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Rush University Medical Center
Chief, Division of Hematology/Oncology
Department of Medicine
Georgetown University Hospital
At the 2020 ASCO Virtual Annual Meeting, important results were presented that have the potential to change treatment of lung and gastrointestinal cancers. In this commentary, Mary Jo Fidler, MD, and John L. Marshall, MD, discuss these key findings. For a more in-depth, interactive discussion with these expert faculty, join us for a 1-hour live Webinar on Tuesday, June 30, 2020, at 7 PM ET by registering here.
Lung Cancer Studies
Mary Jo Fidler, MD:
ADAURA: Adjuvant Osimertinib in Non-Small-Cell Lung Cancer (NSCLC)
This year’s ASCO was exciting with clinically meaningful presentations. First, early results from the international phase III ADAURA trial were presented at the Plenary session. The ADAURA trial randomized stage IB-IIIA (7th edition staging) to 3 years of the EGFR tyrosine kinase inhibitor osimertib or placebo after completion of their definitive surgery and chemotherapy, if administered. The primary endpoint was disease-free survival in stage II and IIIA patients and these early results showed a very significant disease‑free survival benefit for osimertinib with a hazard ratio of 0.17 and the median disease-free survival not reached in the osimertinib arm. In all stages (N = 682 randomized) disease-free survival was better with osimertinib, whether or not patients received post-operative chemotherapy.
The early look at the data was suggested by the Independent Data Safety and Monitoring Committee and we look forward to longer follow up and information about sites of disease recurrence and quality of life differences among patients, though it may take some time before we know if this strategy translates into an overall survival improvement. Final results of the CTONG trial of post-operative gefitinib vs 4 cycles of cisplatin plus vinerelbine were also presented, and gefitinib failed to improve overall survival in a similar patient population. As osimertinib has better CNS penetration then gefitinib, it could be that reductions in CNS metastases in the ADAURA trial will translate into meaningful benefits in quality of life and, hopefully, overall survival for these patients.
High-Dose Thoracic RT in Limited-Disease Small-Cell Lung Cancer (SCLC)
Gronberg and colleagues conducted a randomized phase II trial that looked at twice‑daily radiation scheduling for patients with limited‑disease SCLC. Previous data have suggested a potential benefit for a twice‑daily regimen, but because this is inconvenient and difficult to schedule, it has not been widely adopted. Patients in this trial (N = 176) received 4 courses of chemotherapy and were randomized to concurrent twice‑daily thoracic radiotherapy with 45 Gy or 60 Gy. Results showed a large 2-year survival benefit with the higher‑dose regimen: 70.2% remained alive vs 46.1% of those receiving 45 Gy. Median OS was longer as well, at 41.8 months with 60 Gy vs 22.9 months with 42 Gy. Of importance, the higher dose did not seem to be associated with higher toxicity than the standard dose. With the caveat that this was a small study, I think it will move the radiation field a bit further and could expand discussions with patients with SCLC about radiation therapy scheduling.
Progress in Mesothelioma
Malignant pleural mesothelioma is a relatively rare lung tumor type typically associated with asbestos exposure. Forde and colleagues presented results from the phase II PrE0505 study (N = 55) that evaluated the addition of a PD-L1 immune checkpoint inhibitor, durvalumab, to first-line chemotherapy (cisplatin and pemetrexed) in patients with unresectable malignant pleural mesothelioma. Results showed a promising median OS of 20.4 months with a 12-month OS rate of 70.4% and 2-year OS rate of 44.2%.
In the second-line setting for advanced malignant pleural mesothelioma, the Italian phase II RAMES study evaluated the addition of the VEGFR2 inhibitor ramucirumab to gemcitabine after platinum and pemetrexed chemotherapy (N = 174). Compared with gemcitabine alone, the combination of ramucirumab and gemcitabine significantly improved median OS from 7.5 months to 13.8 months (HR: 0.71). It is encouraging to see some progress in this disease that has been difficult to treat.
