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Interview with Dr. Ramalingam on First Line Advanced NSCLC and Maintenance Therapy
The ASCO meeting I’m at right now is so insanely busy during the days and nights that it’s next to impossible to carve out the time to write posts during the meeting. While the talk show hosts just show re-runs while they’re on vacation, we’re at least going to put up some new content, even if it’s from work previously done (and this is far from a vacation).
This podcast features Dr. Suresh Ramalingam, Director of the Thoracic Oncology Program from Winship Cancer Institute at Emory University in Atlanta. We discussed recent data that have led to changes in our current treatment standards for first line treatment of advanced NSCLC, as well as emerging evidence leading to debates about maintenance therapy after a fixed amount of initial chemotherapy. The video version includes synchronized figures. The audio is an mp3 file.
Ramalingam interview Adv NSCLC and Maintenance Aud
I’ll add the figures and transcript very soon.
Podcast: Play in new window | Download (62.3MB) | Embed
How Helpful are EGFR Inhibitors in Frail, Poor Performance Status Patients with Advanced NSCLC?
Among the many challenges in clinical oncology is the fact that a very significant proportion of our patients are quite a bit more debilitated than the vast majority of patients in clinical trials that test our anti-cancer therapies. Approximately a third of the patients with advanced NSCLC have what would be considered a poor performance status (PS) of 2 or 3 (0 to 5 scale, 0 being asymptomatic, and 5 being dead), but they are extremely under-represented on our clinical trials. Because our anti-cancer therapies, whether standard chemo or targeted therapies, have challenging side effects for many patients, we struggle to balance between fighting the cancer and harming the patient. In the absence of much evidence, we need to rely on our judgment when we make treatment recommendations.
Many physicians and patients have looked upon so-called targeted therapies as a potential alternative to standard chemotherapy drugs that could allow us to treat the cancer more selectively, with less collateral damage to a person’s normal tissues. The oral epidermal growth factor receptor (EGFR) inhibitors like Iressa (gefitinib) and Tarceva (erlotinib) have been the first agents that have been widely used as single agents, and they certainly have activity and can improve survival. Nevertheless, we’ve seen evidence that Tarceva was convincingly inferior to standard chemotherapy for poor performance status patients (at least “unselected” patients who hadn’t been particularly singled out by having an EGFR mutation, being a never-smoker, etc.); another study compared Iressa to the widely used single agent approach of Navelbine in elderly patients (not synonymous with poor performance status) and showed very comparable efficacy. Patients with both good and poor performance status were included in the important clinical trial that showed a survival benefit for Tarceva compared with placebo as a second or third line therapy, dicussed further below.
We get some additional information from a newly reported trial that randomized 201 poor performance status patients (considered to be “unfit for chemotherapy”) to either Iressa or placebo (plus general supportive care for all patients). The study was conducted in several centers in North America and Europe (so very few Asian patients were enrolled, a significant issue because results with EGFR inhibitors are often very different in Asian vs. Western populations). The majority of patients were also older, about half 75 or older, and most of the rest in the 65-74 age range. Importantly, this trial included not only patients with a PS of 2, who are still up and out of bed more than 50% of the time, but also PS 3 patients, who are pretty debilitated and spend more than half of the day in bed (enrollment was an approximately 60/40 split of PS 2 vs. 3 patients). Our experience in studying such frail patients is extremely limited.
Lung Cancer and the Enzyme Connection
Erlotinib (Tarceva) was approved for treatment of progressive non-small cell lung cancer (NSCLC) after the BR21 study that showed that tarceva not only improved survival but also improved lung cancer symptoms and quality of life. This study and others have also taught us that the benefit of tarceva is much better in those who had never smoked and less effective in current smokers. It is important to note, however, that even those who currently smoke obtain a benefit from treatment with tarceva, albeit smaller.
In the wake of the BR.21 trial, it became known that certain EGFR mutations in the tumor are associated with a dramatic benefit with tarceva, as well as the other EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa).We also began to realize that these EGFR mutations were found most commonly in never smokers and rarely in current smokers.
There it was: the reason why tarceva worked better in never smokers. But in fact that was not the whole story. Tarceva, like many other drugs, is broken down in the body by an enzyme group called CYP 1A1/1A2. Enzymes are proteins that help to break down and digest our food, but enzymes can break down and digest many other things as well. The products in inhaled tobacco smoke stimulate this enzyme CYP, which then further breaks down tarceva in the body before it has a chance to work.
EGFR Mutations Demystified
It has become a common topic of conversation on this site (and in the lung cancer community at large) to discuss mutations in the epidermal growth factor receptor (EGFR). However, since we frequently throw out the terms “deletion 19 mutation”, “L858R”, and “T790M”, I thought would be worthwhile to explain a little bit about the different EGFR mutations and what we know about their clinical significance.
The history and significance of EGFR mutations has been covered quite well in previous posts here, but I’ll provide my own quick synopsis, from the perspective of someone working in Boston during the time this work was being done. In the early 2000s the EGFR tyrosine kinase inhibitors (TKIs) Iressa (gefitinib) and Tarceva (erlotinib) were tested in large numbers of patients with non-small cell lung cancer. It was known the EGFR was an important target in lung cancer, since most NSCLC tumors express it and high levels of expression were associated with a worse prognosis, and the results of numerous trials testing these drugs in unselected patients were modestly positive. In a phase III trial, Iressa did not improve overall survival compared to placebo treatment in previously treated NSCLC patients (leading to the death of this drug in the USA), but the similar BR.21 trial (testing Tarceva rather than Iressa) did show a modest (~2 month) improvement in overall survival in previously treated NSCLC patients. This led to the approval of Tarceva in all NSCLC patients who had failed one or two prior chemotherapy regimens.
