Did cancer clinical trials stay on track at ASCO 2019?

Chicago is recovering after 40,000 oncologists and cancer experts descended on the city for this year’s ASCO conference. pharmaphorum spoke with three experts from Kantar to discuss the most interesting developments and trends in cancer that emerged at the event.

ASCO 2019 is over for another year and it’s time to take stock of the latest developments in cancer care unveiled at the conference.

Developments in pancreatic cancer

With so many companies vying to make their case through new research findings for their various drugs and therapies, it takes something really special to make an impact at McCormick Place.

And it was AstraZeneca and Merck & Co that provided one of the highlights, with new data providing hope for certain patients with pancreatic cancer.

While Lynparza (olaparib) looks like it will only work in the small percentage of patients whose disease has BRCA mutations, the data from the POLO trial suggests that this could be the first time a biomarker-selected targeted therapy has produced a survival benefit in a trial aimed at pancreatic cancer.

Merck & Co’s Keytruda (pembrolizumab) could also work in another small patient group with “MSI High” mutations, but that particular indication applies to all tumours, rather than just pancreatic cancer.

Still there is a pressing need for more treatments for pancreatic cancer, which is notoriously difficult to treat as symptoms usually only become apparent once the disease has spread through the body.

The companies are developing Lynparza as a maintenance therapy, used to hold the disease in check after an initial round of platinum-based chemotherapy.

Kantar’s vice president Stephanie Hawthorne said: “The results showed a compelling level of benefit, with a 47% reduction in the risk of progression or death, equating to a 3.6-month median PFS improvement.

“Now, due to the rare nature of the gBRCA mutations and the need to maintain an initial response for at least 16 weeks, this trial was relatively small for a phase 3 with only 154 patients randomised to Lynparza versus placebo. This may give some pause when considering the robustness of the data.”

At the moment AZ and Merck only have progression-free survival data, and the lack of overall survival (OS) data could be an issue, according to Hawthorne.

She said: “Another concerning point is the lack of overall survival benefit, which wasn’t even a trend at the interim.

“Could crossover have impacted the ability to observe an OS benefit, or is PARP inhibition a short-term solution that impacts PFS only without an OS benefit?”

She said the current situation draws parallels with Eli Lilly’s Alimta (pemetrexed), which was eventually approved as a maintenance therapy in non-small cell lung cancer around a decade ago despite similar issues with survival data.

Hawthorne said: “There was a very similar debate that took place when PFS was the only known improved endpoint; ultimately those trials did show an OS benefit and maintenance became a standard of care. I think final OS results will be equally influential for Lynparza in pancreatic cancer based on the POLO results.”

Hawthorne noted that there are a handful of agents working their way through the pharma pipeline: Boston Biomedical and Dainippon Sumitomo are developing their STAT3 inhibitor napabucasin in combination with GemAbraxane; Halozyme is developing pegylated hyaluronidase PEG-PH20 in combination with GemAbraxane; and Rafael Pharmaceuticals is developing their lipoate analogue devimistat in combination with mFOLFIRINOX.

In second-line, there are a few drugs in phase 3: Syncore’s EndoTAG-1 plus gemcitabine, Eleison’s glufosfamide, and ARMO/Lilly’s pegilodecakin plus FOLFOX.

However, none of the other agents in development are likely to compete directly with Lynparza as it is a maintenance therapy after first line treatment – although if that first line treatment changes this could have implications for Lynparza in the longer term.

Astellas and Seattle Genetics could file enfortumab vedotin in bladder cancer

Seattle Genetics has been making its name with antibody-drug conjugates (ADCs), and its latest bladder cancer contender enfortumab vedotin impressed at ASCO with some strong data from a mid-stage trial.

Seattle and development partner Astellas are trialling the drug in patients who have failed both platinum-based chemotherapy and checkpoint inhibitors.

For these individuals the prognosis is poor and there are few options left other than another bout of chemotherapy.

The rationale behind ADCs is to use an antibody to target cancerous cells, delivering a toxic payload that destroys tumour cells but does not affect healthy cells.

