February 06, 2018 - 08:02 pm 0 Comments
This week is turning out to be a busy and exciting week in readouts from Phase 3 clinical trials, including results from the CheckMate 227 trial in first-line advanced non-small cell lung cancer; the IMmotion 151 trial in unresectable locally advanced or metastatic renal cell carcinoma; and the COLUMBUS trial in melanoma.
Progression-free survival in NSCLC
First up, Bristol-Myers Squibb (BMS) announced yesterday significant results for its ongoing Phase 3 CheckMate 227 study. The study met its co-primary endpoint of progression-free survival (PFS) with an Opdivo (nivolumab; BMS) plus Yervoy (ipilimumab; BMS) combination arm versus chemotherapy in first-line advanced non-small cell lung cancer (NSCLC) patients whose tumors have high (≥10 mutations/megabase, mut/mb) tumor mutation burden (TMB), regardless of PD-L1 expression.
“For the first time, this Phase 3 study shows superior PFS with first-line combination immunotherapy in a predefined population of NSCLC patients with high TMB,” said Matthew D. Hellmann, MD, study investigator and medical oncologist at Memorial Sloan Kettering Cancer Center.
Using Foundation Medicine’s FoundationOne CDx validated assay, CheckMate 227 is an open-label Phase 3 trial that randomized more than 2,500 non-squamous and squamous histologies to an Opdivo-based treatment arm or to platinum-doublet chemotherapy. The study is being carried out in three parts, and yesterday’s announcement is the result of Part 1.
Critics are pointing out the modification of only assessing patients with tumors with high TMB (≥10 mutations/megabase) — BMS enacted a change on the trial design that could have affected whether PFS was significant. Other critics point out that the threshold BMS used for high TMB is far lower than the established FoundationOne threshold of >20 mut/mb found in only about 13% of patients.
Hellmann said, “TMB has emerged as an important biomarker for the activity of immunotherapy.” Hellmann is correct in that statement, but TMB was not a prospectively identified biomarker, and its threshold here does not align with a consensus of TMB threshold. Subset analyses and the overall survival (OS) readout should provide a much clearer picture on the best candidates for and the efficacy of the Opdivo plus Yervoy combination in advanced NSCLC.
Lung cancer expert Jack West, MD, is an editor on the OBR editorial board. He provided OBR with a full analysis of these results. To see his comments please click here.
Results from IMmotion 151 in renal cell carcinoma
Continuing in immunotherapy, Roche announced results from its Phase 3 trial, IMmotion 151, of Tecentriq (atezolizumab; Genentech) plus Avastin (bevacizumab; Genentech) versus standard-of-care Sutent (sunitinib; Pfizer) in patients with unresectable locally advanced or metastatic renal cell carcinoma (RCC).
Treatment-naive patients of any prognostic risk category (N=915) were randomly assigned to an atezolizumab plus bevacizumab treatment arm or to a sunitinib arm; and were stratified by PD-L1 status.
IMmotion 151 met one of its two endpoints, with significantly improved PFS in patients with tumors expressing PD-L1. Median PFS was 11.2 months in the atezolizumab plus bevacizumab treatment arm versus 7.7 months in the sunitinib arm (hazard ratio, 0.74; [95% CI, 0.57–0.96]; P=.02). However, that association was not clearly supported using independent, blinded reviewer-assessed PFS, cautioned lead investigator Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, New York City.
The combination of atezolizumab plus bevacizumab is gaining momentum: In December 2017, Roche announced that this combination with chemotherapy in front-line NSCLC improved 12-month PFS in the Phase 3 IMpower150 study.
Results from the COLUMBUS study in melanoma
In melanoma, Array Biopharma’s binimetinib—a MEK inhibitor—in combination with encorafenib—a BRAF inhibitor—in patients with BRAF-mutant melanoma reduced the risk of death compared with vemurafenib (Zelboraf; Genentech) in the Phase 3 trial (hazard ratio 0.61, [95% CI 0.47, 0.79]; P<0.001).
The combination arm almost doubled median OS compared with vemurafenib: 33.6 months vs 16.9 months, respectively.
