The 51st American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago during May 29- June 2, 2015 brought together 30,000 oncology professionals from around the world. Latest ground-breaking research was presented at the conference by world-renowned faculty and key opinion leaders discussing state-of-the-art treatment modalities, new therapies, and ongoing controversies in the field.
Many exciting advances in lung cancer diagnosis and treatment were presented at the meeting. A few of the most exciting presentations are summarized below.
New drugs for other segments of the lung cancer pie:
- Lung cancer is not one disease, it is a heterogenous collection of several subtypes, each of which has a different underlying ‘driver’ mutation. Targeted therapies against these driver mutations have been shown to halt disease progression, e.g. Erlotinib (Tarceva) in EGFR+ pts, Crizotinib (Xalkori) in ALK+ patients etc.
- Because several known cancer-causing mutations occur in multiple types of tumors, cancer is increasingly defined not just by the organ in which it originated but by the mutations that drive its growth.
- 1-2 % of NSCLC patients present with RET fusions. Data presented at the ASCO meeting suggested that a drug active in medullary thyroid cancer, cabozantinib might be effective in this lung cancer subtype, with a median duration of response of 8 months, median progression-free survival of 7 months, overall survival of 10 months.
EGFR (Epidermal Growth Factor Receptor) TKIs (Tyrosine Kinase Inhibitors):
- EGFR is a protein that is mutated in a subset of non-small cell lung cancer (NSCLC). Mutated EGFR can be easily identified by a lab test, and we have targeted therapies that are effective against the various mutations in EGFR.
- Patients with EGFR mutations that receive EGFR-directed targeted therapy usually develop resistance to these treatments over time- 60% of patients develop resistance to these therapies in a year. Therefore, the need for newer, more effective EGFR-targeted agents.
- Several are under development. The top two contenders are third-generation EGFR inhibitors from AstraZeneca and Clovis, its a David Goliath story. Data on these two drugs was presented in the same session.
- Rociletinib or CO-1686, Clovis’ EGFR inhibitor demonstrated a median progression-free survival (PFS) of 8 months in heavily pretreated EGFR+ NSCLC patients compared to the 13.5 month PFS with the AZ drug, AZ9291.
- In terms of side effects, the AZ drug was related to “interstitial lung disease-like” side effects vs. Clovis’ drug that’s associated with hyperglycemia or high blood sugar, caused by insulin resistance mediated by the drug. Both these side effects are manageable, AZ9291 by adjusting the dose, and CO1686 by commonly prescribed medication. Interestingly, the Clovis drug is active in T790M-ve patients as well, which may be attributed to a false negative, i.e. these patients were actually T790M+ but were falsely diagnosed as T790M negative due to imperfections in the testing (assay sensitivity issues) or tumor heterogeneity, etc. Also, an interesting phenomenon noted was that patients develop resistance to the Clovis drug over time and in 50% of these patients that were originally T790M+ became T790M negative.
- The study on Rociletinib also evaluated the ability to detect the T790M mutation in plasma DNA. Patients with T790M positive disease identified by plasma had response rates similar to those identified by biopsy/tissue-based molecular testing. This is very interesting that it shows up in plasma DNA despite tumor heterogeneity. Secondly, non-invasive detection is any time better than getting multiple biopsies.
- Rociletinib was active in T790M negative patients. Further evaluation in this patient population is ongoing.
- AstraZeneca is currently also investigating AZD9291 as first line therapy for EGFRm NSCLC patients, and in combination with MEDI4736 (anti-PDL1 immunotherapy), selumetinib (MEK inhibitor) and AZD6094 (MET inhibitor) in NSCLC. n
- Several other EGFR TKIs are under development. Preclinical and phase 1 data on a new EGFR inhibitor AZD3759 in NSCLC were presented in a poster. This new inhibitor presents with excellent blood brain barrier penetration and is effective against brain metastases. Further clinical evaluation is underway in the Asian market by AstraZeneca.
- Unanswered questions:
- Additional clinical investigation will also be required to determine the ideal sequence of the various EGFR TKIs, and how best to prevent or manage the different mechanisms of resistance to the EGFR TKIs. Need randomized clinical trials to evaluate these.
- If 3rd gen agents begin to be used in the frontline setting, would there be a role for the 1st/2nd gen agents? Yes and no. New pathways of resistance to these new inhibitors are beginning to be identified, e.g. new EGFR mutations are being identified in resistant tumors (C797S, which confers resistance to third-generation TKIs, so it is important to sequence for C797S mutation in patients with acquired resistance to third-generation TKIs to determine further treatment strategies), NSCLC to small cell transformations. One recent study has shown that using an EGFR inhibitor in combination with an EGFR directed monoclonal antibody (Cetuximab) is effective against the most resistant clone in these resistant tumors.
- Though the T790M mutation remains the most common resistance mechanism, other resistance mechanisms are emerging: MET amplification, HER2, transformation to small cell lung cancer, and these need to be studied further.
