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.