Andrew Smith

In 1992 when investigators began testing trastuzumab (Herceptin) in women with HER2-positive breast cancer, many observers predicted failure—and they kept on predicting failure throughout the trial process. Even after the FDA approved the drug in 1998, some observers scoffed at the modest survival benefit it had demonstrated to that point and predicted that targeted therapy would never be a major form of cancer treatment. “There was a great deal of skepticism about targeted monoclonal antibodies back in the 1990s. People didn’t believe that it would be possible to make antibodies that bound specifically to cancer cells or, if it was possible, that the antibodies would kill the cancer cells. It’s hard to imagine now, but those first trastuzumab trials I did in the mid-’90s were actually controversial,” said Howard A. “Skip” Burris III, MD, president of clinical operations and chief medical officer at Sarah Cannon in Nashville, Tennessee.

“It wasn’t until the subsequent trials that used trastuzumab in women with early-stage breast cancers, trials that showed a much bigger survival benefit than the trials in metastatic cancers, that everyone saw trastuzumab as a major breakthrough, and many people realized that targeted therapies might proliferate quickly,” he said.

There was, of course, reason for skepticism. A small number of successful targeted therapies existed longbefore trastuzumab, but none of them launched a new class of cancer treatments that successfully fought a wide range of tumor types.

Indeed, physicians have known since the 1940s that iodine-131 therapy can selectively target thyroid cancer and that androgen deprivation therapy can selectively target prostate cancer. Hormone deprivation did find one other major use in the 1970s, when tamoxifen (Soltamox) was approved for hormone receptor–positive breastncancer, but neither iodine-131 nor any other elemental radioisotopes have become major treatment types.

Thus, many people doubted that the approval of the first 2 monoclonal antibodies, trastuzumab and rituximab (Rituxan), signified an explosion in new targeted therapies, and if not for rapid advances in genetics, proteomics, and molecular synthesis, the doubters may have been right.

But the 2001 approval of a third novel targeted therapy, imatinib mesylate (Gleevec), turned many skeptics into believers. Unlike trastuzumab and rituximab, imatinib is a small molecule drug, but it is a highly specific inhibitor of tyrosine kinase enzymes that are overactive in a number of cancers that are Philadelphia chromosome positive. It was also obvious, from the very first trials, that imatinib was an incredibly effective treatment, particularly for chronic myelogenous leukemia (CML). A phase 1 trial launched in 1998 reported that the drug caused CML to quickly disappear in the vast majority of patients with early-stage disease, and a 5-year follow-up found that 98% of patients were still in remission.

Within a decade of trastuzumab’s initial approval, the FDA approved another 23 targeted cancer therapies. More than 80 targeted cancer therapies are now available to patients.

“It’s been an amazingly rapid proliferation, and it’s happened because we’ve made huge technical advances on 2 distinct fronts,” Burris said. “When trastuzumab arrived, we were still working to sequence one human genome at a cost of many billions of dollars. Systematically analyzing tumors for druggable driver mutations seemed unrealistically expensive, but then, over the course of just a few years, the technology became so much faster and so much cheaper that it was entirely feasible. The other big advance has been on the chemistry side. Pharmaceutical and biotech companies have gotten much better at creating molecules that will bind to their intended targets. Better chemistry has allowed medications to bind to many targets like KRAS that were once considered undruggable.”

The first attempt to develop a targeted monoclonal antibody treatment for cancer dates back to 1980, when a team led by Lee Marshall Nadler, MD, treated a patient affected by non-Hodgkin lymphoma with the murine monoclonal antibody AB 89. The treatment, however, did not produce a significant clinical response.

Several other research groups tested monoclonal antibodies against hematological cancers over the next decade, but none of them worked well enough for FDA approval. In fact, many of these murine formulations induced immune reactions that both created adverse effects and reduced therapeutic half-life.

The first monoclonal antibody to demonstrate itself safe and effective enough for FDA approval was rituximab, which kills B cells by targeting the surface antigen CD20. The drug, which was first approved in 1997 for B-cell lymphoproliferative disorders, is currently indicated, alone or in various combinations, to treat forms of non-Hodgkin lymphoma and chronic lymphocytic leukemia.

Trastuzumab, which was approved a year later, is a genetically engineered, humanized monoclonal antibody that fights cancer 2 ways. First, it inhibits HER2, a glycoprotein receptor with tyrosine kinase activity that promotes breast cancer cell growth. Second, it induces cancer cell death via antibodydependent cell-mediated cytotoxicity.

Trastuzumab was developed at the University of California, Los Angeles (UCLA) by a team led by Dennis Slamon, MD, PhD. Slamon identified the HER2-positive subtype of breast cancer in the early 1980s, demonstrated that this subtype was particularly deadly and aggressive, and hypothesized that a HER2 inhibitor would extend life. The team spent several years developing drug candidates, and the very first human trials were conducted at UCLA in 1990.

Trastuzumab has since shown significant—and often dramatic—benefit when used in a variety of ways against HER2-positive breast cancer. For example, a 2005 trial of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer found that after a median follow-up of one year, 1693 women assigned to the observation group had nearly twice as many events (recurrence, contralateral breast cancer, second non–breast malignant disease, or death) as the 1694 women assigned to the trastuzumab group.

In the early 1990s, women with the HER2-positive subtype had an average life expectancy after diagnosis of 3 to 5 years. Today, an estimated 3 million patients have an average life expectancy of 7 to 10 years, thanks largely to receiving trastuzumab.

The next targeted therapy to reach patients was gefitinib (Iressa), an EGFR tyrosine kinase inhibitor (TKI) approved in 2003 for the treatment of non–small cell lung cancer (NSCLC). Studies published the following year showed that a particular subset of patients with 

 mutation– positive NSCLC were far more likely than others to respond to gefitinib

and a second EGFR TKI approved in 2004, erlotinib (Tarceva).

The phase 3 trial that led to erlotinib’s approval found that only 8.9% of patients responded to the drug and that it increased median overall survival (OS) by just 2 months to 6.7 months,

 but the subgroup analysis found traits ranging from female sex to never smoking to 

Later research demonstrated that EGFR TKIs greatly increase survival in patients with 

-positive NSCLC. Combination chemotherapy in advanced NSCLC typically results in a median OS of 8 to 12 months and a median progression-free survival (PFS) of 5 to 6 months.10 Among 137 patients with 

-mutant metastatic lung adenocarcinoma treated with erlotinib or gefitinib at Dana-Farber Cancer Institute between 2002 and 2009, however, median PFS and OS were 12.1 months and 30.9 months, respectively. Twenty patients (14.6%) were 5-year survivors.

