FDA Approves Record Number of Precision Oncology Drugs in H1 2020

NEW YORK – In the first six months of 2020, amid a pandemic, the US Food and Drug Administration approved 21 precision oncology drugs, blowing past the number of approvals during the same period last year and exceeding its total for the full year in 2019.

Precision Oncology News defines "precision" cancer drugs as therapies that are indicated for a molecularly defined population of patients, which usually rely on diagnostics to identify the patients who are likely to benefit from them. During the six months ended June 30, the FDA approved seven new molecular entities (NMEs) and expanded the use of 14 already approved drugs into new molecularly defined indications (see list of approved drugs here).

In comparison, in the first six months of 2019, the agency approved 12 precision oncology drugs: two NMEs and 10 expanded indications. During that entire year, the agency approved a total of 20 precision oncology drugs. 

The rate of precision oncology drug approvals continues to validate the thinking of scientific leaders who years ago encouraged studying drugs using biomarkers that identify patients most likely to benefit from them, said Jeff Allen, CEO of the advocacy organization Friends of Cancer Research. In his view, the life sciences community's investments in biomarker-informed drug development are paying off by improving understanding of disease biology, identifying more druggable targets, and getting drugs through the FDA and onto the market.  

"That's in large part why there are so many drugs getting approved in what appears to be a rapid timeframe," Allen said in an interview. "By selecting the right patients in clinical trials, the effect sizes will be larger, and that probably makes it easier for everyone to determine what trials should move forward and what the priority compounds are, and ultimately, get the drugs approved."

Merck came out ahead with three drug approvals during the first half of 2020, followed by two approvals each from Pfizer, Eli Lilly, AstraZeneca, and Genentech. Roche, with the help of its subsidiary Foundation Medicine, was the most favored companion diagnostic partner, netting six new FDA-approved CDx indications alongside drugs.

However, after factoring in the rarity of the biomarker of interest in an indication and the need for new treatments in that setting, the agency didn't always require a new FDA-approved companion test. In fact, the agency approved new companion tests alongside 10 drugs, but allowed several new drugs for rare molecularly defined indications to come to market without a specific CDx, such as Retevmo (Eli Lilly's selpercatinib) for lung and thyroid cancers with RET mutations and fusions. Such drugs will rely on already available tests on the market to identify best responders.  

Allen observed that these recently approved drugs rely on a mix of new biomarkers like homologous recombination repair deficiency and tumor mutational burden (TMB), and established biomarkers like HER2 expression. For example, the FDA approved a new drug combination, neratinib (Puma Biotechnology's Nerlynx) with capecitabine, for advanced HER2-positive breast cancer patients who are refractory to other HER2-targeted drugs, which Allen said shows that older biomarkers can continue to be useful in bringing new treatment options for a subgroup of patients. "That's really important work to create additional options or address resistance … things that are all part of the complexity of cancer," he said.

Complex biomarkers

Last week, FOCR hosted a virtual panel discussion on the application of increasingly complex biomarkers in drug development and cancer care, focusing in particular on the agency's tissue-agnostic approval of pembrolizumab (Merck's Keytruda) in June using TMB at 10 mutations/megabase as a threshold for determining which cancer patients with refractory solid tumors should receive the drug. 

Richard Pazdur, director of FDA's Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products, acknowledged during the virtual meeting that biomarker-guided drug development is challenging because it involves advancing not just a drug, but also biomarkers, and requires significant collaboration between pharmaceutical companies, diagnostics firms, and the agency.

As the biomarkers become more complex, the collaborations needed to understand them and establish standard testing and reporting methods, also become more involved, requiring the engagement of not just a drug firm and its diagnostic partner with the FDA, but multiple stakeholders. Ahead of the TMB-guided tissue-agnostic approval of pembrolizumab, FOCR convened such a multi-stakeholder workgroup to try to improve understanding of the various ways labs were calculating and reporting TMB and develop some baseline standards. FOCR is thinking of doing a similar project around homologous recombination deficiency.

In May, the FDA approved olaparib (AstraZeneca/Merck's Lynparza) for men with metastatic castration-resistant prostate cancer who had mutations in 15 genes involved in homologous recombination repair as defined by Myriad Genetics' BRACAnalysis CDx and Foundation Medicine's FoundationOne CDx. Earlier that same month, the agency had approved olaparib and bevacizumab (Genentech's Avastin) as first-line maintenance therapy for advanced ovarian cancer patients responsive to platinum chemotherapy, who have homologous recombination repair deficiency. But the biomarker in the ovarian cancer indication is defined differently than in the prostate cancer setting and is determined by Myriad's myChoice CDx.