DESTINY-Lung01: Trastuzumab Deruxtecan (T-DXd) in HER2-Positive NSCLC
The phase II DESTINY-Lung01 study is evaluating the HER2-targeted antibody–drug conjugate T-DXd in patients with relapsed/refractory, metastatic, HER2-positive NSCLC (planned N = 170). At ASCO 2020, interim results were presented from 42 patients with HER2-mutated NSCLC. In this presentation, the ORR was 61.9% with median duration of response not reached. This is the type of response rate we like to see when targeting driver mutations, and I am hopeful that this study will broaden our treatment options for HER2-positive NSCLC.
Supportive care is a critical component in every patient’s anticancer regimen to maintain optimal quality of life and maximize clinical benefit from anticancer therapies. Our cancer center has disease-specific nurse navigators assigned to small groups of physicians, which has worked well. The nurse navigator checks in with patients, follows up on lab tests, discusses any reported symptoms, and builds a relationship with patients that benefits them in the long run.
We also recently implemented a multidisciplinary effort to improve supportive care for patients receiving treatment for NSCLC, specifically including nausea. Our institution’s pharmacy and nursing staff conducted a comprehensive review of the guidelines, recommendations, and evidence for available antiemetics and then met with staff from the whole cancer center to make sure patients receive the best supportive care while receiving treatment.
An important question in managing patients with cancer-related anorexia and cachexia is when to involve a palliative care service. We have seen studies showing a survival benefit for patients with lung cancer who received early palliative care and a study showing that better symptom reporting also led to improved survival. Focusing on symptoms and palliative care will, hopefully, help our patients live longer with a better quality of life. When considering whether to refer patients to a palliative care service, we may delay that option if they are feeling fine. The other consideration is optimizing supportive care with our nursing navigator team, as they discuss symptoms with patients and provide feedback to clinicians. Regarding anorexia and cachexia specifically, the first thing I do is educate caregivers and family members because often the anorexia and the cachexia are causing much more distress to them than to the patient (who is not hungry or eating).
Though we do see patients with a new lung cancer diagnosis who have cancer cachexia, cancer cachexia becomes more common with more lines of therapy. The best way to treat cancer cachexia is to treat the underlying illness and thereby, hopefully, reduce the associated chronic inflammation. Reducing that chronic inflammation could also help improve efficacy of immune checkpoint inhibitors because they work best in the absence of chronic inflammation. My hope is that increasing use of new cachexia drugs will correspond with increasing efficacy of cancer therapies. Medications used to treat cachexia include steroids and mirtazapine, a common antidepressant that also can stimulate appetite. Late-phase clinical trials of ghrelin agonists such as anamorelin look promising as well.
Key Gastrointestinal Cancer Studies
John L. Marshall, MD:
A key theme in gastrointestinal cancer treatment was evident in the ASCO 2020 results: Everything is going neoadjuvant. The older algorithm was to use surgery followed by chemotherapy followed by radiotherapy, that is, adjuvant treatment. Today, neoadjuvant therapy flips this approach to give chemotherapy before surgery. It is effective in pancreatic cancer, gastric cancer, and now colorectal cancer as well. This shift is because we now have more-effective drugs, such that giving systemic therapy first, even in resectable patients, will provide benefit. Compared with previous treatment eras, modern drugs are tolerated better and allow patients to be downstaged so that surgeries are more successful with easier recovery. Relatedly, there is now solid and dramatic evidence from the IDEA series of studies that 3 months of chemotherapy, at least in colorectal cancer, provides a similar OS benefit as 6 months. In the clinic, this means we can use just 3 months of chemotherapy before surgery, with no additional chemotherapy, and this will be much easier for patients. Neoadjuvant approaches are also useful in drug development because they allow faster testing of new agents than in postsurgical settings.
New Targets: Microsatellite Instability (MSI) and Mismatch Repair (MMR) Defects
Another theme seen in gastrointestinal cancer at ASCO 2020 was new targets. Andre and colleagues presented results from the phase III KEYNOTE-177 study, which evaluated first-line pembrolizumab vs chemotherapy in patients with MSI-high or MMR-defective colorectal cancer. An important aspect of this study was that testing for MSI and MMR was required for enrollment. The results were fascinating, in that initially chemotherapy was winning the day, but eventually immunotherapy showed a significantly longer PFS than chemotherapy: 16.5 months vs 8.2 months (HR: 0.60). We all hope that this will result in a new approval for pembrolizumab as first-line therapy for MSI-high metastatic colorectal cancer. These results also reinforce existing recommendations to test all patients with colorectal cancer for MSI status prior to selecting treatment.