“This data suggest that the combination of encorafenib and binimetinib may have the potential to become a meaningful new therapy for patients with advanced BRAF-mutant melanoma,” said Keith T. Flaherty, M., Director of the Termeer Center for Targeted Therapy, Massachusetts General Hospital Cancer Center and Professor of Medicine, Harvard Medical School.
These results come as a major win for Array, which in March 2017 pulled its New Drug Application (NDA) for binimetinib monotherapy in NRAS-mutant melanoma after results from the Phase 3 NEMO trial showed no difference in median OS when compared to standard-of-care chemotherapy.
Binimetinib monotherapy and binimetinib plus encorafenib remain under review for BRAF-mutant advanced, unresectable, or metastatic melanoma, with an FDA decision expected by June 30, 2018.
Lastly, in non-metastatic, castration-resistance prostate cancer
Finally, Janssen’s next-generation androgen inhibitor, apalutamide, showed a 72% reduced risk for metastasis or death compared with placebo among men with non-metastatic castration-resistant prostate cancer at high risk for developing metastatic disease.
In yesterday’s ASCO pre-GU Symposium press cast, Eric J. Small, MD, FASCO, professor of medicine at University of California, San Francisco, said, “To date there has been no therapy approved for this disease state, and the aim of this study was to see if the development of metastases in the transition from non-metastatic to metastatic could be slowed.”
In the Phase 3, SPARTAN trial, patients (N=1207) were randomized 2:1 to daily apalutamide or placebo, in addition to continuous androgen deprivation therapy (ADT). The primary endpoint was metastasis-free survival (MFS). The trial ended early when the interim analysis showed the primary endpoint had been met.
Median MFS in the apalutamide treatment arm was 40.5 months versus 16.2 months in the placebo arm, representing a 72% reduction in the hazard for metastatic progression or death.
Even though apalutamide was associated with a reduced risk of death, according to Dr. Small, “that was not significant at this early interim analysis and will continue to be followed. The trend was certainly encouraging,” he said.
The FDA granted priority review to apalutamide, with an estimated PDUFA date by April 11, 2018.
The apalutamide program is also being assessed in the Phase 3 TITAN trial, comparing apalutamide combined with ADT to ADT alone in metastatic, hormone-sensitive prostate cancer.
By Megan Garlapow
On the eve of the 2018 Genitourinary Cancers Symposium to be held in San Francisco February 8-10, a pre-meeting presscast featured four noteworthy abstracts: two related to immunotherapy with a PD-L1 inhibitor atezolizumab in urothelial cancers and two to treatment of non-metastatic advanced prostate cancer.
PD-L1 Inhibitor Plus Anti-Angiogenesis Inhibitor in Metastatic Renal Cell Carcinoma
The combination of atezolizumab plus bevacizumab delayed cancer progression by 3.5 months compared with standard sunitinib in a Phase 3 trial of patients with previously untreated metastatic renal cell cancer. Patients whose tumors expressed PD-L1 had the most benefit. The side effects of atezolizumab plus bevacizumab were less severe compared with sunitinib.
“Because the side effects were decidedly less harsh, and the progression-free survival was better, this relatively easy-to-administer combination should be considered a first-line option for PD-L1-positive advanced renal cell carcinoma,” said lead author Robert J. Motzer, MD, Memorial Sloan-Kettering Cancer Center, New York City.
Dr. Motzer suggested that the rationale for combining atezolizumab, a PD-L1 inhibitor, with bevacizumab, an anti angiogenic agent, is that theoretically the combination could prime tumor and immune cells to respond to atezolizumab.
The Phase 3 IMmotion151 study enrolled 915 patients with untreated metastatic renal cell cancer and randomized them 1:1 to treatment with atezolizumab plus bevacizumab versus sunitinib, which has been standard of care for about 10 years. Patients were stratified for PD-L1 expression (<1% vs >1% on tumor infiltrating immune cells). Of the 915 patients, 362 were PD-L1-positive.
Among PD-L1 positive patients, median progression-free survival (PFS) was 11.2 months on the combination therapy versus 7.7 months on standard sunitinib, representing a 26% reduction in the likelihood of disease progression (P=.02).
