 4 months for placebo.”

Prospective pooled analysis of four randomized trials investigating duration of adjuvant (adj) oxaliplatin-based therapy (3 vs 6 months {m}) for patients (pts) with high-risk stage II colorectal cancer (CC). Abstract #3501

In this prospective, pre-planned pooled analysis, data from patients with high-risk stage II colorectal cancer in 4 concurrently conducted randomized phase III trials were analyzed for an interaction between duration and regimen.

“In colorectal cancer, further analysis from the IDEA trials was presented, specifically regarding data in stage II colon cancer. Iveson et al looked at 3 versus 6 months of adjuvant chemotherapy for patients with high-risk stage II colorectal cancer,” said Zafar. “Patients received investigator’s choice of FOLFOX or CAPOX but were randomized to duration of therapy.”

“Similar to the stage III data, this study suggested non-inferiority for 3 months versus 6 months of CAPOX, but inferiority of 3 months versus 6 months of FOLFOX,” added Zafar. “CAPOX for 3 months is likely sufficient for these patients, but I would avoid 3 months of FOLFOX. An important point to consider is that high-risk stage II disease might be too broad a category and might be a different entity than stage III disease.”

GU Cancers

Survival Is Improved in Metastatic Castration-Sensitive Prostate Cancer With Apalutamide

In topline results from the phase III TITAN trial, patients with metastatic castration-resistant prostate cancer showed an increased rate of OS at 2 years when treated with apalutamide (Erleada) plus androgen deprivation therapy (ADT) versus ADT alone (82.4% vs 73.5%;P= .005).

&ldquo;TITAN showed that the combination of apalutamide (a second-generation non-steroidal anti-androgen) and ADT improved radiographic PFS (HR, 0.48; 95% CI, 0.39-0.60;P<.0001) and OS (HR, 0.67; 95% CI, 0.51-0.89;P= .0053) compared to ADT alone. The benefit was consistent across treatment subgroups, most importantly the benefit seemed to be the same regardless of volume of disease and prior docetaxel use,&rdquo; said Toni Choueiri, MD, and Zaid El Bakouny, MD, MSc, both of Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, in a joint statement.

Survival Improved at 3 Years With Enzalutamide Versus Other Anti-Androgens in mHSPC

According to interim results from the phase III ENZAMET trial, survival was increased in patients with metastatic hormone-sensitive prostate cancer (mHSPC) who were treated with enzalutamide (Xtandi) plus standard of care compared to those treated with other non-steroidal anti-androgens plus standard of care.

&ldquo;The long-awaited ENZAMET trial results was the biggest event within the genitourinary oncology space at ASCO 2019 and was presented as a plenary session talk,&rdquo; said Choueiri and El Bakouny. &ldquo;The trial showed that the combination of enzalutamide and ADT improved both clinical PFS (HR, 0.40; 95% CI, 0.33-0.49;P<.001) and OS (HR, 0.67; 95% CI, 0.52-0.86;P= .002) compared to standard non-steroidal anti-androgens (bicalutamide, nilutamide, or dlutamide) and ADT, including in both low- and high-volume disease patients.

&ldquo;Overall, TITAN and ENZAMET are practice-changing phase III randomized, controlled trials which both suggest that the addition of more potent androgen-targeted therapies improves outcomes in patients with mHSPC in both low- and high volume-disease patients,&rdquo; concluded Choueiri and El Bakouny. &ldquo;The role of concurrent docetaxel with apalutamide and enzalutamide needs to be further investigated given the potential for less benefit and more toxicity with such a combination.&rdquo;

Enfortumab Vedotin Achieves Responses in Advanced Urothelial Carcinoma

&ldquo;Enfortumab vedotin (EV), an antibody—drug conjugate targeting Nectin-4, showed very strong data in this phase II trial (EV-201) of patients with advanced urothelial carcinoma,&rdquo; said Choueiri and El Bakouny.&nbsp;&ldquo;This presentation reported the results from cohort 1, the subgroup of patients who had been treated by both platinum-based chemotherapy and immune checkpoint inhibitors, for whom few therapeutic options are currently available.&rdquo;

According to the results from the phase II EV-201 trial, 44% of patients with locally advanced or metastatic urothelial cancer achieved a response with EV. This includes 12% of patients who reached a complete response (CR).

&ldquo;The responses were relatively durable with a median DOR of 7.6 months, median PFS of 5.8 months, and OS of 11.7 months,&rdquo; said Choueiri and El Bakouny.&ldquo;These are the most exciting results for advanced urothelial carcinoma presented at this ASCO meeting and this agent is currently being investigated in other settings, including combinations and cisplatin-ineligible immune checkpoint-treated patients.&rdquo;

Gynecologic Oncology

PFS Prolonged With Olaparib in Patients WithBRCA+ Ovarian Cancer

The PARP inhibitor olaparib reduced the risk of disease progression or death by 38% in patients with platinum-sensitive, relapsed, germlineBRCA1/2-mutant ovarian cancer who were previously treated with &ge;2 prior lines of chemotherapy in the phase III SOLO3 trial.

Compared to chemotherapy, olaparib led to a PFS of 13.4 months versus 9.2 months. By independent review, the ORR was 72% with the PARP inhibitor compared with 51% with chemotherapy. The CR and PR rates were 9% versus 3% and 63% versus 49% with olaparib versus chemotherapy, respectively.