Top line data from the EV-201 trial showed an overall response rate from 125 treated patients of 44%, with 12% showing a complete response and 32% experiencing a partial response.

Median duration of response was 7.6 months, the median progression-free survival was 5.8 months, and overall survival was 11.7 months.

Coupled with a manageable toxicity profile there was already talk at ASCO that enfortumab vedotin could be approvable based on these data.

Kantar’s Stephanie Hawthorne said she was “impressed” with the data revealed at ASCO and agreed with the sentiments that the drug could be approved on the basis of EV-201.

The FDA is keen to bring new cancer drugs to market and often grants “accelerated approval” based on such data, with safety and efficacy confirmed by a larger final stage study.

Hawthorne said: “For an accelerated approval, this data looks sufficient to me. If seeking approval based on single-arm phase 2 data, the primary endpoints to evaluate are ORR and that those responses are durable.

“While there’s no set definition for what constitutes ‘durable’, 7.6 months definitely feels in that range to me. With no other approved or good alternative treatment options and good data, accelerated approval feels like a shoe-in to me.”

The companies have already begun the phase 3 EV-301 trial, comparing enfortumab vedotin versus physicians’ choice of chemotherapy.

Serious side-effects, including one case of the serious skin disease Stevens-Johnson syndrome, and diabetes and neuropathy occurred at low rates in the phase 2 trial, and in Hawthorne’s opinion these will be unlikely to deter the FDA from approval.

“However, physicians may ultimately decide on an individual basis whether to use enfortumab vedotin in the case of patients with pre-existing neuropathy or diabetes,” she added.

Competition-wise there is an indirect rival from Janssen, Balversa, which works in a subgroup of patients with a certain biomarker.

There are also a handful of drugs in the mid-stages of the pipeline from the likes of Altor BioScience, Mirati Therapeutics and ImmunoMedics, Hawthorne noted.

“It’s possible any of them may choose to follow the same route as enfortumab vedotin and seek an accelerated approval based on phase 2 data, thus speeding up timelines.”

Prostate of independence

Two of the biggest players in prostate cancer were also on hand at ASCO, with Pfizer and Astellas highlighting findings of the ENZAMET trial, and Johnson & Johnson giving details of the TITAN trial, both in metastatic hormone-sensitive prostate cancer.

The ENZAMET trial evaluated Xtandi (enzalutamide) in combination with standard of care therapy (LHRH analog with or without docetaxel) versus a nonsteroidal anti-androgen plus standard of care therapy in 1,125 patients with metastatic hormone-sensitive prostate cancer (mHSPC). Addition of Xtandi to standard of care demonstrated a 3-year OS of 80% compared to NSAA plus standard of care at 72%, with a hazard ratio of 0.67.

TITAN trial compared Erleada (apalutamide) with placebo and androgen deprivation therapy in patients with mHSPC.

Results showed that adding Erleada to ADT improved radiographic PFS, with a reduction in risk of death or radiographic progression by 52%, and a 2-year OS of 82% compared to 74% for placebo plus ADT, a 33% reduction in risk of death.

Adverse events between the arms were similar, with a slight increase in rash with Erleada. Janssen has already filed for approval based on these results, and approval of Erleada here could help the company recover from the impending patent expiration for Zytiga (abiraterone acetate).

Kantar’s vice president Jay Grisolano said: “The results of these trials support the use of Xtandi and Erleada in mHSPC patients.

Grisolano noted that a new filling for Xtandi may be held off until read out of OS results from ARCHES, an Astellas-sponsored phase 3 trial of ADT with or without Xtandi in mHSPC.

“Along with Zytiga, which is already approved for use in mHSPC based on results of the LATITUDE trial, there will soon be several options for physicians,” Grisolano said.

However, many questions remain. Grisolano pointed out that it’s unclear how doctors will choose from the three agents, and whether they can be used sequentially and the optimal sequence for doing so.

Existing data from metastatic castration-resistant prostate cancer, a more advanced form of the disease, show Xtandi is efficacious following Zytiga, but not the reverse.