“Even though targeted therapies had already proven themselves effective against other tumor types, especially imatinib against CML, a lot of people were still skeptical that they would work against lung cancer,” said Paul Bunn, MD, distinguished professor of medicine-medical oncology and the James Dudley Chair in Cancer Research at the University of Colorado School of Medicine in Aurora, Colorado. “But the skeptics were quickly silenced. The trial results were pretty convincing.”

Shortly after the FDA approved erlotinib, it also approved bevacizumab (Avastin), the first example of another novel form of targeted therapies called antiangiogenics, which are designed to deprive tumors of blood.

Many targeted therapies were conceived long before they were approved, including antiangiogenics. The idea of fighting cancer by starving tumors of blood first occurred to Judah Folkman, MD, in 1963, when he and Fred Becker, MD, were comparing possible substitutes for blood transfusions. During those experiments, the 2 young doctors injected adult mouse melanoma cells into isolated, perfused thyroid glands taken from dogs and noticed that while tumors did form, they never developed blood vessels or grew beyond 2 mm in diameter.

Other investigators had already made similar observations, but Folkman’s efforts to understand his findings led him to complete a few more experiments and then to hypothesize, via a 1971 piece in the New England Journal of Medicine, 13 several very new ideas:

Tumors cannot grow dangerously large unless they develop vascular networks.

Tumors cannot build their own vascular networks, so they must trick their hosts into building such networks through angiogenesis.

An angiogenesis inhibitor could therefore treat cancer effectively.

The paper drew such negative response that it quickly made Folkman a pariah.

The approval of bevacizumab in 2004 was a triumph for Folkman, but because he died in 2008, he did not live long enough to see how broadly the use of antiangiogenics would expand. Bevacizumab alone is now approved as monotherapy or in combination with other medications to treat 7 different tumor types,

 and more than a dozen other angiogenesisinhibiting medications have subsequently been approved as cancer treatments.

Many of them work by binding to VEGF, preventing it from activating the VEGF receptor, and blocking the formation of new blood vessels. The first 2 approved drugs that targeted this pathway were sorafenib (Nexavar), which was approved in 2005, and sunitinib malate (Sutent), which was approved in 2006.

Oddly, an antiangiogenic drug had already been approved for use in most of the world (just not the United States) slightly before Folkman first devised the idea in 1963, but it was approved to treat sleeplessness and morning sickness rather than cancer. That drug, of course, was thalidomide (Synovir, Thalomid), which was later approved to treat multiple myeloma, many decades after the discovery that it causes birth defects.

Molecules that inhibit PARPs, which play a major role in DNA damage repair, were another form of targeted therapy that existed long before FDA approval to treat cancer. PARP-inhibiting substances, such as nicotinamide, have been used for various indications over the decades. In the 1970s, some thought these substances might prime patients for better response to chemotherapy or radiation.

The FDA, however, did not support a PARP inhibitor for cancer treatment until 2014, when it approved olaparib (Lynparza) for advanced ovarian cancer with a deleterious or suspected deleterious germline BRCA mutation.19 It has since approved more PARP inhibitors, including\ rucaparib (Rubraca), niraparib (Zejula), and talazoparib (Talzenna) across a wide variety of tumors, including metastatic prostate cancer and certain subtypes of breast cancer (TABLE19-22).

Immunotherapies are another type of targeted cancer treatment that were hypothesized many decades before they were realized. A German physician working in the mid-19th century noticed that tumors tended to regress when cancer patients were infected by erysipelas, so in 1868, he intentionally infected a patient with erysipelas to treat their cancer.

In the 19th century, the American doctor William Coley began directly injecting tumors with mixtures of live and inactivated Streptococcus pyogenes and Serratia marcescens. He reported more than 1000 regressions or cures over the course of his career, but he was poorly esteemed among researchers of the day and his findings were largely ignored.

The work that laid the foundation for today’s immunotherapies took place in 1982, nearly a century after Coley’s first efforts at immunotherapy, when James Allison, PhD, and colleagues identified and described tumor-specific antigens in a mouse model of T-cell lymphoma. 25 A year later, they described the first T-cell antigen receptor.

The first immune checkpoint molecule was discovered in 1987 and named CTLA-4. Just one year later, the first CTLA-4–blocking antibody was discovered, and in 2011, the first CTLA-4–blocking drug, ipilimumab (Yervoy), was approved by the FDA.

“The sheer number of targeted therapies that have been approved in the [past] 20 years is amazing, even if you’re just looking at my specialty of lung cancer,” said Bunn, who is a past president of the American Society of Clinical Oncology. “And thanks to those treatments, along with earlier diagnosis, survival rates have improved considerably, from roughly 4 to 6 months untreated to a year with chemotherapy to 5 years or more with TKIs. But there’s still work to be done because neither the TKIs nor the immunotherapies, or anything else, tends to produce complete responses or absolute cures. We need to find things we can pair with TKIs to kill the cancer cells they don’t, and there are a large number of combinations that are currently being investigated.”

Burris is also excited to see so many new targeted treatments—and combinations of targeted treatments—in trials right now. He is particularly optimistic about antibody-drug conjugates, therapies that combine antibodies that bind to tumors with a second agent that attacks the tumor. The most successful such product may be ado-trastuzumab emtansine (Kadcyla), which combines trastuzumab with a cytotoxic drug that’s released after the molecule binds to the cancer.

“When you see what big pharmaceutical companies are paying to acquire the makers of antibody- drug conjugates, you get a good sense of how promising the technology is,” Burris said. “The technology for binding the antibody and the cytotoxic agent, for getting the antibody to bind with the tumor, and for releasing the cytotoxic agent at the right time all keep improving. This is a promising strategy for attacking a wide range of tumors that don’t have a druggable driver mutation.”

1. Druker BJ, Guilhot F, O’Brien SG, et al; IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. 

. 2006;355(23):2408-2417. doi: 10.1056/NEJMoa063867

2. Targeted therapies: overview of targeted therapies for cancer. My Cancer Genome. Updated May 27, 2019. Accessed November 2, 2020. https://bit.ly/385txmr

3. Nadler LM, Stashenko P, Hardy R, et al. Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen. 

4. Dillman RO, Beauregard JC, Halpern SE, Clutter M. Toxicities and side effects associated with intravenous infusions of murine monoclonal antibodies antibodies. 

5. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. 

. 2005;353(16):1659-1672. doi:10.1056/NEJMoa052306

6. UCLA oncologist Dennis Slamon wins 2019 Lasker Award for clinical medical research. UCLA newsroom. September 9, 2019. Accessed November 2, 2020. https://bit.ly/2TKzvkt

7. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. 

. 2004;304(5676):1497-1500. doi:10.1126/science.1099314

8. Tsao M-S, Sakurada A, Cutz J-C, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. 

. 2005;353(2):133-144. doi:10.1056/NEJMoa050736

9. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al; National Cancer Institute of Canada Clinical Trials Group. Erlotinib in previously treated nonsmall-cell lung cancer. 