&ldquo;It is reassuring to see the early results for olaparib inBRCA-mutant ovarian cancer confirmed in a large phase III trial. This treatment has become part of our typical practice in the treatment of women with relapsed ovarian cancer,&rdquo; said Shannon Westin, MD, an associate professor at The University of Texas MD Anderson Cancer Center.

Chemo-Free Doublet Significantly Improved PFS in Recurrent Ovarian Cancer

Based on results from the randomized ENGOT-OV24 trial, the combination of PARP inhibitor niraparib (Zejula) plus bevacizumab (Avastin) led to a significant increase in PFS versus with niraparib alone in patients with platinum-sensitive recurrent ovarian cancer.

&ldquo;We have seen the activity of PARP inhibition and anti-angiogenics in other trials,&rdquo; Westin said. &ldquo;This was a nice confirmation that there is a clear benefit to the addition of an anti-angiogenic to PARP, especially in those patients who do not harbor aBRCAmutation in their tumor.&rdquo;

Patients who received the combination therapy has a median PFS of 11.9 months versus 5.5 months in those who received niraparib alone. In addition, there was a similar benefit from the combination treatment in patients who had previously received a platinum-free interval (PFI) of 6 to 12 months (11.3 vs 2.2 months;P= .0006), or >12 months (13.1 vs 6.1 months,P= .0062).

Mansoor Mirza, MD, lead author, chief oncologist in the Department of Oncology at Copenhagen University Hospital, alsospoke to the findings from this trial in an interview withTargeted Oncology.

Melanoma

RFS Increased With Neoadjuvant T-VEC Therapy in Advanced Melanoma

According to findings from a randomized trial, neoadjuvant talimogene laherparepvec (T-VEC; Imlygic), an oncolytic immunotherapeutic, led to a significant improvement in the 1-year recurrence-free survival rate compared to surgery alone (33.5% vs 21.9%;P= .048) in patients with resectable advanced melanoma.

&ldquo;Neoadjuvant immunotherapy resulting in pathologic CR demonstrates an impressive survival benefit compared to neoadjuvant targeted therapy resulting in pathologic CR,&rdquo; said Sapna P. Patel, BA, MD, associate professor of melanoma medical oncology at The University of Texas MD Anderson Cancer Center. &ldquo;These results are intriguing and need further investigation as to the mechanism of pathological CR durability, or lack thereof, with various neoadjuvant approaches.&rdquo;

Pathological response and survival with neoadjuvant therapy in melanoma: A pooled analysis from the International Neoadjuvant Melanoma Consortium (INMC). Abtract #9503

In a pooled analysis, neoadjuvant immunotherapy and targeted therapy regimens were active in patients with resectable stage III melanoma and were associated with high pathological CR rates. This correlated with improved relapse-free survival.

&ldquo;Adjuvant ipilimumab at 3 mg/kg is superior to adjuvant high-dose interferon in overall survival,&rdquo; said Patel. &ldquo;Although the field has moved onto adjuvant anti—PD-1 therapy, adjuvant ipilimumab with 3 mg/kg may represent an option for local recurrences after adjuvant anti-PD-1 failure.&rdquo;

Multiple Myeloma

Risk of Progression Reduced With Isatuximab Triplet in Phase III Multiple Myeloma Trial

According to data from the phase III ICARIA-MM trial, PFS was significantly improved with the triplet regimen of isatuximab, pomalidomide (Pomalyst), plus low-dose dexamethasone in patients with relapsed/refractory multiple myeloma compared to pomalidomide with dexamethasone alone.

&ldquo;Isatuximab is an anti-CD38 monoclonal antibody not too dissimilar from daratumumab (Darzalex),&rdquo; said Jesus Berdeja, director of Myeloma Research at the Sarah Cannon Research Institute. &ldquo;The triplet arm had a near doubling of both ORR and PFS from 35.3% to 60.4% and 6.47 to 11.53 months, respectively. This is the first randomized trial of a pomalidomide/dexamethasone plus an anti-CD38 antibody and may lead to the FDA approval of isatuximab in this combination.&rdquo;

A Subcutaneous Daratumumab Found Noninferior to IV Formulation in Multiple Myeloma

In the phase III COLUMBA trial, a subcutaneous formulation of daratumumab showed similar efficacy to the original intravenous formulation of daratumumab (Darzalex) in patients with relapsed/refractory multiple myeloma. There was also a reduction in the treatment burden with the subcutaneous flat dose.

&ldquo;This study showed that the subcutaneous route of administration was not inferior to intravenous and greatly reduced administration time from as much as 7 hours to 5 minutes,&rdquo; said Berdeja. &ldquo;This should have significant impact for clinic staff and, ultimately, improvement in patients&rsquo; QoL.&rdquo;

Overall, Berdeja concluded, &ldquo;ASCO 2019 provided very interesting, practice-changing data that spanned the entire spectrum of multiple myeloma from smoldering to relapsed/refractory.&rdquo;

Other Areas

Racial Disparities in Cancer Care Access Reduced With Medicaid Expansion

&ldquo;The plenary session by Dr Blythe Adamson highlighting improvement in racial disparity with Affordable Care Act Medicaid expanded access shows that effective health policy can be as impactful as any drug,&rdquo; said Graff.

This analysis demonstrated that Medicaid was associated with a 6.1 percentage point improvement in timely access to cancer care treatment for African American patients compared to 2.1 in white patients. Prior to the Medicaid expansion, African American patients were 4.9 percentage points less likely to receive treatment within the first 30 days of diagnosis of an advanced cancer. By identifying such issues, physicians hope to then be able to identify solutions as well.

See more fromthe 2019 ASCO Annual Meeting.