Grisolano added: “Importantly, as agents like Zytiga and Xtandi move into earlier treatment settings, it leaves a void in the mCRPC setting, creating an unmet need for new agents.”

Is margetuximab benefit too marginal in breast cancer?

MacroGenics had already raised its profile in the oncology community with its margetuximab ahead of ASCO.

The US biotech tested margetuximab in HER2 positive breast cancer patients who had already failed to respond to several approved targeted therapies such as Herceptin (trastuzumab).

In the SOPHIA trial, involving these very sick patients, the median progression-free survival (PFS) of patients treated with margetuximab and chemotherapy was 5.8 months compared to 4.9 months in patients treated with Herceptin and chemotherapy.

Among the approximately 85% of patients carrying the CD16A genotype with a 158F allele, a pre-specified exploratory subpopulation in the study, PFS was prolonged by 1.8 months in the margetuximab arm compared to the trastuzumab arm (6.9 months versus 5.1 months).

The objective response rate, a secondary outcome measure in the SOPHIA study, was 22% in the margetuximab arm compared to 16% in the trastuzumab arm at data cut-off in October.

Jay Grisolano, vice president at Kantar, said that it is in patients with CD16A and a 158F allele where the drug will be most useful and likely to succeed in the clinic.

He added: “It remains to be seen whether the results for margetuximab will be viewed as clinically meaningful for all relapsed/refractory HER2+ metastatic breast cancer patients or only in a select population with specific CD16A polymorphisms. Demonstrating a significant overall survival improvement would go a long way.”

MONALEESA-7

While MacroGenics is looking to take on Roche in the late stages of HER2-positive breast cancer, the other big Swiss pharma Novartis is targeting the early stages of the disease with Kisqali (ribociclib).

The CDK4/6 inhibitor is already approved in ER-positive, HER2-negative disease but facing intense competition from Pfizer’s Ibrance and Lilly’s Verzenio.

But Kisqali is approved as a first-line therapy in premenopausal patients for this indication, and results from MONALEESA-7 announced at ASCO 2019 will help encourage doctors to prescribe it.

Grisolano said: “The trial not only demonstrated a doubling of mPFS with addition of ribociclib, but also showed an OS improvement (median not reached for ribociclib vs. 40.9 months for endocrine therapy alone). This is the first trial of a CDK4/6 inhibitor in HR+ breast cancer to show significant improvement in OS.

“However, it is also the first trial of a CDK4/6 inhibitor in patients less than 59 years of age. The results of MONALEESA-7 led to a label expansion for Kisqali and certainly give Novartis an edge in the peri- /premenopausal HR+ breast cancer space. However, based on Kantar’s CancerMPact Treatment Architecture data Ibrance is fairly entrenched as standard of care in the post-menopausal space, and result of MONALEESA-7 may not influence this,” said Grisolano.

AMG-510 stuns on its debut

It’s not just the big late-stage trials that cause a stir at ASCO – molecules showing promise at the very start of clinical development can also generate some interest.

One such potential drug is AMG-510, for which only phase 1 data was available at ASCO. But Otavio Clark, Kantar’s vice president for oncology, said that this drug has captured the imagination of many oncologists at the conference as it works in a completely new way.

Scientists have known about the role mutant KRAS cell switching proteins can play in cancers for years, but have never been able to make a drug that interacts with the dysfunctional protein.

It is implicated in cancers such as lung adenocarcinoma, ductal carcinoma of the pancreas, and colorectal cancer.

AMG-510 has changed all this after showing promise in advanced solid tumours with the mutation known as KRASG12C, found in around 13% of lung adenocarcinomas and 1-3% of other solid tumours.

A first-in-human, open-label multicentre study enrolled 35 patients with various tumour types (14 non-small cell lung cancer (NSCLC), 19 colorectal cancer (CRC) and two others).

Results published at ASCO showed five out of 10 evaluable patients with NSCLC had a partial response, and another four had stable disease, for a disease control rate of 90%.