. 2005;353(2):123-132. doi:10.1056/NEJMoa050753

10. Schiller JH, Harrington D, Belani CP, et al; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced nonsmall- cell lung cancer. 

. 2002;346(2):92-98. doi:10.1056/NEJMoa011954

11. Lin JJ, Cardarella S, Lydon CA, et al. Five-Year survival in EGFR-mutant metastatic lung adenocarcinoma treated with EGFR-TKIs. 

l. 2016;11(4):556-565. doi:10.1016/j.jtho.2015.12.103

12. Folkman J, Long DM Jr, Becker FF. Growth and metastasis of tumor in organ culture. 

. 1963;16:453-467. doi:10.1002/1097-0142(196304)16:4<453::aid-cncr2820160407>3.0.co;2-y

13. Folkman J. Tumor angiogenesis: therapeutic implications. 

d. 1971;285(21):1182-1186. doi:10.1056/NEJM197111182852108

14. Bevacizumab. National Cancer Institute. October 5, 2006. Updated September 10, 2020. Accessed November 2, 2020. https://bit.ly/2TKcNcn

15. Angiogenesis inhibitors. National Cancer Institute. Updated April 2, 2018. Accessed November 2, 2020. https://bit.ly/325ldQ0

16. Nexavar. Prescribing information. Bayer HealthCare Pharmaceuticals Inc; 2010. Accessed November 2, 2020. https://bit.ly/360eQid

17. Sutent. Prescribing information. Pfizer Inc; 2011. Accessed November 2, 2020. https://bit.ly/2I0jzbr

18. Clark JB, Ferris GM, Pinder S. Inhibition of nuclear NAD nucleosidase and poly ADP-ribose polymerase activity from rat liver by nicotinamide and 5’-methyl nicotinamide. 

a. 1971;238(1):82-85. doi:10.1016/0005-2787(71)90012-8

19. FDA approves olaparib tablets for maintenance treatment in ovarian cancer. FDA. Updated August 17, 2017. Accessed November 3, 2020. https://bit.ly/324l5Ah

20. FDA grants accelerated approval to new treatment for advanced ovarian cancer. News release. FDA. December 19, 2016. Accessed November 3, 2020. https://bit.ly/34Pzsu7

21. Niraparib (Zejula). FDA. Updated May 30, 2017. Accessed November 2, 2020. https://bit.ly/36bQT7J

22. FDA approves talazoparib for gBRCAm HER2-negative locally advanced or metastatic breast cancer. FDA. Updated December 14, 2018. Accessed November 2, 2020. https://bit.ly/3jUsp7r

23. Busch W. Aus der Sitzung der medicinischen Section vom 13 November 1867. Berlin Klin Wochenschr. 1868;5:137. (Ger).

24. Dobosz P, Dzieciątkowski T. The intriguing history of cancer immunotherapy. Front Immunol. 2019;10:2965. doi:10.3389/fimmu.2019.02965

25. Allison JP, McIntyre BW, Bloch D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody.

26. Yervoy. Prescribing information. Bristol Myers Squibb; 2018. Accessed November 2, 2020. https://bit.ly/2HQsQT7

Articles

After decades of use in clinical settings, targeted therapies now enjoy favored status in the cancer treatment landscape.

A Look Back Prompts Memories of Initial Skepticism for Targeted Agents Shattered by Positive Efficacy Trials

Immune checkpoint inhibitors (ICIs) have demonstrated significant and lasting benefits in some patients with urothelial cancer (UC), but objective response rates to ICI monotherapy have only been 14.5% to 24%, and only about half of those patients experience long-term remissions.

Ongoing research seeks to boost those numbers by developing biomarkers to predict which ICI a patient is most likely to respond to and by testing ICIs in combination with each other and other treatment types to increase both the number and duration of responses.

The combinations being tested pair medicines that bind to programmed death receptor 1 (PD-1) or its ligand (PD-L1) with a wide variety of immunotherapies: cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4) inhibitors, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors, 4-1BB inhibitors, OX40 agonists, antibody&ndash;drug conjugates (ADCs), T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) inhibitors, and lymphocyte activation gene-3 (LAG3) inhibitors. Other research is testing PD-1/ L1 blockades with chemotherapies; radiation and targeted therapies, such as fibroblast growth factor receptor (FGFR) inhibitors cabozantinib (Cabometyx) and acalabrutinib (Calquence); and other medications suggested by patient biomarkers.

&ldquo;The approval of checkpoint inhibitor monotherapy has already had a very significant impact on the treatment of urothelial cancer, which had not seen any entirely new treatments for several decades before they came along. Bladder cancers benefitted minimally from the advent of targeted therapies because they are so heterogeneous on the molecular level that they do not really share any druggable targets. The finding that PD-1/L1 inhibitors produced durable responses in a significant minority of patients was a major breakthrough,&rdquo; said Roger Li, MD, a genitourinary oncologist at Moffitt Cancer Center in Tampa, Florida.

&ldquo;Now there is evidence that we can boost response rates and durations even further by pairing PD-1/L1 inhibitors with other medications [that] enhance their effect by potentiating the immune response,&rdquo; said Li, who is participating in several trials of UC or bladder cancer treatments. &ldquo;The idea is to create an immunogenic microenvironment so that high numbers of immune cells are around when you add the checkpoint inhibitor to stimulate even more aggressive attacks on the cancer.&rdquo;

UC, which originates in the bladder or upper urinary tract, is the most common histological type of cancer. It constitutes the majority of all types of bladder cancer, which is diagnosed in about 81,000 Americans each year and accounts for more than 17,000 annual deaths.

Cisplatin-based combination chemotherapy has long been the standard of care in unresectable and metastatic/advanced UC. Such treatment produces an overall response rate (ORR) of 40% to 50% and a median overall survival (OS) of 14 to 15 months.

However, issues such as impaired renal function or poor performance status prevent up to half of patients with metastatic UC from qualifying for cisplatin-based chemotherapy. Such patients typically receive carboplatin-based regimens, which produce an ORR of 30% to 40% and OS of 9 to 10 months.3,4 Second-line chemotherapies, including paclitaxel, pemetrexed (Alimta), docetaxel, and vinflunine, have shown a median OS of 5 to 7 months.

Recent years have seen the FDA approve 5 ICIs for UC treatment. Pembrolizumab (Keytruda) and nivolumab (Opdivo) both block PD-1, and atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) all block PD-L1. All 5 have undergone trials as second-line treatment in platinum-refractory patients with UC. ORRs have ranged from 14.8% for atezolizumab7 to 21.1% for pembrolizumab,

and the median OS has ranged from 6.5 months for avelumab

Atezolizumab and pembrolizumab have also undergone trials as first-line treatment in platinum-ineligible patients. Atezolizumab produced an ORR of 23% and median OS of 15.9 months,

and pembrolizumab produced an ORR of 24%; OS results have not matured yet.