The development of these types of complex biomarkers, particularly when they lead to tissue-agnostic approvals, as in the case with TMB and pembrolizumab, results in a redefinition of disease, Pazdur said, adding that such biomarker-guided paradigms may be the future of oncology. "This does require people to start thinking out of the box, [looking to] where the future is, rather than … tenaciously clinging to the past," he said during the webcast discussion.

The agency has now approved four tissue-agnostic indications, and two of them have been for pembrolizumab, first using microsatellite instability and mismatch repair status, and now, relying on TMB to predict which cancer patients with refractory solid tumors might respond. "The FDA staff in general has really incorporated this into their thinking and really embraced the concept of tissue-agnostic indications and biomarkers," Pazdur said.

Elizabeth Jaffee from Johns Hopkins University's Sidney Kimmel Comprehensive Cancer Center agreed during the panel discussion that in the era of biomarker-guided precision oncology, academic researchers, industry players, and FDA regulators have become more nimble in quickly moving new concepts into patients "as long as they are scientifically sound."

Eric Rubin, senior VP of clinical oncology at Merck, recounted that initially the company was going to pursue a more traditional approval paradigm for pembrolizumab in colorectal cancer patients with mismatch repair deficiency, but was encouraged by Pazdur to go for a tissue-agnostic indication. "I remember getting a call from Dr. Pazdur … and he said, 'Why are you stopping with just colon cancer? Why not consider a tissue-agnostic [indication]?'" Rubin recalled. "Perhaps we should have come to that earlier, but change is difficult, and we were following more traditional tumor-based development paths, but when we got the opportunity from Dr. Pazdur, we pursued it with vigor."

In recent years, the FDA has not only embraced tissue-agnostic indications in refractory cancer patients who are out of options, but also has been willing to approve drugs for rare, molecularly defined tumor types based on small, single-armed studies that show impressive response rates. In fact, eight of 21 precision oncology drugs the FDA approved in the last six months were based on non-randomized, single-arm or multi-cohort trials, where response rate was the primary endpoint.

When predictive biomarkers successfully identify the best responder population, it makes FDA's job much easier, Pazdur noted. "It's so much easier for us to approve a drug that has a 60, 70, or 80 percent response rate, than something that has a 10 percent response rate, and we're arguing about the risk-benefit relationship with that drug," he said. Among the drugs the FDA approved over the last six months, avapritinib (Blueprint Medicines' Ayvakit) demonstrated more than an 80 percent response rate in patients with advanced gastrointestinal stromal tumors and PDGFRA exon 18 mutations, a subgroup that doesn't respond to standard treatments. 

The agency's regulatory flexibility has been lauded by proponents of precision oncology and criticized by oncologists and researchers who say that the agency isn't rigorously vetting these drugs to ensure that they will extend patients' lives. Some oncologists have been particularly critical of the FDA's latest tissue-agnostic approval for pembrolizumab, pointing out that the registrational data from a multi-cohort single-arm study showed only around a 30 percent response rate and failed to show a survival advantage for high TMB patients. 

Amid a pandemic

FDA's rate of precision cancer drug approvals in the first half of 2020 would be notable under normal circumstances but it is particularly so during a pandemic.

The uptick in approvals was expected by some industry observers, who had expressed pre-pandemic optimism that this trend will continue for the next few years since an increasing number of late-phase studies are slated to read out. According to an analysis by diagnostics data analytics company Diaceutics, there are more than 500 Phase III precision medicine trials slated for completion over the next two years, primarily for various biomarker-defined cancer indications. If only 20 percent of these studies are successful, the company has projected that drugmakers may submit around 100 new drug or biologic license applications to the FDA in the coming years. 

What was unexpected, however, was a pandemic that would turn out to be particularly deadly for cancer patients and usurp the resources of the entire life sciences sector. Researchers published a study in The Lancet last month involving 928 patients with cancer and SARS-CoV-2 infection in the US, Spain, and Canada, and reported that 13 percent died within 30 days of their COVID-19 diagnosis. Comparatively, in the US general population, the overall latest COVID-19 mortality rate is 3.8 percent as estimated by JHU. 

In an effort to protect high-risk populations from SARS-CoV-2 exposure, some health systems have deferred care and preventive services not considered essential, and drugmakers and researches have had to halt enrollment in clinical trials. The National Cancer Institute noted a 40 percent decline in enrollment in its sponsored clinical trials in the first few months of the pandemic compared to the same period last year.