Looking at the entire intent-to-treat cohort (n=915) of patients with all levels of PD-L1 expression, median PFS was 11.2 months for the combination versus 8.4 months for standard sunitinib, a 17% reduction in the likelihood of disease progression for the combination therapy (P=.0219).
Treatment-related grades 3-4 adverse events were reported in 40% of those treated with atezolizumab plus bevacizumab versus 54% of those in the sunitinib group.
“For an aggressive cancer like this, where less than 20% of people survive 5 years after diagnosis, we think a 3.5 month longer PFS…. is an important development,” said Dr. Motzer.
Who Will Respond to Atezolizumab?
With five new immunotherapies FDA-approved for the treatment of urothelial cancers, it is important to identify which patients might gain the most benefit from these new and expensive drugs. Researchers have developed a model that appears to predict overall survival (OS) for people with advanced urothelial cancer treated with atezolizumab.
“We believe we have developed the first prognostic model that, once confirmed in larger studies, could provide a critical decision-making tool for clinicians,” stated lead author Gregory Pond, PhD, McMaster University, Hamilton, Ontario, Canada.
The model was based on data from the Phase 2 IMvigor210 clinical trial atezolizumab in 310 patients with advanced urothelial cancer that progressed on standard cisplatin chemotherapy, and then validated in 95 people with bladder cancer enrolled in a Phase 1 trial.
The researchers evaluated traditional factors associated with survival in patients with advanced bladder cancer treated with chemotherapy that included performance status, site of tumor, sites of metastasis, tumor stage, blood test results, smoking status, and prior treatments. They also assessed PD-L1 status, a marker for the efficacy of atezolizumab.
The six factors found to predict OS were:
The higher the number of these six prognostic factors, the worse the survival among these patients. In the IMvigor210 trial, median OS was 19.6 months for those with 0-1 factors; 5.9 months for those with 2-3 factors; and 2.6 months for those with 4 factors or more.
The authors plan to validate this model among different datasets and try to determine whether specific subgroups have an improved response to atezolizumab.
“It’s important to remember … that it is the minority of patients who have long-term responses [to immunotherapies] and we currently have no way of pinpointing who these patients are. As this study demonstrates, prognostic models may help us apply immunotherapy to patients who stand to derive the most benefit,” said ASCO Expert Sumanta K. Pal, MD, who moderated the presscast.
Moving Docetaxel Up to Non-Metastatic Advanced Prostate Cancer
A new analysis of the ongoing STAMPEDE trial showed that the addition of docetaxel to hormone therapy for advanced prostate cancer that had not metastasized improved quality of life (QoL) and reduced the need for subsequent therapy. A previous study showed that the addition of docetaxel reduced the risk of recurrence in this setting.
“We already knew that docetaxel prolongs survival for men with metastatic prostate cancer, but this improvement in quality of life and reduction in subsequent treatment, and therefore costs, in non-metastatic disease is somewhat surprising and may cause clinicians to re-think how and when they use docetaxel to treat prostate cancer,” said lead author Nicholas D. James, MD, PhD, University of Birmingham, U.K.
STAMPEDE is a very large trial that includes more than 9000 men with non-metastatic and metastatic advanced prostate cancer and to date, has evaluated 10 different drugs. An earlier analysis of STAMPEDE found that 592 men treated with docetaxel lived about 10 months longer versus men on standard hormonal therapy. The present analysis looked at health-related quality of life and cost-effectiveness of the addition of docetaxel and prednisolone to hormone therapy compared with hormone therapy alone (standard of care).
Participants rated five aspects of their health on a self-reporting tool called EuroQol EQ-5D: mobility, self-care, activities of daily life, pain levels, and anxiety and depression levels. Based on responses the authors modeled changes in predicted length of survival, quality-adjusted life years (QALY), and incremental cost-effectiveness.
For men with metastatic disease treated with docetaxel plus hormone therapy, predicted survival was 0.89 years longer compared with hormone therapy alone, and QoL was preserved for 0.51 years longer. For men with non-metastatic disease, predicted survival was 0.78 years longer and QoL was preserved for an additional 0.39 years with docetaxel plus hormone therapy versus hormone therapy alone.