Research in other tumor types has shown that PD-1/L1 blockades produce more numerous and more durable responses when used in combination with other medications than when used as monotherapies. The most successful of those multidrug regimens combine PD-1/L1 blockades with CTLA-4 inhibitors, and early trial data suggest that such combinations may also benefit patients with UC.

Still more early stage trials are assessing the safety and preliminary activity of regimens that combine ICIs with personalized vaccines that take tumor samples from individual patients, find antigens that occur on the tumors but not in a patient&rsquo;s healthy cells, and teach the immune system to attack those antigens.

Preliminary results from the phase I/II CheckMate 032 trial found that combination treatment with nivolumab and ipilimumab (Yervoy) was associated with an ORR of 26% to 38.5% and a complete response (CR) rate of 2.9% to 3.8% in 208 patients with locally advanced or metastatic UC that had previously been treated with a platinum-based combination. Most responses occurred early, and 70% to 80% of patients showed ongoing response at the time of analysis. Most treatment-related adverse events (AEs) were low grade and manageable.

The phase III CheckMate 901 study (NCT03036098) will compare standard first-line platinum-based chemotherapy, alone or with nivolumab, versus nivolumab 1 mg/kg plus ipilimumab 3 mg/kg for 4 cycles followed by nivolumab monotherapy in patients with treatment-na&iuml;ve metastatic or unresectable UC (TABLE 1). Another randomized phase III trial, DANUBE (NCT02516241), will pit both durvalumab monotherapy and a combination of durvalumab and tremelimumab against standard first-line platinum chemotherapy in patients with metastatic or unresectable UC.

Other possible complements for PD-1/L1 inhibitors in patients with UC are medications that bind to IDO1, an intracellular enzyme that creates an immunosuppressive microenvironment by inducing tryptophan degradation and kynurenine production. Earlier study results suggest some solid tumors may upregulate IDO1 to evade immune response, and some investigators have hypothesized that targeting both the PD-1/L1 and IDO1 pathways would enhance outcomes.

KEYNOTE-037 is an ongoing phase I/II study evaluating the safety and efficacy of the oral IDO1 inhibitor epacadostat in combination with pembrolizumab across multiple tumors (NCT02178722). Preliminary results from 40 patients in the UC expansion cohort showed that combination therapy was associated with an ORR of 35%. Patients who were PD-L1positive (those with a combined positive score &ge;1%) experienced an ORR of 64%, while patients who were PD-L1&ndash; negative experienced a 13% ORR. Median duration of response (DOR) was 30.6 weeks. Grade 3/4 AEs occurred in 22.5% of patients, and the overall safety profile of the combination was comparable to that of pembrolizumab monotherapy.

The combination is currently being studied in 2 phase III trials: the KEYNOTE-672 study, which is comparing pembrolizumab with either epacadostat or placebo in 650 untreated, cisplatin-ineligible patients with advanced UC (NCT03361865), and the KEYNOTE-698 study, which will test the same treatments in 648 patients with advanced UC who have already failed on first-line platinum chemotherapy (NCT03374488). There is, moreover, at least 1 other study designed to test a PD-1/L1 inhibitor (nivolumab) combined with an IDO1 inhibitor (BMS-986205). The phase I trial will test safety and ORR in 18 patients with UC (NCT03192943).

Another drug that might enhance the efficacy of PD-1/L1 inhibitors in the treatment of patients with UC is utomilumab, a monoclonal antibody that increases T-cell proliferation and cytokine production by binding to the 4-1BB receptor on natural killer cells, CD8-positive T cells, and CD4-positive T cells. The KEYNOTE-0036 phase Ib trial of utomilumab and pembrolizumab in 23 patients with various advanced solid tumors reported no dose-limiting toxicities or treatment related discontinuations and an ORR of 26.1%.16 Those results, combined with strong activity in preclinical trials, have led investigators to design phase II trials of utomilumab and pembrolizumab in patients with UC. Similar trials could also test combinations of utomilumab and avelumab, pending positive results from the JAVELIN Medley study (NCT02554812) and the NCT03217747 study in patients with many solid tumor types.

Other early-stage trials have produced some response in patients with UC who take combinations of utomilumab and the OX40 inhibitor PF-04518600. OX40 is a costimulatory immune checkpoint receptor that is expressed on activated CD4-positive T cells and regulatory T cells (Tregs). Preclinical trial results have shown that agonistic monoclonal antibodies that bind to OX40 can reduce the inhibitory effect of Tregs in the tumor microenvironment, and that work has led to early stage clinical trials such as NCT02315066, which is testing utomilumab and PF-04518600 in 42 patients, including 5 with previously treated UC. Among the 37 patients who were evaluable when investigators calculated preliminary results, the ORR was just 5.4%; however, the stable disease rate was 29.7%. Among the 4 evaluable patients with UC, 2 experienced stable disease and 2 experienced progressive disease. Treatment-related AEs were mostly grade 1/2.17 These preliminary results have convinced investigators to continue the trial to evaluate the combination in patients who do not respond (or have stopped responding) to other ICIs. The JAVELIN Medley study and NCT03217747, moreover, are evaluating the safety and preliminary activity of avelumab plus PF-04518600, with or without utomilumab or radiation, in patients with UC and other solid tumors.

A different class of medications that might team effectively with ICIs in UC treatment are ADCs, which combine antibodies designed to bind with tumor-surface antigens and toxic drugs that are released after binding has taken place.

A phase I/II study has tested the safety and activity of the ADC sacituzumab govitecan in patients with previously treated advanced solid tumors, including an expansion cohort of 41 patients with advanced UC (NCT01631552).

Patients with a median of 3 prior therapies (range, 1-6), including platinum combinations (93%) and ICIs (34%), received 10 mg/kg on days 1 and 8 of 21-day cycles until progression or unacceptable toxicity.

Treatment was associated with an ORR of 34%, and CT scans showed at least some shrinkage of the target lesion in 72% of patients. The median DOR was 12.9 months (95% CI, 7.5-12.9), median PFS was 7.2 months (95% CI, 5.0-10.7), and median OS was 16.1 months (95% CI, 10.5-17.7). The most common grade 3/4 AEs were neutropenia (39%), anemia (10%), fatigue (7%) and diarrhea (7%).

A phase I dose-escalation study evaluated the safety and efficacy of a different ADC, enfortumab vedotin, in 81 patients with advanced UC.20 More than 60% had received &ge;2 prior therapies, 45% had prior platinum combinations, and 46% had undergone prior ICI therapy.

The ORR was 41%, and the disease control rate (partial response plus CR plus stable disease) was 72%. Median DOR was 24 weeks (range, 0.14-40.3). Those results spurred a dose-expansion cohort in 67 patients with advanced UC who had already been treated with ICIs. The ORR in that group was 54%.

