June 2019 Edition Vol.11, Issue 6

A Multimedia Review of ASCO ’19 Highlights

At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, OBR spoke with experts about the top studies at ASCO, and featured here are their insights and commentary. Scroll down or use these the links provided here:

Breast Cancer  |  GI Cancer  |  Lung Cancer  |  Pancreatic Cancer  |  Prostate Cancer
Renal Cell Carcinoma  |  Multiple Myeloma  |  Chronic Lymphocytic Leukemia

 

Breast Cancer


MONALEESA-7

The addition of ribociclib to frontline endocrine therapy not only improved progression-free survival for premenopausal women with advanced hormone receptor-positive/HER2-negative breast cancer but also significantly extended overall survival—reducing the risk of death by nearly 30%—according to data from the phase III MONALEESA-7 trial (abstract LBA1008).

The currently available CDK inhibitors—ribociclib, palbociclib, and abemaciclib—have consistently shown similar improvements in progression-free survival but a statistically significant survival gain among premenopausal women has not been seen until now.

“For the first time—for all the CDK inhibitor trials—we are seeing a survival benefit,” said Debu Tripathy, MD, Professor and Chair, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, during a video interview with OBR.  “We can say pretty confidently that ribociclib does extend survival in premenopausal patients.”

“This was the only randomized phase III trial that has specifically been done to address the benefits of adding a CDK 4/6 inhibitor to premenopausal women,” said Sara M. Tolaney, MD, MPH, Associate Director, Susan F. Smith Center for Women’s Cancers, Director, Clinical Trials, Breast Oncology, Senior Physician, Assistant Professor of Medicine, Harvard Medical School, during a video interview with OBR.

 

View Dr. Tripathy’s expert commentary on MONALEESA-7 in the OBR Video Center

View Dr. Tolaney’s expert commentary on MONALEESA-7 in the OBR Video Center

SOPHIA

In previously treated patients with HER2-positive metastatic breast cancer, margetuximab plus chemotherapy provided a modest, statistically significant improvement in median progression-free survival (PFS) compared with trastuzumab plus chemotherapy, according to a primary analysis of the phase III SOPHIA trial (abstract 1000). A second interim overall survival analysis is anticipated for late 2019.

“The difference [in PFS] between the two arms was only about a month, but what they did find was that there is even greater benefit within a particular genotype of CD16A,” said Sara M. Tolaney, MD, MPH, Associate Director, Susan F. Smith Center for Women’s Cancers, Director, Clinical Trials, Breast Oncology, Senior Physician, Assistant Professor of Medicine, Harvard Medical School, during a video interview with OBR.

Margetuximab differs from trastuzumab in that the Fc portion of the antibody is engineered to have higher affinity for the activating Fc receptor allele CD16A and lower affinity for the inhibitory Fc receptor allele CD32B. In a planned exploratory analysis, patients on the margetuximab arm who were carriers for an CD16A F allele had a nearly two-month gain in PFS compared with those on the trastuzumab arm (6.9 vs 5.1 months; HR=0.68; P=0.005), making the SOPHIA trial the first prospective analysis to identify a CD16A genotype as a predictor of anti-HER2 therapy efficacy.

“I do think it does suggest that there may be ways to better enhance the way these monoclonal antibodies work against anti-HER2,” said Dr. Tolaney.

View Dr. Tolaney’s expert commentary on SOPHIA in the OBR Video Center

 

IMpassion130

A second interim survival analysis of IMpassion130 showed that patients with advanced triple-negative breast cancer (TNBC) indeed survived longer with frontline atezolizumab plus nab-paclitaxel compared with nab-paclitaxel alone, especially those with PD-L1–positive disease (abstract 1003). Earlier this year in March, the FDA granted an accelerated approval for atezolizumab plus nab-paclitaxel, making it the first immunotherapy combination approved for breast cancer.

“The results of the IMpassion130 trial have been monumental for triple-negative breast cancer patients,” said Debra Patt, MD, MPH, MBA, Executive Vice President, Policy, Academic Programs, Strategic Initiatives, Texas Oncology, during a video interview with OBR. “The addition of atezolizumab to nap-paclitaxel gave a substantial overall survival advantage, that we weren’t really anticipating, and is the first real evidence of survival benefit of immunotherapy in patients with advanced breast cancer.”