The addition of docetaxel to hormone therapy was cost-effective for both non-metastatic and metastatic prostate cancer. The annual estimated cost of docetaxel in the U.K. is about 5000 British pounds (about $6750 dollars in the U.S.) per QALY gained. Dr. James and co-authors noted that the estimated cost of delaying or avoiding recurrence in the U.S. should be the same if not greater, due to higher drug prices in the U.S.
STAMPEDE is continuing to study newer drugs, including abiraterone. In the U.S., patients have a choice between abiraterone (an oral drug) and docetaxel, but docetaxel is about one fifth of the cost of abiraterone.
Apalutamide Delays Metastatic Prostate Cancer
There are no FDA-approved therapies for men with non-metastatic castrate-resistant prostate cancer (nmCRPC) following surgery or radiation plus androgen deprivation therapy (ADT). Some physicians advocate watchful waiting. But men with a rapidly rising PSA on ADT (doubling time of less than 8 to 10 months) are at significantly greater risk of developing metastases or death.
A new study shows that the oral androgen receptor inhibitor apalutamide reduced the risk of metastasis or death by 72% compared to placebo in men with nmCRPC; all patients were taking ADT.
“These data demonstrate that the use of apalutamide prior to the development of metastases clearly benefitted patients whose prostate cancer no longer responded to conventional hormonal therapy. It is exciting that there now exists such a well-tolerated agent for this group of high-risk patients for whom no approved therapies currently exist,” said lead author Eric J. Small, MD, University of California at San Francisco.
The SPARTAN study enrolled 1207 men with non-metastatic CRPC that stopped responding to ADT and were at high risk of metastasis with a PSA doubling time of 10 months or less and randomized them in a 2:1 ratio to receive oral apalutamide versus placebo added to ongoing ADT. When metastases developed, second therapies were added with an option to receive on-study abiraterone acetate plus placebo, a standard of care.
At entry, median PSA doubling time was 4.5 months in both arms. Apalutamide reduced the risk of metastasis and death by 72% compared with placebo and significantly prolonged median metastasis-free survival by 2 years (40.5 months in the apalutamide group vs 16.2 months in the placebo group, P<.001). Apalutamide significantly improved time to metastasis, PFS, and symptom progression compared to placebo.
Although it is too early to establish a survival benefit, a trend toward improved survival was observed for the apalutamide-treated group.
At a median follow-up of 20.3 months, 61% of the apalutamide group and 30% of the placebo group were still on therapy.
Apalutamide was well tolerated, and QoL scores were maintained when apalutamide was added to ADT.
“Until now, the optimal management of patients with prostate cancer and no visible evidence of spread with a rise in blood markers remained an enigma. These finding suggest that there may finally be a treatment that holds real promise for extending their health and their lives,” said Dr. Pal, presscast moderator.
By Adrian Barfield
The 2018 Gastrointestinal Cancers Symposium is gearing up for its meeting in San Francisco, January 18 through January 20. Presentations will include important studies on topics such as a new way to detect colorectal cancer early, novel surgical approaches for GI cancers, the role of immunotherapy, and long-term evaluation of outcomes of patients receiving standard therapy for colorectal cancer.
Here is a summary of some meeting highlights:
CTC Blood-Based Assay (Abstract 556)
A simple blood test to detect the presence of circulating tumor cells (CTCs) — a liquid biopsy — identifies colorectal cancer (CRC) at early treatable stages with an accuracy of 84% to 88%. This is one of the first studies using the CTC blood test to detect GI cancer at early, rather than later, stages.
Lead author, Wen-Sy Tsai, MD, Linkou Chang Gung Memorial Hospital, Taipei, Taiwan, said that the CTC blood test “may point to a solution for people who are reluctant to get an initial screening colonoscopy or are not compliant in returning stool-based test kits that they get from their doctors.”