Based on this small sample the safety looks promising too – treatment-related adverse events (AEs) were primarily grade 1 events (approximately 68%).

Two grade 3 treatment-related AEs were reported (anaemia and diarrhoea). No grade 4 treatment-related AEs and no serious treatment-related AEs were reported. Enrolment into dose expansion is underway.

Clark said: “The data were exciting, it was phase 1 with a very small number of patients. These patients had different types of cancer. They have remarkable responses.

“Everybody is excited because this is a population that is heavily pretreated. We have to be careful and await the results of later phase 2 results, which we hope to be presented next year,” Clark concluded.

BLU-667 sees lung cancer response

Another notable mention in tumour agnostic drug development goes to Blueprint Medicines’ BLU-667, which produced a 60% response rate in advanced lung cancer patients with RET mutations.

This was only in a small study involving 35 patients, but results from a larger group are due at next year’s ASCO, said Clark.

“This is a drug with a new biomarker that may be used to better select the patients. These patients usually don’t have another alternative treatment beyond the current chemotherapy that we use, and this drug shows really remarkable results for this population.”

While the last few ASCOs have been dominated by the rise of checkpoint inhibition and CAR-T therapies, it seems that this year the long-awaited “tumour agnostic” technology is beginning to gain traction.

Since ASCO, Japan’s regulator has already approved Roche’s tumour-agnostic drug Rozlytrek (entrectinib) which generated interest at previous meetings.

Kantar’s Stephanie Hawthorne concluded that Blueprint is certainly targeting this kind of approach with BLU-667, while Amgen certainly has the option of trying to develop AMG-510 using “tumour agnostic” trials depending on the data it collects in the coming months or years.

Looking back, it’s easy to think that AstraZeneca and Merck & Co could have decided to develop Lynparza with trials targeting tumours with BRCA mutations irrespective of where they originated in the body.

However, AZ and Merck & Co seem to be enjoying considerable success by targeting BRCA mutations in tumour-specific trials and POLO adds a new indication to the list in which PARP inhibitors can be used if these mutations are present.

Stephanie Hawthorne

Dr Hawthorne co-leads the team who monitors the current and emerging treatment patterns in the United States, Western Europe, Japan, and China for 30+ oncology indications.

Dr Hawthorne has broad experience and knowledge of the oncology pharmaceutical market, both in the US and internationally. Dr Hawthorne has 15 years of experience moderating in-person and telephone interviews with key opinion leaders and community oncologists, with experience in breast, bladder, colorectal, head and neck, NSCL, and pancreatic cancers, melanoma, RCC, AML, multiple myeloma, MDS, and CLL.

Dr Hawthorne has a PhD in Genetics from Stanford University in Stanford, California, and a BS in Biochemistry from California State University in Los Angeles, California.

Jay Grisolano

Dr Jay Grisolano is a vice president in the Clinical & Scientific Assessment group and has 15 years consulting experience with a focus on custom engagements in the therapeutic area of oncology.

His capabilities include commercial and technical assessment, strategic planning, competitive analysis and profiling, primary market research, licensing/due diligence support, and forecasting. Dr Grisolano has 15 years of experience moderating in-person and telephone interviews with key opinion leaders and community oncologists, with experience in breast, colorectal, gastric, glioblastoma, NSCL, and prostate cancers, melanoma, HCC, AML, multiple myeloma, and NHL.

Dr Grisolano previously worked as a postdoctoral fellow at Washington University School of Medicine in St. Louis. He earned a Ph.D. in Molecular Cell Biology from Washington University in St. Louis, Missouri, and a B.S. in the Biology-Honors Program, from the University of Illinois at Urbana-Champaign.

Otavio Clark

Dr Otavio Clark is a medical oncologist, with a PhD in medical sciences, having been a fellow at the H Lee Moffitt Cancer Center at the University of South Florida in Tampa, FL. He currently develops a vast array of projects, including real world evidence studies, economic analyses, meta-analyses, clinical research, and market access strategies for pharmaceutical and device industries. With 20 years of experience in the area, he has published extensively in some of the best and most respected medical journals.

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