View Dr. Patt’s expert commentary on IMpassion130 in the OBR Video Center

Listen to Dr. Denduluri’s expert commentary on IMpassion130 in this OBR PeerSpectives podcast

 

Gastrointestinal Cancer


High Level View

“I don’t think there are practice-changing studies in colorectal cancer being presented this year,” Leonard Saltz, MD, Executive Director for Clinical Value & Sustainability, Head, Colorectal Oncology Section, Memorial Sloan Kettering Cancer Center, during a video interview with OBR.

“I think we’re seeing some revalidation of some of the thoughts that we’ve had, and we’re seeing some indications of what might be coming in the future,” Dr. Saltz said. “But I would caution that a lot of time we get excited about something before the data arrive and then when we see the data, it’s not quite what we hoped it would be.”

View Dr. Saltz’s expert commentary on GI Cancer in the OBR Video Center

 

AMG 510

The results of a phase I trial with KRAS inhibitor AMG 510 suggest that KRAS, which has long been deemed untargetable, may actually be targetable (abstract 3003). The trial showed that AMG 510 had anti-tumor activity for most patients with advanced solid tumors harboring a KRASG12C mutation. This included 13 of 18 patients with colorectal cancer who achieved stable disease.

“KRASG12C has a specific configuration that allows it to be inhibited with a small molecule,” said Marwan G. Fakih, MD, Fakih, Medical Director, Judy & Bernard Briskin Center for Clinical Research, Co-Director, Gastrointestinal Cancer Program, Section Head, GI Medical Oncology, City of Hope, during a video interview with OBR. Dr. Fakih was an investigator on the trial.

Dr. Fakih explained that AMG 510 has been specifically designed to bind to the cysteine moiety on KRASG12C, and when it binds to cysteine in KRASG12C, it locks KRAS in a GDP-bound state, preventing KRAS activation.

View Dr. Fakih’s expert commentary on
AMG 510 in the OBR Video Center

 

KEYNOTE-062

The phase III KEYNOTE-062 trial hit its primary endpoint, showing that pembrolizumab monotherapy is noninferior to chemotherapy in the first-line setting for patients with PD-L1−positive, HER2-negative, advanced gastric or gastroesophageal junction (G/GEJ) cancer (abstract LBA4007). Pembrolizumab was granted an accelerated approval in 2017 for patients with recurrent locally advanced or metastatic, G/GEJ cancer that expresses PD-L1.

A survival benefit with pembrolizumab was also seen in patients with tumors that had high PD-L1 expression (defined as a combined positive score of at least 10), and overall pembrolizumab monotherapy had a better safety profile with fewer treatment-related adverse events overall and grade 3 or higher adverse events than chemotherapy.

“Pembrolizumab is a comparable option to chemotherapy in this setting,” said Josep Tabernero, MD, PhD, Head of Medical Oncology, Vall d’Hebron Barcelona Hospital Campus, Director, Vall d’Hebron Institute of Oncology (VHIO), during a video interview with OBR. Dr. Tabernero was the lead study author.

View Dr. Tabernero’s expert commentary on KEYNOTE-062 in the OBR Video Center

Listen to Dr. Hochster’s expert commentary on KEYNOTE-062 in this OBR PeerSpectives podcast

 

 

Ongoing Trials in HCC

Immunotherapy has moved into the hepatocellular carcinoma space, with pembrolizumab and nivolumab earning accelerated approvals in 2018 for second-line treatment. Pembrolizumab, however, failed in the confirmatory phase III KEYNOTE-240 trial and its approval status has not changed, and the field still awaits the results from the confirmatory phase III CheckMate 459 trial.

“Now, there’s a lot of efforts ongoing with combining different IO agents, whether dual blockade of CTLA-4 and PD-L1, or combining IO agents with other TKIs,” said Imane El Dika, MD, Assistant Attending Physician, Memorial Sloan Kettering Cancer Center, during a video interview with OBR. For example, ipilimumab plus nivolumab (CheckMate 040) and atezolizumab plus bevacizumab (IMbrace150) are each being evaluated in the upfront setting.

Cabozantinib, which earned FDA approval earlier this year as a second-line therapy on the basis of the phase III CELESTIAL trial results, is currently being evaluated in the first-line setting in combination with atezolizumab in the phase III COSMIC-312 trial.

“There is the potential for synergy with these tyrosine kinase inhibitors with immune checkpoint inhibitors [in COSMIC-312],” said Daneng Li, MD, Assistant Clinical Professor, Department of Medical Oncology & Therapeutics Research, Liver Program Disease Team Lead, City of Hope, during a video interview with OBR. “It makes a lot of sense from preclinical modeling to combine these agents.”