The study enrolled 620 people over the age of 20 coming to a single center for routine colonoscopies or with a confirmed diagnosis of CRC. Based on colonoscopy and biopsy, 438 people were found to have either adenomatous polyps or early- to late-stage CRC; the remainder had no evidence of pre-cancer or cancer. All 620 people had a blood analysis for CTC using the CMx assay. Blood test results were compared with colonoscopy results in a blinded fashion.
The assay was 97.3% specific with less than a 3% probability of a false-positive test. Sensitivity of the test was 77% for detection of pre-cancerous lesions and up to 87% for stage I-IV CRC. Considering both specificity and sensitivity, the accuracy of the test ranged from 84% to 88% for pre-cancerous and cancerous samples, respectively. The CTC blood test has superior accuracy compared with the fecal occult blood test, say the authors.
The CTC test is inexpensive, and the authors envision using it to screen people in Taiwan for CRC, continuing to use colonoscopy as a definitive diagnostic test if the CTC test is positive.
Surgical Approaches (Abstracts 6, 206)
A randomized, controlled trial found that robot-assisted minimally invasive thoraco-laparoscopic esophagectomy (RAMIE) improved overall surgery-related and cardiopulmonary outcomes, postoperative pain, as well as quality of life and functional recovery compared with open transaortic esophagectomy (OTE), the current standard curative treatment for resectable esophageal cancer.
Oncologic outcomes in the 112 patients enrolled in the trial, including disease-free survival (DFS) and overall survival (OS), were similar between the two groups at 38 months of follow-up. Mean cost of RAMIE was about 5000 € less than that for OTE. Lead author was Pieter Christiaan Van Der Sluis, MD, University Medical Center, Utrecht, The Netherlands.
The Phase II TACTICS trial found that sorafenib in combination with transarterial chemoembolization (TACE) improved outcomes over TACE alone in patients with unresectable hepatocellular carcinoma (HCC). Patients randomized to TACE plus sorafenib (n=80) had improved progression-free survival (PFS) compared with TACE alone (N=76): Median PFS was 25.2 months versus 13.5 months, respectively (P=.006). Median time to progression was 24.1 months and 13.5 months, respectively. Survival is still immature. There was no unexpected toxicity.
This study provides the first evidence for the benefit of adding sorafenib to TACE in this setting. Lead author was Masatoshi Kudo MD, Kindai University Faculty of Medicine, Osaka, Japan.
Immunotherapy in GI Cancer (Abstracts 209 and 553)
The anti-PD1 inhibitor pembrolizumab achieved durable responses and favorable PFS and OS in patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib (79.8% progressed on sorafenib and 63.5% had extra-hepatic disease). In the phase II KEYNOTE-224 trial, 104 patients were treated with pembrolizumab. At data cut-off and a median follow-up of 8.4 months, 23% of patients were still on pembrolizumab.
Objective response rate (ORR) was 16.3% and was similar across subgroups with different etiology. Median time to response was 2.1 months, and 94% of responders were estimated to have a duration of response of 6 months or longer. Disease control rate was 65% (complete response 1 [1%], partial response 16 [15.4%], and stable disease in 47 [45.2%]), and progressive disease occurred in in 34 (32.7%). Median PFS was 4.8 months, and median OS was not reached. At 6 months, PFS was 43.1% and OS was 77.9%. Treatment-related adverse events occurred in 73.1%, and no new treatment-related concerns for pembrolizumab were raised.
Andrew X. Zhu, MD, Massachusetts General Hospital, Boston, was lead author.
First reports of efficacy and safety in the nivolumab plus ipilimumab cohort of CheckMate-142 demonstrate that 85% of patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic CRC had clinical benefit from the combination with manageable toxicity. This is the largest single study report of an immunotherapy regimen in patients with this disease type, and it suggests that nivolumab plus ipilimumab may represent a new standard of care, according to lead author Thierry Andre, MD, Saint-Antoine Hospital, Paris, France, and co-authors.
The study included 119 previously treated patients with dMMR/MSI-H metastatic CRC, 76% of whom received at least 2 prior lines of therapy. At a median follow-up of 13.4 months, ORR was 55% and disease control rate was 80%. CR was 3%, PR was 51%, and stable disease rate was observed in 31%. Median duration of response has not yet been reached, and 94% of responses were ongoing at data cut-off. Nine-month PFS was 76% and OS was 87%. About one third of patients reported grades 3 or 4 treatment-related adverse events. No treatment-related deaths were reported.