These findings led to a phase Ib dose-escalation study of enfortumab vedotin in combination with pembrolizumab or atezolizumab in patients with advanced UC pretreated with platinum-based chemotherapy or who were cisplatin ineligible (NCT03219333).

Other early-stage trials are investigating combinations of PD-1/L1 inhibitors and drugs that block the TIGIT pathway. BMS-986207, a monoclonal antibody targeting TIGIT, is currently being investigated in a phase I/IIa trial in combination with nivolumab in advanced solid tumors, including UC (NCT02913313). Another monoclonal antibody that binds to TIGIT, MTIG7192A, is being evaluated as a monotherapy and in combination with atezolizumab in a 2-step phase I study in patients with UC and a variety of other advanced tumors (NCT02794571).

Trials that combine PD-1/L1 inhibitors with ICIs that inhibit LAG3 are also at the phase I/II stage in patients with UC and other tumor types. LAG3 is expressed on tumor-infiltrating T lymphocytes, and it is thought that blocking the LAG3 receptor may enhance immune response to tumors in a way that complements a blockade of PD-1, which is also expressed on tumor-infiltrating T lymphocytes.

Another major strategy for increasing both the number of responses to PD-1/L1 inhibitors and the duration of those responses is pairing the ICIs with targeted therapies such as cabozantinib and acalabrutinib, FGFR inhibitors, and other medications selected via tumor biomarkers (TABLE 2).

Cabozantinib is a tyrosine kinase inhibitor that targets VEGFR2, MET, RET, FLT3, cKIT, and AXL. A phase I expansion study in 75 patients with metastatic UC and other genitourinary cancers initially split patients among 7 regimens before giving them cabozantinib 40 mg daily, nivolumab 1 mg/kg, and ipilimumab 3 mg/kg in the expansion part of the study.15 Among the patients who had not previously received an ICI, the ORR was 42.1%, the CR rate was 10.5%, and the clinical benefit rate was 84.2%. The UC cohort had a median PFS of 12.8 months (95% CI, 1.8-undefined) and a 12-month OS rate of 70.2% (95% CI, 44.4%-85.8%).

Acalabrutinib is a second-generation inhibitor of the Bruton tyrosine kinase. The phase II KEYNOTE-143 trial (NCT02351739) is investigating its effect, when paired with pembrolizumab, in platinum-refractory UC. Preliminary results for 75 patients randomized between pembrolizumab alone and a pembrolizumabacalabrutinib combination report a higher ORR for the monotherapy (25.7% vs 20%), but among responders, the combination was more likely to produce a response that lasted at least 12 months (63.5% vs 83.3%).

Other agents that inhibit FGFRs, which is amplified in UC and other solid tumors, are also being tested in combination with ICIs. The BISCAY phase Ib trial includes a module that combines durvalumab with AZD4547, an inhibitor of FGFR-1, -2, and -3, in patients presenting FGFR3 mutations or FGFR fusions (NCT02546661). Another 2 clinical trials are assessing the safety and efficacy of pembrolizumab in combination with an anti-FGFR3 monoclonal antibody called B-701 in patients with metastatic UC (NCT02925533, NCT03123055).

The BISCAY trial is also looking at other biomarker-based treatment combinations in patients with metastatic UC. Patients with tumors showing mutations in a homologous recombination repair gene panel will receive durvalumab in combination with the PARP inhibitor olaparib (Lynparza). Patients with tumors showing mutations in genes involved in cell-cycle regulation will receive durvalumab in combination with the WEE1 inhibitor AZD1775. Patients with tumors showing genomic alterations that have potential to respond to mTOR inhibitors (RICTOR amplification, TSC1/2 mutations) will receive durvalumab in combination with vistusertib, a selective mTORC1 and mTORC2 inhibitor. Patients with no specific genomic alterations will receive either durvalumab monotherapy or durvalumab plus the STAT3 inhibitor AZD9150.

And that is not all. Other trials are exploring the effects of combining ICIs with chemotherapy or with radiation.

&ldquo;Barring some truly incredible results from early-stage trials, we are probably a couple of years away from any results that could change the standards of care,&rdquo; Li said. &ldquo;But there is considerable optimism that treatment will improve, because several different combinations have produced promising early-stage results. It also makes theoretical sense that immunotherapies would be effective in urothelial cancers because they have some of the highest metastatic burdens of all tumor types and previous research has shown a correlation between tumor burden and immunotherapy efficacy.&rdquo;

National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: bladder cancer. SEER website. seer.cancer.gov/statfacts/html/urinb.html. Accessed February 26, 2019.

Clark PE, Spiess PE, Agarwal N, et al. NCCN guidelines insights bladder cancer, version 2.2016 featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2016;14(10): 1213-1224.

Alfred Witjes J, Lebret T, Comp&eacute;rat EM, et al. Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder dancer. Eur Urol. 2017;71(3):462-475. doi: 10.1016/j.eururo.2016.06.020.

DeSantis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2): 191-199. doi: 10.1200/JCO.2011.37.3571.

Galsky MD, Pal SK, Lin SW, et al. Real-world effectiveness of chemotherapy in elderly patients with metastatic bladder cancer in the United States. Bladder Cancer. 2018;4(2): 227-238. doi: 10.3233/BLC-170149.

Niegisch G, Gerullis H, Lin SW, et al. A real-world data study to evaluate treatment patterns, clinical characteristics and survival outcomes for first- and second-line treatment in locally advanced and metastatic urothelial cancer patients in Germany. J Cancer. 2018;9(8): 1337-1348. doi: 10.7150/jca.23162.

Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single arm, phase 2 trial. Lancet. 2016;387(10031): 1909-1920. doi: 10.1016/S0140-6736(16)00561-4.

Bellmunt J, deWit R, Vaughn DJ, et al; KEYNOTE-045 Investigators. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11): 1015-1026. doi: 10.1056/NEJMoa1613683.

Patel MR, Ellerton J, Infante JR, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 2018;19(1):51-64. doi: 10.1016/S1470-2045(17)30900-2.

Powles T, O'Donnell PH, Massard C, et al. Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma. Updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;3(9): e172411. doi: 10.1001/jamaoncol.2017.2411.

Balar AV, Galsky MD, Rosenberg JE, et al; IMvigor210 Study Group. Atezolizumab as first-line therapy in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064): 67-76. doi: 10.1016/S0140-6736(16)32455-2.

Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492. doi: 10.1016/S1470-2045(17)30616-2.