ALK rearranged Lung Cancer
- Alectinib for ALK+ NSCLC patients: Alectinib is a highly selective ALK inhibitor that is five times more potent than crizotinib (Xalkori), and is active in both Crizotinib-naive and Crizotinib-refractory patients.
- One benefit over Crizotinib is that Alectinib crosses the blood-brain barrier very effectively and is very effective against central nervous system (brain) metastases, that are commonly seen in patients that progress on crizotinib. Only 2% of current drugs pass the BBB, which is both a good and a bad thing, Erlotinib (Tarceva) concentrations in the CNS are typically 1-10% of what they are in the blood, while Crizotinib (Xalkori) is only 0.3%.
- Phase 2 data on Alectinib was presented at the ASCO Annual Meeting that demonstrated that the drug was well tolerated and achieved a robust treatment response, including excellent intracranial activity, in ALK+ NSCLC pts who had progressed on crizotinib; most had also failed prior chemo and had CNS mets. Alectinib treatment resulted in an overall response rate of almost 50% in patients with advanced ALK-positive NSCLC whose disease had progressed after crizotinib. A phase 3 trial of first-line alectinib vs crizotinib and an expanded access program are ongoing.
ALK/ ROS Rearrangements
- Alice Shaw presented a poster on PF-06463922, a selective, brain-penetrant ALK/ROS1 tyrosine kinase inhibitor (TKI) with potent activity against de novo fusions as well as resistance mutations, including ALKG1202R, that arise during treatment with other TKIs. PF-06463922 was well tolerated and had clinical activity in patients with ALK+/ROS1+ NSCLC, most of whom had CNS metastases and received ≥ 1 prior tyrosine kinase inhibitors. Further evaluation is ongoing.
New drug targets in LC: MET exon splice mutations and NF1 mutations.
Small Cell Lung Cancer (SCLC)
- It has traditionally been the most aggressive subset of lung cancer for which there has been no new treatment option for the past 30 years.
- The current standard of care is platinum-based chemotherapy that works remarkably well for a few months, after which invariably most patients develop resistance.
- It was encouraging to see that new treatments are being evaluated in this subset of the disease and some positive data is coming out, e.g. SCLC is responsive to immunotherapy.
- Reasons: SCLC is predominantly a smokers’ disease, smoking causes multiple mutations in the genomes of these tumors, resulting in a high ‘mutational burden’ in SCLC. And a high mutational burden is a predictive biomarker of response to immunotherapy, as in, higher the number of mutations in a tumor, greater the likelihood for immunotherapy to be active against it.
- Immunotherapy has been shown to work in the platinum-refractory patients as well, i.e. patients who had stopped responding to platinum-based chemo.
- Combinations of immunotherapy have been evaluated in clinical trials in these patients and have shown promising results.
- Basic research into the biology of SCLC has identified some new drug targets that were presented at the meeting: DNA repair pathway- PARP, Cyclin Dependent Kinases (CDK), topoisomerases, polokinases, microtubule inhibitors
Cost of Drugs
On the first day of the meeting, an oncologist from Memorial Sloan Kettering Cancer Center, Leonard Saltz, presented a talk on the skyrocketing costs of breakthrough cancer drugs, and presented an example of the cost of two immunotherapies (both manufactured by Bristol Myers Squib): Nivolumab (Opdivo) and Ipilimumab: a whopping ~$300,000.
Dr. Saltz said “the unsustainably high prices of cancer drugs is a big problem, and it’s our problem… Cancer-drug prices are not related to the value of the drug. Prices are based on what has come before and what the seller believes the market will bear.” This talk has been picked up by media outlets everywhere and has initiated a lot of discussion on the cost of oncology care, an important discussion that needs to happen.
Obesity is a major unrecognized risk factor for Cancer:
- Obesity is associated with worsened prognosis after cancer diagnosis and also negatively affects the delivery of systemic therapy, contributes to morbidity of cancer treatment, and may raise the risk of second malignancies and comorbidities.
Early Initiation Of Palliative Care Improves Patient Well-Being:
- Recent research has shown that palliative care services not only improve physical symptoms and emotional and mental well-being for patients with advanced cancer, but can also extend life. However, palliative care is often offered too late in the course of the disease—typically in the last 2 months of life, after all curative treatments have been exhausted.
- Discussion during a session at the meeting pointed to the fact that early palliative care with chemotherapy is typically better for ambulatory lung cancer patients than chemo alone. These patients typically end up receiving lesser chemo in the last 14 days of life 17.5% relative to 24% in the patients who didn’t receive palliative care.
- The ENABLE study conducted in community centers, NCI and the VA hospitals that compared early palliative care vs late PC showed that at 1 year there was a 15% survival difference- 63% vs 48% with just a 3 mo diff in palliative care administration.
- Compared with patients who received standard cancer care only, patients who also received palliative care services had improvements in several aspects of quality of life—spiritual well-being, quality of life at the end of life, symptom severity, and satisfaction with care—at 4 months after diagnosis.