Outcomes Over Time (Abstract 724)
Patients with stage III colon cancer treated in the “modern era” with FOLFOX adjuvant therapy (i.e, 2004-2009 after bevacizumab was approved by the FDA) had improved OS and nearly double survival after recurrence (SAR) compared with patients treated between 1998 and 2003 (“old era”), according to a large retrospective study based on the ACCENT database that includes 6 adjuvant therapy trials including FOLFOX, with a total of 7230 patients (stage II, 1122; stage III, 6108). Thirty-two percent were treated in the old era and 68% in the new era.
Stage III patients enrolled in the new era were significantly younger, more likely to have T4/N2 disease, higher tumor grade, and left-sided tumors. In an analysis adjusted for patient characteristics, no difference in disease-free survival (DFS) was observed between the old and new eras. However, median SAR was significantly prolonged from 14.8 months in the old era to 26.4 months in the new era (P<.001) and 5-year OS was significantly higher in the new era (75.2% versus 80.2%, respectively; P=.004).
These findings suggest that the optimal duration of OS follow-up to evaluate the benefits of adjuvant therapy should be reassessed, the authors state. It is currently 5 years. The ACCENT investigators plan to conduct additional longer-term analyses using their large database.
Lead author was Mohamed E. Salem, MD, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC.
by Adrian Barfield, Founder and President, Medallion Healthcare
January 08, 2018 - 03:01 pm 0 Comments
By Michael D. Taylor, Ph.D.
When the “War on Cancer” was declared in 1971, the weapons available were blunt instruments – mainly surgery and early forms of chemotherapy – resulting in limited efficacy and lots of collateral damage to the patient. Now, nearly 50 years later, new therapeutic platforms have improved our ability to treat cancer, but the tumor remains a determined and creative foe. We’ve gone through three stages: first, using a scorched earth approach with chemotherapy; second, deploying smart bombs with targeted therapies; and third unleashing the immune system with immuno-oncology drugs.
Every cancer is different so we must learn how to match these different therapies, deployed singly or in combination, with each tumor type to maximize response. Yet even when we do so successfully, the cancer often responds with new defenses resulting in drug resistance.
At an impasse when resistance hits
Nobody in the cancer world is a stranger to the challenge of drug resistance. Resistance develops to non-selective chemotherapies, to molecularly targeted drugs and even to immunotherapies. The precision targeted therapies that serve as ‘smart bombs’ to thwart cancer progression were designed to target specific mechanisms that support tumor growth (e.g. bevacizumab) or protein mutations (e.g. imatinib) that result in the increased cell proliferation that drives the disease. In the face of such therapeutic pressure, tumor cells often respond by co-opting new molecular pathways or developing new mutations that cause drug resistance. In these cases, patients, who may have enjoyed significant clinical benefit for a time to a targeted therapy, are then often left without treatment options as the cancer evades the drug’s effects and may become even more aggressive. This resistance phenomenon occurs across tumor types including solid tumors such as breast or lung cancer as well as hematologic cancers like CML, and the mechanism of resistance can take many forms. No molecular target is impervious either as inhibitors of VEGF, ABL, EGFR, HER2, ALK, KIT, and many others become ineffective over time in many patients due to the development of new mutations in the target protein or via work-arounds by activating other signaling pathways.
The conventional wisdom of targeted therapy is that successful drugs will be highly selective for the target – “Silver Bullets” – designed to hit only the relevant targets and spare related cellular processes, thus limiting the collateral damage, or toxicity, to the patient. Ironically, it is often the drug’s selectivity that is the feature tumor cells exploit to escape by developing new mutations in the target protein or finding alternative pathways to compensate for the drug’s inhibitory action. Selectivity is the drug’s “Achilles Heel.” To date, our primary solution to drug resistance is to develop a succession of new therapies, so that patients can move to a new ‘smart bomb’ after the previous one lost its power due to resistance. But for many tumors, the pace of resistance is too great, and the cancer escapes each new therapy and grows stronger. For drug developers, it becomes a game of “whack-a-mole” trying to produce a new drug for each new mutation. And importantly, with each progression of the disease the tumor burden increases creating ever more tumor cells that may evolve new resistance mechanisms.