Rosenberg JE, Sharma P, de Braud F, et al. Nivolumab (N) alone or in combination with ipilimumab (i) in patients (pts) with platinum-pretreated metastatic urothelial carcinoma (mUC), including the nivolumab 1 mg/kg + ipilimumab 3 mg/kg expansion from CheckMate-032. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA32. oncologypro.esmo.org/Meeting-Resources/ESMO-2018-Congress/Nivolumab-N-Alone-or-in-Combination-With-Ipilimumab-I-in-Patients-pts-With-Platinum-Pretreated-Metastatic-Urothelial-Carcinoma-mUC-Including-the-Nivolumab-1-mg-kg-Ipilimumab-3-mg-kg-Expansion-From-CheckMate-032.

Smith DC, Gajewski T, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol. 2017;35:15(suppl; abstr 4503). http://ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.4503

Rodriguez-Vida A, Perez-Gracia JL, Bellmunt J. Immunotherapy combinations and sequences in urothelial cancer: facts and hopes. Clin Cancer Res. 2018;24(24); 61156124.

Tolcher AW, Sznol M, Hu-Lieskovan S, et al. Phase Ib study of utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in combination with pembrolizumab (MK-3475) in patients with advanced solid tumors. Clin Cancer Res. 2017;23(18):5349-5357. doi: 10.1158/1078-0432.CCR-17-1243.

Hamid O, Ros W, Thompson JA, et al. Safety, pharmacokinetics (PK) and pharmacodynamics (PD) data from a phase I dose-escalation study of OX40 agonistic monoclonal antibody (mAb) PF-04518600 (PF-8600) in combination with utomilumab, a 4-1BB agonistic mAb. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 1142PD. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/Safety-pharmacokinetics-PK-and-pharmacodynamics-PD-data-from-a-Phase-I-dose-escalation-study-of-OX40-agonistic-monoclonal-antibody-mAb-PF-04518600-PF-8600-in-combination-with-utomilumab-a-4-1BB-agonistic-mAb.

Faltas B, Goldenberg DM, Ocean AJ, et al. Sacituzumab govitecan, a novel antibody-drug conjugate, in patients with metastatic platinum-resistant urothelial carcinoma. Clin Genitourin Cancer. 2016;14(1):e75-e79. doi: 10.1016/j.clgc.2015.10.002.

Tagawa S, Faltas B, Lam E, et al. Sacituzumab govitecan (IMMU-132) for patients with pretreated metastatic urothelial uancer (UC): interim results. Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 858P. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/Sacituzumab-govitecan-IMMU-132-for-patients-with-pretreated-metastatic-urothelial-uancer-UC-interim-results.

Petrylak DP, Perez RP, Zhang J, et al. A phase I study of enfortumab vedotin (ASG-22CE; ASG-22ME): Updated analysis of patients with metastatic urothelial cancer. J Clin Oncol. 2017;35:15(suppl; abstr 106). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.106.

Petrylak DP, Smith DC, Flaig TW, et al. Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: A prospective cohort of an ongoing phase 1 study. J Clin Oncol. 2018;36:6(suppl; abstr 431). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.431.

Nadal RM, Mortazavi A, Stein M, et al. Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. J Clinical Oncol. 2018;36:6(suppl; abstr 515). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.515.

Zhang T, Harrison M, O'Donnell P, et al. Phase 2 study of pembrolizumab alone or combined with acalabrutinib in platinum-refractory metastatic urothelial carcinoma (mUC). Presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 863P. oncologypro.esmo.org/Meeting-Resources/ESMO-2017-Congress/Phase-2-study-of-pembrolizumab-alone-or-combined-with-acalabrutinib-in-platinum-refractory-metastatic-urothelial-carcinoma-mUC.

Ongoing research seeks to boost objective response rates in urothelial cancer by developing biomarkers to predict which immune checkpoint inhibitors a patient is most likely to respond to and by testing these in combination with each other and other treatment types to increase both the number and duration of responses.

Unique Immunotherapy Combinations Provide an Optimistic Outlook in Early Urothelial Carcinoma Trials

New draft guidelines from the FDA endorse the use of multiple expansion cohorts in first-in-human (FIH) clinical trials as a means of speeding lifesaving medications to market, but the document warns that the difficulties and dangers of using such complex studies so early in the testing process necessitate unusually careful design and oversight.

&ldquo;Sponsors and investigators have found in recent years that they could save significant amounts of time and money by increasing the size and scope of initial studies rather than formally closing each study and going through the whole process of getting another few studies approved. However, there was a tendency to expand in a relatively unplanned way that didn&rsquo;t always lead to the best data,&rdquo; said Joseph Paul Eder, MD, director of the Early Drug Development Program at Yale University. &ldquo;This seems like the FDA&rsquo;s way of acknowledging the value of multicohort expansions and trying to help sponsors and investigators do them right.&rdquo;

Typical phase I trials use 20 to 80 patients to determine the pharmacokinetic and pharmacologic actions of an investigational drug as well as the adverse effects associated with increasing doses. Their main goal is to uncover the information needed to design safe, well-controlled, and scientifically valid phase II studies of safety and efficacy. Any preliminary efficacy data uncovered by a phase I study are a bonus (

FIH trials that employ multiple, concurrently accruing patient cohortseach designed to assess different aspects of the safety, pharmacokinetics, and antitumor activity of a particular drug&mdash;seek to cut years from drug development time by seamlessly moving from the initial determination of pharmacokinetics, pharmacologics, and dosing to the estimation of antitumor activity and safety.

However, the FDA believes that rapid enrollment of hundreds (or thousands) of patients in very early trials exposes more people to relatively unknown toxicities, while the necessity of doing such trials at multiple sites, often spread around the world, makes it hard to communicate toxicity data immediately and adjust dosing accordingly. Moreover, potential on-the-fly adjustments to treatment protocols, data collection, and other factors can compromise the validity of data from poorly planned trials.

The FDA&rsquo;s new guidance applies to trials with at least 1 traditional FIH dose-escalation cohort and at least 3 other cohorts, with cohort-specific objectives such as assessing antitumor activity in a disease-specific setting, establishing safety and efficacy in special populations (eg, pediatric cohorts), testing alternate dosing schemes, validating biomarkers, and combining the experimental medication with some other drug.

The dose-escalation cohort usually begins first, but the additional cohort studies almost always get under way before the dose-escalation phase has produced conclusive data, so patients in all cohorts are exposed to what is essentially an untested drug. The FDA believes that the obvious risk of such trials necessitates that they be undertaken only in patients with serious, incurable diseases. Agency experts also believe that some types of experimental drugs (eg, immediate-release oral products, nonliposomal injections) are probably more appropriate than others, such as those with large inter- and intrapatient variability.

No matter the patient population or the drug type, sponsors or investigators hoping to win approval for FIH trials with multiple expansion cohorts should provide a robust rationale for such a trial design, demonstrate that their experimental drug has the potential to meet the criteria for breakthrough therapy, and provide a scientific basis for including each of their proposed cohorts.