However, what was immediately evident from these and earlier trials, was that about 10% of Western patients treated with either of these drugs had dramatic and sometimes long-lasting responses. When they looked at who these people were, they found that most were women, all had adenocarcinoma (or BAC, a type of adenocarcinoma), many were Asian ethnicity, and most had either never smoked or smoked very little compared to average NSCLC patients. In 2004, investigators at the Dana Farber Cancer Institute and at Massachusetts General Hospital in Boston, and also at Memorial Sloan Kettering Cancer Center in NYC, simultaneously published results showing that most of these “dramatic responders” had specific mutations in the tyrosine kinase (TK) domain of the EGFR gene. The EGFR protein sits in the cell membrane and straddles the inside and outside of the cell.
(Click to enlarge)
How Much Does Treatment Sequence Matter in Lung Cancer?
One of the general rules in oncologist is that we typically use our most effective treatments first, and often early, though there are certainly exceptions. Women with metastatic breast cancer may have a higher response rate by receiving combination chemotherapy than single agent chemo, but when a gentle single drug chemotherapy or hormone therapy option will do very well and provide fewer side effects, that’s usually the approach we recommend until bigger guns are needed. Similarly, patients with slow-growing cancers like chronic lymphocytic leukemia (CLL) often do well for many years and sometimes forever without needing treatment, so we often hold on initiating any treatment unless there’s a good reason to (and I think the same argument can be made for some lung cancers, most commonly indolent bronchoioloalveolar carcinoma, or BAC). So we don’t want to treat patients with less therapy than they need, but we’d also prefer not to treat them with more.
When you have multiple potential treatments to pursue, one question that becomes relevant is whether the sequnce matters. If you have choices A, B, and C, does it matter if you give AB followed by C, or C followed by AB or even A followed by B and then C? First, we need to take a step back and recognize that this is a good dilemma to have, because 10 years ago we didn’t have multiple effective treatments to try to position. For advanced NSCLC, the value of giving chemo for metastatic disease was debated until about 10-12 years ago, when the survival benefit of platinum-based doublet chemo regimens became a clear standard. In 2000 or so, second line taxotere emerged as a second line treatment option that improved survival and was approved by the FDA in that setting. A few years later, additional treatment options for previously treated patients with advanced NSCLC were approved, ushering in agents like alimta and EGFR inhibitors (initially iressa and then tarceva, with iressa removed from the US marketplace. These all became viable options, and over the last few years all of these agents have also been studied as first line treatments. Taxotere and alimta are now both FDA approved as first line combination therapy with platinum, and the EGFR inhibitors have also been studied as first line treatment and have appeared particularly attractive in certain subsets of patients, such as those with an EGFR mutation or patients with advanced BAC.
EGFR Tyrosine Kinase Inhibitors for Patients with EGFR Mutations
Back when I first started doing this, one of my earliest posts (see here) was on the question of whether EGFR tyrosine kinase inhibitors (TKIs) (see introduction to this work in prior post). My point, which is still true, is that EGFR TKIs aren’t only effective in a narrow population of patients, whether identified based on molecular or clinical variables. But in the more limited number of patients who have the “activating mutation” in the actual receptor, who might be expected to do especially well with an EGFR TKI, how do they do? How does a targeted therapy do in a precisely targeted population?
There are several studies that have now tested this by identifying patients who have an EGFR mutation and received an EGFR TKI. As shown in the table below, the results are very clear and consistent.
(Click to enlarge)
Iressa for Elderly and/or Poor Performance Status Patients with an EGFR Mutation
Several years ago, we learned that EGFR tyrosine kinase inhibitors (TKIs) were not a very helpful strategy for an unselected population of frail patients in the US, clearly inferior to standard chemotherapy (see prior posts here and here). This work was in patients who hadn’t been tested for molecular markers like EGFR mutations, and our interpretation of the previous US-based trial left us with the conclusion that an EGFR TKI like tarceva (erlotinib) or iressa (gefitinib) was an inferior chemotherapy alternative and apparently ineffective treatment for the majority of patients with a marginal performance status, but it could still be an effective option for patients selected to be especially likely to benefit from this class of agents, like patients with an EGFR mutation.
This was the subject of pure speculation until now. A manuscrupt by Inoue and colleagues (abstract here) has just been published that describes the experience of treating patients with an EGFR mutation and who are either elderly or have a poor performance status or both with an EGFR TKI (iressa at the standard 250 mg/day) as first line therapy. Specifically, they enrolled 30 patients who either had a poor performance status (3 or 4 on a scale of 0 to 5 where 0 is asymptomatic and 5 is dead: details here), or were 70 or older with a marginal performance status (2 -4) or 80 or older with any symptoms (1-4). It’s worth noting that there are relatively few studies that include patients with a performance status of 2, and almost none that have included patients with a performance status of 3, who spend more than half of their day in bed and can’t take care of many of their activities of daily living. Continue reading
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