There are a broad range of cancers and targeted drugs that fit this profile where targeted therapies become resistant. These include EGFR, ROS1 and ALK inhibitors for lung cancer, ABL inhibitors for CML just for example. Some limited progress has been made with “second generation” inhibitors that can target the original mutation and the newly identified resistant mutation. EGFR inhibitors are a notable example, but these too become susceptible to the next mutation to appear. For these tumors, the ideal “targeted therapy” is not selective for a specific protein mutation but has the power to address the current driver mutation and to smother new potential resistance mutations before they emerge to extend the duration of disease control and keep the tumor burden as low as possible.
Let’s consider one interesting cancer, gastrointestinal stromal tumors (GIST), in which nearly all patients hit this impasse and new drug resistance mutations arise in substantial numbers in response to targeted therapy.
Gastrointestinal stromal tumors (GIST) was one of the early success stories for targeted cancer therapies. One of the very first such therapies, imatinib (Gleevec), has dramatically changed the landscape for this formerly intractable cancer and improved prognosis for many patients living with this cancer by targeting the mutations in KIT kinase, which causes disease in the great majority of GIST patients. But inhibiting those driver mutations did not produce long-term disease control in most patients. New mutations emerged producing resistance. Sunitinib (Sutent) was developed for those imatinib-resistant patients, but resistance to sunitinib emerged even more rapidly than to imatinib. And the story repeats with regorafenib (Stivarga) developed for sunitinib resistance. Although the three targeted therapies extended the lives of GIST patients for a few years, 90% of patients end up with uncontrolled disease as they exhaust their therapeutic options. The GIST tumors, and the KIT gene that drives them, are slowed but not beaten.
The Battle Continues
With the medical need for drug-resistant GIST remaining great despite three approved targeted therapies, drug developers continue to bring forward new treatments.
Blueprint Medicines is developing BLU-285, which continues the strategy of targeting a subset of mutations, primarily Exon 17 KIT mutations which are common in later-stage GIST and a PDGFRα mutation (D842V) that causes GIST in a small fraction of patients.
But clearly for GIST, targeted therapies, once perceived as a ‘smart bomb’, ultimately fail because they were specifically designed to address a single mutation, or subset of mutations, while cancer cells are known to constantly mutate in an effort to evade inhibition. As a result, targeted therapies do not provide the breadth of mutational inhibition necessary to overcome treatment resistance and outsmart these constantly morphing cancer cells.
GIST, in particular, demands a broader approach because these tumors are so facile in developing mutations.
A Different Approach
In order to overcome the perennial challenge of treatment resistance in cancers like GIST, one drug developer is evaluating a different approach.
Deciphera Pharmaceuticals, a clinical stage biopharmaceutical company, is developing a new anticancer treatment that is still targeted, but designed to act more like a multiple-warhead missile than a smartbomb – hitting multiple mutations in the target protein simultaneously. This broad activity has the potential to address the full spectrum of KIT and PDGFRα mutations known to be active in GIST, with the goal of transforming GIST treatment at all stages of this disease. DCC-2618 has shown promising activity in heavily pretreated late-stage GIST patients in a Phase 1 study.
Deciphera is committed to providing novel broadly acting therapies like DCC-2618 to cancer patients as quickly as possible. The Company recently initiated a Phase 3 pivotal trial with this pan-KIT and PDGFRα kinase inhibitor in fourth-line GIST patients, who have no approved treatment option. If successful, this study is intended to serve as the basis for regulatory approval in this patient population providing an important new option.
Dr. Taylor is President and CEO of Deciphera Pharmaceuticals. Prior to joining Deciphera, Dr. Taylor held senior leadership positions at Ensemble Therapeutics, Pfizer Inc. and Warner-Lambert/Parke-Davis.