Trial plans should quantify the acceptable risks for each cohort&rsquo;s population based on that cohort&rsquo;s prognosis, treatment alternatives, and comorbidities. They should also include a plan for statistical analysis that justifies each protocol&rsquo;s size, as well as its data-collection protocol, and contains rules for stopping treatment because of lack of observed activity.

The draft guidance warns that different types of cohorts will require different types of precautions to ensure patient safety and good data. For example, cohorts that assess the effects of food consumption, organ dysfunction, or concomitant treatments on drug performance will typically require at least preliminary results on pharmacokinetics and safety from the dose-escalation study before they can get under way. Cohorts designed to optimize dosage should randomize patients among 2 or more dosages and justify group sizes, while cohorts designed to validate biomarkers should use biomarkers that are logically related to the experimental drug&rsquo;s action and are analytically validated by prior studies.

The FDA strongly recommends the inclusion of pediatric cohorts whenever significant numbers of children suffer from untreatable cancers and could benefit from the experimental drug because prospective inclusion of such cohorts (rather than separate dose escalation and activity estimating phase I trials) can shorten development timelines and increase options for an underserved patient population. However, the agency also warns that pediatric cohorts require extra planning and precaution. Except under special circumstances, pediatric cohorts should launch only after other cohorts have established safe adult dosages, enroll older children rather than younger children, include extra monitoring to evaluate and adjust dose size, and include only children with incurable cases of relapsed or refractory disease.

Launching multiple cohorts without complete phase I trial data make it far harder to select appropriate patient populations, dose amount, and dosage timing, so all but the best designed trials can possibly expose patients to needless risks, miss potential benefits, or produce misleading results. Designers must state each cohort&rsquo;s goals in advance and show that their plans for cohort size, patient selection, data collection, and statistical analysis will meet those goals. Plans for cohorts that test antitumor activity should prespecify the magnitude of antitumor activity that would warrant further evaluation of the drug. In a nonrandomized cohort, the FDA recommends the use of a Simon 2-stage design1 to evaluate activity and limit exposure to ineffective drugs. In cohorts in which patients are randomized between groups, patient populations must be large enough to demonstrate preselected signs of activity, with statistical significance, in reasonable time frames.

The draft guidelines mention many potential pitfalls of multicohort trial design, and they warn investigators repeatedly against the temptation to make direct comparisons between or among different cohorts. Prior trials have attempted to make such comparisons to reach conclusions about the experimental medication that could not be made from any single cohort&rsquo;s results. However, except when such analyses are part of a protocol design that is reviewed and approved by expert bodies, the FDA believes that valid comparisons between or among different cohorts will be nearly impossible to achieve. Each cohort, therefore, will generally produce results that are entirely independent of any other.

There is, of course, a single major exception to this injunction: using information about medication toxicity in 1 cohort to protect patients in the other cohorts. The draft guidelines actually urge trial designers to create protocols for sharing safety information across cohorts in something approaching real time. Indeed, the FDA believes that the potential hazards of exposing many patients to untested drugs necessitate that FIH multicohort expansion trials all incorporate systematic procedures that ensure rapid communication of all potential safety issues to all investigators as well as regulators and institutional review boards.

Before trials even begin, trial designers should agree with regulators and institutional review boards about which adverse events should lead to the immediate termination of any or all the cohorts, which should lead to certain preselected modifications in treatment regimens, and which would be considered tolerable enough to continue with unmodified protocols. Trial designers can submit their plans to the institutional review board at each participating treatment center, but to facilitate multicenter trial, the draft guidelines recommend a single, central institutional review board for each trial.

Trial designers should then recruit medical monitors who have both training and experience in cancer treatment, as well as clinical trials, and they should instruct all clinicians who sign on as coinvestigators in each trial&rsquo;s chosen system for reporting adverse events.

&ldquo;Early-stage trials used to be so small that they could be handled entirely by specialists,&rdquo; Eder said. &ldquo;These larger trials require participation from far more oncologists, and although the early-stage specialists will still handle the intensive safety monitoring you see in dose-escalation trials, clinical oncologists who choose to participate in these expansion trials may have to do more safety monitoring than is typically required in the sort of late-stage trials that most clinical oncologists are more familiar with.&rdquo;

The FDA believes that reports of adverse events should go to either an independent safety assessment committee or an independent data monitoring committee.

These independent committees should conduct real-time review of all serious adverse events and periodically produce both summaries of all adverse events and suggestions for protocol modifications that would reduce risks for all trial patients. Possible modifications could include changing trial eligibility criteria if certain patient populations suffer higher-than-expected rates of adverse events, adjusting the dose or timing of the experimental medication or amending information given to patients about the possible risks of trial participation. Indeed, informed consent documents should be updated regularly as new safety information becomes available, and higher-than-expected rates of serious adverse events should trigger the submission of those amended consent forms to patients who are already participating in the trial.

Adverse events that meet prespecified criteria, moreover, should be reported immediately to regulators and all participating investigators. Even in instances in which adverse events do not rise to a level that necessitates immediate notification to the FDA, the draft guidelines support protocols for routinely submitting cumulative safety summaries on some preselected timeline that is more frequent than annual.

&ldquo;There is certainly a greater burden for clinical practitioners conducting these early-phase trials than there is in doing the late-phase registration trials. Necessarily closer monitoring is required, which is something to be aware of, but the standards discussed in these guidelines are certainly manageable for physicians who want to take part in what is very definitely valuable work,&rdquo; said Howard A. Burris III, MD, founder of the Sarah Cannon Research Institute in Nashville, Tennessee, and president-elect of the American Society of Clinical Oncology.

&ldquo;Overall, these seem like reasonable guidelines that balance the desire for speed with the need for safety and rigor,&rdquo; said Burris.

Simon R. Optimal two-stage designs for phase II clinical trials.

New draft guidelines from the FDA endorse the use of multiple expansion cohorts in first-in-human clinical trials as a means of speeding lifesaving medications to market, but the document warns that the difficulties and dangers of using such complex studies so early in the testing process necessitate unusually careful design and oversight.

Expansion Cohorts Guidance Balances Drug Development With Safety, Rigor

Complex drug trials that use a single protocol to test either 1 agent against multiple cancers or multiple agents against 1 cancer can make drug testing faster, cheaper, and more informative, particularly when those trials use the data to constantly improve protocols.

Those trials are rare, but the FDA hopes to make them more common with new recommendations for designing and conducting these types of studies. The draft documents do not relax existing trial-design standards. Instead, they are intended to guide investigators in planning trials that meet the standards of good trial design as laid out by the FDA. The guidance will be finalized after the agency reviews comments submitted in November.

&ldquo;A master protocol can create challenges in trial conduct and analysis that, if not properly addressed, can increase risks to patients or delay the development of the drug,&rdquo; said Patricia Keegan, MD, the director of the FDA&rsquo;s Division of Oncology Products 2, Office of Hematology and Oncology Products in the Center for Drug Evaluation and Review, in an interview with Targeted Therapies in Oncology.