View Dr. Dika’s expert commentary on HCC in the OBR Video Center

View Dr. Li’s expert commentary on HCC in the OBR Video Center

 

Lung Cancer


High Level View

Immunotherapy tends to steal the show, but this year all eyes were on targeted therapies and the progress they are making for patients with lung cancer.

“I think ASCO 2019, specifically in thoracic oncology, has shown a variety of targeted therapies that really target nuanced interactions–they’re really targeting the un-targetable,” said Sandip Patel, MD, Assistant Professor of Medicine, Deputy Director, San Diego Center for Precision Immunotherapy, Co-Leader, Experimental Therapeutics (Phase 1), UC San Diego Moores Cancer Center, during a video interview with OBR.

For example, TAK-788 demonstrated activity in non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertions (abstract 9007). Also, BLU-667 showed activity in advanced NSCLC patients that were RET-fusion positive (abstract 9008) and AMG 510 had activity in KRASG12C mutant lung cancer (abstract 3003).

“Really this has been a meeting in which we’ve discussed new targeted therapies for patients with very precise driver mutation oncogenes, and a little less about immunotherapy than we’re used to seeing in most meetings,” said Dr. Patel.

View Dr. Patel’s expert commentary on Lung Cancer in the OBR Video Center

 

RELAY

Patients with EGFR-mutated metastatic non-small cell lung cancer who received the VEGF inhibitor ramucirumab plus erlotinib in the first-line setting had a considerable progression-free survival (PFS) gain compared with placebo plus erlotinib, the phase III RELAY trial showed (abstract 9000).

However, the results do not necessarily change practice because in the United States erlotinib is no longer the standard of care for this patient population, osimertinib is. In addition, the PFS seen in the trial for ramucirumab plus erlotinib is similar to what’s been seen for osimertinib alone.

“It’s not clear whether that information will lead to any sort of practice changes,” said Pasi A. Jänne, MD, PhD, Lowe Center for Thoracic Oncology, Director, Belfer Center for Applied Cancer Science, Senior Physician, Professor of Medicine, Harvard Medical School, during a video interview with OBR. “However, it clearly begs for the question, what now happens if you add ramucirumab to osimertinib? Could you now have a really long initial PFS with that combination?”

“I think that’s the next step that needs to happen,” he said.

View Dr. Janne’s expert commentary on RELAY in the OBR Video Center

 

KEYNOTE-001

According to long-term data from the phase Ib KEYNOTE-001 trial, pembrolizumab has improved the historically dismal 5-year survival rate for advanced non-small cell lung cancer patients (NSCLC), showing the immunotherapy can provide durable, lasting responses (abstract LBA9015).

The 5-year survival for the overall population was 18%, with the highest 5-year survival rate—nearly 30%–for treatment-naïve patients with a PD-L1 tumor proportion score of 50% or greater. By comparison, the 5-year survival rate for advanced NSCLC patients has historically been 5.5%.

“We really have changed what the outcome is in some level—we as a lung cancer community—for patients with advanced non-small cell lung cancer,” said Edward B. Garon, MD, Associate Professor of Medicine, Department of Medicine, Division of Hematology/Oncology, Jonsson Comprehensive Cancer Center, Geffen School of Medicine, University of California, Los Angeles, during an interview with OBR. Dr. Garon was lead author on the study.

View Dr. Garon’s expert commentary on KEYNOTE-001 in the OBR Video Center

Listen to Dr. Garon’s expert commentary on KEYNOTE-001 in this OBR PeerSpectives podcast

 

Pancreatic Cancer


POLO

Maintenance therapy with olaparib, a PARP inhibitor, after first-line, platinum-based chemotherapy significantly extended progression-free survival (PFS) for metastatic pancreatic cancer patients with a germline BRCA1 or BRCA2 mutation on the phase 3 POLO trial (abstract LBA4). The POLO trial is the first trial to successfully show that a biomarker can guide treatment in patients with pancreatic cancer.

“I think it’s already a practice-changing study with respect to that small slice of patients,” said Thomas A. Abrams, MD, Senior Physician, Assistant Professor of Medicine, Harvard Medical School, during a video interview with OBR. An estimated 5% to 10% of pancreatic cancer patients have a BRCA1 or BRCA2 germline mutation.

“For the practicing clinician, the key point here is that any newly diagnosed patient with pancreatic cancer should undergo genetic testing, looking for BRCA 1 and 2 in addition to others,” said Philip Philip, MD, PhD, FRCP, Professor of Oncology, Wayne State University School of Medicine, Clinical Professor of Oncology, Barbara Ann Karmanos Cancer Institute, during a video interview with OBR. “In fact the NCCN guidelines have been amended recently saying that any newly diagnosed pancreatic cancer patient—could be stage I or could be stage IV—has to undergo genetic testing.”