Keeping cancer patients away from healthcare facilities may help lower the infection and mortality rate due to SARS-CoV-2, but such gains may come at a long-term cost in terms of delayed cancer diagnosis and treatment-related research. According to the NCI's own simulation, delays in cancer screenings and diagnosis during the pandemic may cause an additional 10,000 deaths from breast and colorectal cancers through 2030.

Allen noted that some of the cancer centers FOCR partners with are working to resume clinical trials halted in the early months of the pandemic. "It's not like these are extracurricular activities," he said. "A vast majority of patients participate in clinical trials as part of their care."

However, the pandemic-related trial delays are unlikely to have been an issue for precision oncology treatments the FDA approved over the last six months. There's a good chance that the studies that led to these 21 approvals were fully enrolled and ongoing for several years, particularly the first-line indications that rely on randomized trials and survival as the primary endpoint.

For example, of the four indications approved involving checkpoint inhibitors pembrolizumab, nivolumab (BMS' Opdivo) and atezolizumab (Genentech's Tecentriq), three indications were approved based on studies where overall survival was the primary endpoint and all four registrational studies had start dates in 2015, observed Colin Enderlein, a senior associate at DeciBio Consulting, a life sciences consulting and market research firm. Meanwhile, the drugs approved in later-line settings may require a shorter study time frame with study start dates between 2015 and 2017.

"Overall, this trend of increased approvals could simply be that approval rates are finally catching up with the greater quantity of active studies that have been underway for years," Enderlein said.

"In terms of the impact of COVID-19 on drug approvals, we probably haven't seen that quite yet in terms of disruption of clinical trials that were ongoing," Allen added. "That's probably something that will be observed over a longer period of time."

However, the FDA in March issued guidance for sponsors anticipating that the pandemic will disrupt clinical trials for investigational medical products going forward and that sponsors will need to adjust study protocols. For example, since study participants may not be able to come in to far-away study sites as frequently for safety assessments, the agency told sponsors to consider conducting these evaluations via phone or at labs and imaging centers closer to patients. For drugs that must be administered in a healthcare setting, the agency has indicated it is open to discussing the use of nurses or trained non-medical personnel to administer them to patients at home. 

An FDA spokesperson acknowledged that these are uncertain times, and it's difficult to predict how the pandemic might impact drug developers' ability to conduct clinical trials. "No one yet knows what the data will show, but what we do know is this period of time has stimulated us all to rethink how trials are conducted," the spokesperson said, noting that the agency will continue to work with sponsors, patients, and investigators to advance the use of remote assessments and digital health.

The agency has been meeting with companies to discuss modifications to ongoing and future clinical trials to account for COVID-19 diagnosis on cancer patients, how this might impact drug dosing, therapeutic efficacy endpoints, and safety monitoring protocols. "Our hope is that this contributed in part to patients being able to continue to receive investigational therapies in the safest way possible," the spokesperson said.

The drug studies conducted during COVID-19 need to maintain trial integrity while maximizing patient safety, and minimizing the burden on patients, sponsors, and regulators. "We are thinking about how to identify the strengths and limitations of the modifications we were forced to make, such as remote assessments, digital health and other components of decentralized trials that can add efficiencies and decrease burden to patients, while having the least impact on outcome variability and trial integrity," the spokesperson said.

Some of the guidance provided by the FDA during the pandemic allowing for greater use of remote services and decentralization of clinical trials are good strategies for broadening trial access to cancer patients even after the pandemic, FOCR's Allen noted.

For example, in June, the FDA approved a new skin injectable form of the combination of Genentech's pertuzumab (Perjeta) and trastuzumab (Herceptin) for HER2-positive metastatic breast cancer. The injections of the two targeted drugs can be given to patients in their homes by a healthcare professional after they've completed the intravenous chemotherapy portion of the regimen. This will limit how often cancer patients must come into an infusion center, which is a particularly important consideration during the pandemic but also a valuable option for critically ill cancer patients under normal circumstances. 

The FDA has also been using real-world data collected on cancer patients to understand the safety and efficacy of drugs, including precision therapies, and such data can also be useful for understanding how COVID-19 impacts cancer patients and their response to treatments. Both the FDA's Oncology Center of Excellence, and FOCR, are involved in the multi-stakeholder project, COVID-19 Diagnostics Evidence Accelerator, to leverage this type of data. 

Despite the challenges posed by the pandemic, FDA's oncology division under Pazdur appears undeterred in its mission. "Since the onset of this pandemic in March … we wanted patients to feel that they were not lost in everything that is going on with COVID … We've been very active not only in our outreach program with patients during this critical period of time but also in getting drugs out to patients," he said during the panel discussion.

"We are here for you," he added. "We are oncologists, and we want to make sure we've not forgotten our commitment to cancer."