&ldquo;The objective for publishing this draft guidance is to call attention to the potential challenges posed by these trial designs, to provide advice to industry and researchers on the information that sponsors should submit to the FDA to support the planned trial design, and [to advise] on how sponsors should interact with the FDA to facilitate efficient review,&rdquo; Keegan added.

Adaptive trial protocols allow for prospectively planned modifications to 1 or more aspects of the trial based on data gathered from trial subjects from a prespecified analysis in the trial design. Such modifications may be able to shift trial patients away from experimental treatments that appear to be performing poorly, toward treatments that appear to be performing well, or they may be used to reduce the number of patients needed to detect efficacy in a certain subpopulation.

Master protocol control trials consist of multiple substudies evaluating 1 or more investigational drugs, disease types, or both. Variable terms exist for different variations of the term master protocol, but all can streamline drug testing.

Basket trials test a single drug or drug combination against several tumor types. In most cases, a targeted therapy agent accounts for at least 1 part of the experimental regimen, and most trial patients have tumors that express an aberration consistent with the agent being used, regardless of where the tumor appears in the body.

Even though they express the same aberrations, tumors from different locations often respond differently to targeted agents and are said to constitute a different basket (

A prominent example of a basket trial is KEYNOTE-028, which is testing the PD-L1 inhibitor pembrolizumab (Keytruda) in more than 450 patients whose tumors express PD-L1.

Most basket trials have relatively small numbers of patients in each basket. If a drug performs well against a specific tumor type, its manufacturers typically initiate a traditional phase III trial. A number of approvals for pembrolizumab stemmed from trials initiated by Merck because of the drug&rsquo;s performance in an arm of the KEYNOTE-028 trial.

Trials that test multiple agents against the same tumor type are considered umbrella trials. Investigators test each patient&rsquo;s tumor for relevant mutations, then assign them to the most appropriate treatment based on the results. In many cases, umbrella trials come late enough in the testing process that patients with a particular mutation will be randomized to receive either an experimental treatment or the existing standard-of-care drug.

Subsequent patients within a given study expressing other mutations or aberrations will similarly be randomized to receive a therapy targeting abnormalities expressed by their tumors or the standard-of-care drug, and so on (

For example, the FOCUS4 trial is enrolling patients with previously untreated metastatic colorectal cancer and providing them with 16 weeks of standard chemotherapy. Biomarkers are then used to assign them to 1 of 4 cohorts, where they are randomized to receive additional treatment with either a targeted agent or placebo.

Other examples of umbrella trials include the lung cancer trials ALCHEMIST and Lung-MAP.

Umbrella trials that use more sophisticated protocols based upon previous outcomes are often referred to as platform trials. The I-SPY 2 trial is testing neoadjuvant treatments for locally advanced breast cancer and is regarded as one of the pioneering models for platform trials.

I-SPY investigator Hope S. Rugo, MD, the director of the Breast Oncology Clinical Trials Program at the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, boasted about the advantages of trials that can evaluate several agents all at once. &ldquo;Even with the simplest of traditional trials, it often takes years of effort to get from initial idea to patient enrollment, mostly because of all the different organizations that need to approve every trial,&rdquo; she said in an interview. &ldquo;It&rsquo;s very slow. It&rsquo;s very expensive.&rdquo;

I-SPY 2 uses a standard therapy control arm as well as an automated algorithm that updates randomization probabilities according to biomarker signature, MRI scans, and pathologic complete response results.

Each new patient&rsquo;s cancer is evaluated and placed into 1 of 10 molecular subtypes before being electronically randomized to a given study arm.

The primary endpoint of pathologic complete response is assessed at the time of surgery. When efficacy is determined, results are then immediately fed back into the algorithm to modify future randomization.

When an experimental agent reaches a predetermined level of efficacy in 1 or more molecular subtypes, it &ldquo;graduates&rdquo; to a phase III trial. In 2014, neratinib (Nerlynx) advanced from I-SPY 2 to a phase III study testing its use in HER2-positive, hormone receptor (HR)negative breast cancer.9 It later went on to receive FDA approval in July 2017 for the treatment of adult patients with early stage, HER2-overexpressed and amplified breast cancer following adjuvant trastuzumab (Herceptin).

Conversely, agents that fail to reach the efficiency threshold after a prespecified number of patients fail out of the trial.

As many as 5 agents can be tested at one time, and new agents can be plugged in when vacancies open up. This system has allowed I-SPY 2 to perform preliminary evaluations on 15 regimens over the past 8 years and &ldquo;graduate&rdquo; 6 of those agents on to phase III trials.

&ldquo;The more frequently we can combine multiple individual trials into single complex trials, the faster we will make progress against cancer and the further our research dollars will go,&rdquo; Rugo said.

Investigators struggle to quantify the temporal and monetary savings that complex protocols can achieve over traditional trials. An analysis of the ongoing STAMPEDE prostate cancer trial, which simultaneously tests 5 experimental regimens against a single control arm, suggests that complex designs can significantly cut trial times and costs.

The original arms of the trial, which began in 2005, included men randomized to either androgen deprivation therapy (ADT) alone, ADT plus zoledronic acid, ADT plus docetaxel, ADT plus docetaxel and zoledronic acid, ADT plus celecoxib, or ADT plus zoledronic acid and celecoxib. Another trial arm added in 2010 tested abiraterone acetate (Zytiga), followed by new arms testing abiraterone plus enzalutamide (Xtandi), radiation therapy, and metformin.

The trial has already changed the standard of care for high-risk prostate cancer and is expected to have produced 8 major results by 2020. Those results are being produced at accelerated speeds as the trial becomes more efficient. STAMPEDE is on pace to produce 1 major result every 18 months from 2015 to 2020. Plans to test further treatments, specifically targeted therapies in those patients who would likely glean the greatest benefit, are in the works. Individual trials running parallel would likely have taken decades longer.

The key aspects of the FDA guidance for Master Protocols has a number of specific recommendations:

Protocols should reduce the necessary number of trial patients by using a single control arm, with control patients receiving the existing standard of care.

Protocols that employ combinations of 2 or more agents should provide strong reasons for their selection for the regimen. All data about safety, pharmacology, and efficacy, as well as a rationale for using the combination over a single agent and evidence of any synergy when used in combination, should be presented to the FDA.

Andrew Smith | Authors

Articles

A Look Back Prompts Memories of Initial Skepticism for Targeted Agents Shattered by Positive Efficacy Trials

Unique Immunotherapy Combinations Provide an Optimistic Outlook in Early Urothelial Carcinoma Trials

Expansion Cohorts Guidance Balances Drug Development With Safety, Rigor

Trial Investigators Discuss FDA Draft Guidance on Master Protocols