View Dr. Abram’s expert commentary on POLO in the OBR Video Center

View Dr. Philip’s expert commentary on POLO in the OBR Video Center

Listen to Dr. Chung’s expert commentary on POLO in this OBR PeerSpectives podcast

 

APACT

The phase III APACT trial did not meet its primary endpoint, failing to show an improved radiologic disease-free survival (DFS) via central review for patients with surgically resected pancreatic adenocarcinoma who received nab-paclitaxel plus gemcitabine compared to gemcitabine alone (abstract 4000).

However, the interpretation of the trial is not as clear cut because the trial did not use a standard endpoint; it was the first trial in adjuvant pancreatic carcinoma to use radiographic DFS as an endpoint determined by a blinded radiology panel that did not have knowledge of clinical features.

“The hope was that that was going to add rigor and clarity to the endpoint,” said Leonard Saltz, MD, Executive Director for Clinical Value & Sustainability, Head, Colorectal Oncology Section, Memorial Sloan Kettering Cancer Center, during a video interview with OBR.

Although technically a negative study, APACT had a preplanned secondary analysis using the conventional investigator-assessed radiographic DFS and showed that patients who received nab-paclitaxel plus gemcitabine had prolonged DFS compared with gemcitabine alone (16.6 vs 13.7 months; HR=0.82) and this was mirrored in preliminary median overall survival data (40.5 vs 36.2 months; HR=0.82).

“Right now we only have about 48% of the data analyzed,” said Vincent Chung, MD, Associate Clinical Professor, Department of Medical Oncology & Therapeutics Research, Director Phase I Program, Medical Oncologist, City of Hope, during a video interview with OBR. “It’s going to be interesting to see how that overall survival really pans out on the APACT trial.”

View Dr. Saltz’s expert commentary on APACT in the OBR Video Center

View Dr. Chung’s expert commentary on APACT in the OBR Video Center

Prostate Cancer


ENZAMET and TITAN

Two phase III trials—ENZAMET and TITAN—showed that adding a next-generation androgen-targeted therapy following androgen-deprivation therapy (ADT) improved overall survival for patients with metastatic hormone-sensitive prostate cancer (abstract LBA2; abstract 5006). Specifically, ENZAMET showed this for enzalutamide and TITAN for apalutamide, but the trials were designed slightly differently, affecting some of the conclusions.

Specifically, ENZAMET allowed patients to receive docetaxel during the trial whereas TITAN only allowed prior receipt of docetaxel, raising the question of where docetaxel fits in.

“A key question for both these trials TITAN and ENZAMET is whether patients should get docetaxel with an AR pathway inhibitor,” said Kim Chi, MD, Medical Oncologist, Senior Scientist, Medical Director, Clinical Trials Unit, BC Cancer Agency, during a video interview with OBR. Dr. Chi was the lead author of the TITAN trial. “This was not the primary question of these studies, whether patients should receive the triplet of ADT, docetaxel, and apalutamide or enzalutamide.”

In ENZAMET, the subgroup of patients who received concurrent docetaxel had worse survival, whereas in TITAN the subgroup of patients who received prior docetaxel had survival benefit.

Although the question remains unanswered, Dr. Chi said, “There is some data that suggests for certain patients, we could consider the use of apalutamide after docetaxel.”

View Dr. Chi’s expert commentary on ENZAMET and TITAN in the OBR Video Center

 

Renal Cell Carcinoma


High Level View

Advanced renal cell carcinoma has seen significant progress in the first-line treatment setting, with several immunotherapy or immunotherapy plus tyrosine kinase inhibitor (TKI) combinations now approved: nivolumab plus ipilimumab, pembrolizumab plus axitinib, and—most recently—avelumab plus axitinib. However, the preferred combination is still a matter of debate, which the decision, in part, depending on whether a patient had favorable, intermediate, or poor risk disease.

At ASCO, the results of the pivotal phase III KEYNOTE 426 trial that led to the approval of pembrolizumab plus axitinib back in April were presented, showing an overall survival benefit for the combination across favorable, intermediate, or poor risk disease (abstract 4500).

“For patients with favorable risk IMDC, their standard of care should be pembrolizumab plus axitinib,” said Che-Kai Tsao, MD, Associate Professor of Medicine, Icahn School of Medicine at Mt Sinai, Medical Director, Ruttenberg Treatment Center, Mt. Sinai Hospital.