CheckMate 142 is a phase II study of nivolumab plus low-dose ipilimumab as first-line therapy for patients with MSI-high or MMR-defective metastatic colorectal cancer. At ASCO 2020, Lenz and colleagues presented 2-year results from CheckMate 142 (N = 45) that showed a 69% ORR with a 13% CR rate, and the median duration of response was not reached. Median PFS and OS are not yet reached. In my opinion, both single‑agent pembrolizumab and the combination of nivolumab and low-dose ipilimumab may receive FDA approval as first-line therapy for metastatic colorectal cancer.
New HER2-Targeted Approach: T-DXd
As HER2-targeted drugs are increasingly developed in breast cancer, there is a “trickle down” of these agents into colorectal cancer and gastric cancer, as well as lung cancer as Dr. Fidler discussed above, all of which have HER2 overexpression. Key among these is the antibody–drug conjugate T-DXd. This comprises an HER2-targeted monoclonal antibody conjugated to a cytotoxic topoisomerase‑1 inhibitor payload. Results with T-DXd have been promising in patients with HER2-positive refractory gastric and colorectal cancers. For example, at ASCO 2020, Siena and colleagues presented results from the phase II DESTINY-CRC01 study of T-DXd in refractory, HER2-expressing, metastatic colorectal cancer (cohort n = 53), showing “remarkable activity” including a 45.3% ORR and median OS not reached. Likewise, in the phase II DESTINY-Gastric01 study in a similar population with HER2-positive gastric or gastroesophageal junction cancers (N = 187), T-DXd significantly improved both ORR and OS vs standard chemotherapy.
Two studies have assessed HER2-targeted agents as neoadjuvant therapy for gastric cancer. Results showed no significant benefit, which is curious given that HER2 targeting works in the metastatic setting. Certainly, the biology of HER2 expression and targeting seems to be different in the metastatic setting compared with the neoadjuvant setting.
Most patients with gastrointestinal cancers need of some form of palliative care. These are difficult diseases that cause pain, anorexia, and disruption of the gastrointestinal tract. For all of those reasons, patients require a high level of supportive care right from the beginning. This is particularly true for metastatic disease and increasingly true through lines of therapy. As clinicians, we need to dedicate time to palliative care and consider referral to palliative care specialists if available.
Unlike many tumor types, all gastrointestinal cancers disrupt nutrition to some degree, either through direct anorexia or cachexia. Pancreatic cancer may be the most infamous type in this regard, as the disease itself causes the problem. Depending on what the specific problem is, we support it differently. If it is a “plumbing problem”, often that requires nutritional support, which can encompass everything from tube feeding all the way to total parenteral nutrition. Sadly, this is routine for many of our patients.
Managing disruption of nutrition is particularly important in the neoadjuvant setting, as patients often present at diagnosis having already lost a significant amount of weight. They need nutrition support as part of neoadjuvant or first-line therapy. This is complicated because chemotherapy can cause anorexia as well as the disease itself, which is a major problem. Strategies to improve appetite include medicines like mirtazapine, steroids, megestrol, and progesterone agonists. In addition, cannabis is legal to use and recommended as medicine in 2 of the 3 jurisdictions in which I work, and in my clinical experience, it does help patients. We continue to seek out new therapies to improve this aspect of treatment because cachexia and anorexia are not only a quality-of-life issue for our patients, but are also comorbidities which shorten patients’ survival. It is important to intervene early with effective therapies to maintain optimum quality of life and survival.
How do you manage cancer-related anorexia and cachexia in your patients with lung and gastrointestinal cancers? Do you initiate appetite stimulants and nutritional consults during anticancer therapy if the patient meets criteria for cancer-related cachexia? Please share your thoughts in the comment box below and join us on Tuesday, June 30 at 7 PM ET for our live Webinar as we discuss these and other important new findings in lung and gastrointestinal cancers!