However, for intermediate-risk and poor-risk disease both pembrolizumab plus axitinib and nivolumab plus ipilimumab have shown a survival benefit, and both phase III trials to show these data used the same control arm, sunitinib.

“The question now becomes what do you do in intermediate-risk and poor-risk patients, where you either give them an IO/IO or an IO/TKI,” said Nancy A. Dawson, MD, Professor of Medicine, Lombardi Cancer Center, Georgetown University Hospital, during a video interview with OBR. “I think the jury is still out on that.”

View Dr. Tsao’s expert commentary on RCC in the OBR Video Center

View Dr. Dawson’s expert commentary on RCC in the OBR Video Center

Multiple Myeloma


ECOG

Lenalidomide reduced the risk of progression from smoldering to active multiple myeloma among high-risk patients compared to observation alone, the standard of care (abstract 8001). These phase III ECOG trial results complement those from the Spanish trial that showed lenalidomide/dexamethasone delayed the development of myeloma, and while the ECOG trial was positive, the reality is the treatment landscape has changed for multiple myeloma since the trial was designed, limiting the applicability of the results.

“[The trial] was designed and implemented in a different era when single-agent lenalidomide or doublet therapy was standard for multiple myeloma,” said Parameswaran Hari, MD, Professor of Hematology, Medical College of Wisconsin, during a video interview with OBR. “Now we are in the era of combinations.”

View Dr. Hari’s expert commentary on ECOG in the OBR Video Center

 

Isatuximab

A phase III trial showed that adding isatuximab, an anti-CD38 monoclonal antibody, to pomalidomide and dexamethasone, which is the current standard of care, improved progression-free survival and response rates in patients with relapsed/refractory multiple myeloma (abstract 8004). Another anti-CD38 monoclonal antibody, daratumumab, has also shown clinical benefit as a combination therapy for multiple myeloma patients.

“What I’m intrigued by with isatuximab is it does have preclinical properties that are distinctly different [from daratumumab],” said Paul G. Richardson, MD, Clinical Program Leader, Director of Clinical Research, Jerome Lipper Multiple Myeloma Center, Institute Physician, RJ Corman Professor of Medicine, Harvard Medical School, during a video interview with OBR. Dr. Richardson was the lead study author. For instance, isatuximab has more of a direct apoptotic effect and also has different properties in the immune microenvironment.

“Now these are preclinical observations,” Dr. Richardson said. “Do they mean something in the clinical setting? We don’t know yet.”

View Dr. Richardson’s expert commentary on Isatuximab in the OBR Video Center

 

Chronic Lymphocytic Leukemia


CLL-14

One-year of venetoclax plus obinutuzumab resulted in prolonged progression-free survival and high rates of minimal residual disease negativity compared with chlorambucil plus obinutuzumab in treatment-naïve patients with CLL and comorbidities (abstract 7502). These results from the phase III CLL-14 trial led to the FDA approval of the chemotherapy-free combination as a frontline treatment option for this patient population on May 15, 2019.

“It begs the question, how should we treat the majority of patients moving forward?” said Paul M. Barr, MD, Associate Professor of Medicine, Director of the Clinical Trials Office, Wilmot Cancer Institute, during a video interview with OBR. “I think the honest answer is we have good options, where we have treatment strategies based on the novel agents, and again more options for patients is a better thing.’

View Dr. Barr’s expert commentary on CLL-14 in the OBR Video Center

 

RESONATE

Ibrutinib alone or in combination has become a routine treatment option for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and long-term data from the phase III RESONATE trial shows that the efficacy seen with ibrutinib is long-lasting, even among those with high-risk disease (abstract 7510).

“What we’re learning from the mature data set is that ibrutinib remains very efficacious,” said Paul M. Barr, MD, Associate Professor of Medicine, Director of the Clinical Trials Office, Wilmot Cancer Institute, during a video interview with OBR. Dr. Barr was a study investigator of RESONATE.

Specifically, at 6-years follow-up, ibrutinib showed a 36-month gain in median progression-free survival compared to ofatumumab arm for previously treated patients with relapsed/refractory CLL or SLL (44 vs 8 months; HR 0.15; 95% CI 0.11-0.20; P˂0.0001). The median overall survival was also longer (67.7 vs 65.1 months; HR=0.81; 95% CI, 0.60-1.09).

“I would say ibrutinib remains a very important treatment option for relapsed/refractory patients,” said Dr. Barr.

View Dr. Barr’s expert commentary on RESONATE in the OBR Video Center

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