Updates in NSCLC Management: What Does the Future Hold for First‐Line Therapy?

Course Director

Howard (Jack) West, MD

Howard (Jack) West, MD
Thoracic Oncology Program
Swedish Cancer Institute
Seattle, Washington

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Part 1 of a 2-part series

Dr. West provides expert feedback to the questions submitted by your peers during a recent survey on this topic.


Extraordinary progress has been made in the management of non–small-cell lung cancer (NSCLC). Individualizing therapy based on mutational status, performance status, as well as other clinical factors has become the standard of care, with all patients benefitting from optimal first-line therapy. In the first part of this series, Dr. Howard (Jack) West answers questions submitted by US oncologists regarding current evidence and practice for optimal first-line therapy for NSCLC.

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What is optimal treatment for elderly patients with adenocarcinoma and good performance status who do not have EGFR mutation(s)?

Dr. West: We have seen converging evidence over the last several years that fit elderly patients should really be treated identically to the way we would treat younger patients with a good performance status, with the potential exception of whether to include bevacizumab or not. With regard to chemotherapy, studies have shown that elderly patients enjoy the same kind of benefit with a carboplatin-based chemotherapy doublet compared with single-agent therapy that younger, fit patients do.1

With bevacizumab, a subset analysis by Dr. Ramalingam and colleagues looking at the ECOG 4599 trial suggested that patients over 70 [years of age] did not experience a survival benefit with the addition of bevacizumab, unlike younger patients.2,3 This might have been because they experienced disproportionally greater toxicity issues with the addition of bevacizumab. There was also an analysis of the SEER database that suggested that there was no survival benefit with the addition of bevacizumab to carboplatin and paclitaxel in elderly patients, as well.4

So, I think that [the] addition of bevacizumab is a debatable point and still worth individualizing, based on judgment and the patient in front of you. However, I think that the approach with carboplatin-based chemotherapy would be a very appropriate choice for a good–performance-status elderly patient; and you can use whatever doublet—based on histology and other individual factors, [such as] schedule, desire to avoid toxicity—that you would be inclined to do for a patient who is younger.

Narrator: A phase 3 study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naïve patients demonstrated that overall survival was superior for the cisplatin/pemetrexed combination in patients with adenocarcinoma, with a better tolerability profile.5

Dr. West: I have personally favored a combination of carboplatin and nab-paclitaxel for patients with a squamous histology, [in part] because of a subset analysis of the pivotal trial that appeared to demonstrate particularly favorable results with the nab-paclitaxel combination in older patients and those with a squamous histology.6

Narrator: In addition, Dr. West notes that because it is a weekly regimen, this allows clinicians to get quick feedback on how well patients are tolerating the treatment, and adjust the regimen as needed.

Dr. West: So, in our older patients, we certainly do want to be especially mindful of potential tolerability issues, and I've found that both of those regimens have been very promising. And I think we are moving toward a more histology-specific approach to treatment with our chemotherapies, as well as targeted treatments.

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In the future, will crizotinib be used with chemotherapy for first-line treatment of ALK-positive NSCLC?

Dr. West: At this point, we really don't have evidence to support combining crizotinib with chemotherapy in the first-line setting for ALK-positive patients. That's not to say that it can't or shouldn’t be done in certain situations, but I think that we have learned from the experience with erlotinib and other EGFR tyrosine kinase inhibitors [TKIs] for patients with an activating EGFR mutation, where the data really don't support a combination of conventional chemotherapy with concurrent targeted therapy in the first-line setting.7,8  

We might well consider combining them in the setting of acquired resistance, although that remains an undefined question. But right now, to my knowledge, there really has not been a study to support this. We have seen remarkably good results with crizotinib as a single agent that really eclipse what we expect to see with most first-line chemotherapies.9 And so, I would say that there's more enthusiasm for using a sequential approach and favoring the least toxic and the least treatment necessary to enjoy good control of the cancer for the foreseeable future. In the majority of patients with an ALK-positive lung cancer, that can be crizotinib or, potentially in the future, a next-generation ALK inhibitor that is [currently] in clinical development.10 

One issue that not uncommonly occurs in patients who have an ALK rearrangement or an activating EGFR mutation is that they may start on chemotherapy-based first-line treatment and then be subsequently found, partway through one or two cycles of chemotherapy, to have one of these driver mutations. So, the question is how do you integrate or transition from chemotherapy to targeted therapy or combine them? That has yet to be defined, but I would say that the majority of experts favor giving the treatment that you have initiated enough of a chance to see what that's going to do. In other words, if you’ve given one or two cycles of chemotherapy, get a repeat CT scan and, if they are responding well to treatment, don't necessarily discontinue that after one or two cycles, but maybe continue that through four or even potentially six cycles. And just know that you have a very attractive treatment option waiting in the wings to use later. You might well want to use a switch maintenance-type approach to transition right into an EGFR or ALK inhibitor, depending on the mutation in question.

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What are the key treatment options for a patient with local symptoms of obstruction and EGFR-positive disease: Is erlotinib monotherapy an appropriate choice, or should the patient receive radiation followed by chemotherapy (ie, carboplatin and a taxane)?

Dr. West: I have come across this issue in some of my own patients, whether it is with local obstruction in the chest or potentially brain metastases, for which we would reflexively reach for a local therapy—most commonly radiation-based in the setting of metastatic lung cancer with brain mets.
In patients with a driver mutation and a systemic therapy, where you now have a treatment with a high probability of good and durable response in the 60% to 75% range, I would say that this gives us the opportunity to use the systemic therapy as a window of opportunity—essentially a short course of treatment—and see whether you might have a dramatic response within a couple of weeks. I have had several patients, including many in the last few months, whom I've treated with crizotinib or with erlotinib for an ALK rearrangement or EGFR mutation, respectively, who have reported a staggering improvement in their symptoms within just a matter of days, and who have subsequently had radiographic evidence of a dramatic response, as well.

And so, if you have a realistic possibility or even probability of that kind of response with a daily oral therapy and no radiation, I think that is a very strong leading consideration. In these situations, I’ve often had a patient meet with a radiation oncologist who is familiar with the case and can intervene immediately if we see worsening of symptoms, rather than improvement. But I would absolutely say that starting with a very promising, and often very tolerable, systemic therapy is [a] completely reasonable approach and may well be preferred over starting with radiation when you have such a good chance of success with it. Most of the studies just haven't looked at it because it's such a common-sense issue; all of the clinicians who have treated patients with these targeted therapies for the right population have seen these kinds of responses.        

So, the point is that you do have this window of opportunity, and if they have a great response, well, you’ve obviated the need for radiation or some other local therapy. If they don't, then radiation is still a very appropriate consideration. And so, the first-line therapy that would be routinely favored for patients who don't need radiation for tumor bulk or some other issue would usually be a targeted therapy, if you know that patients have the driver mutation in question—rather than chemotherapy. It's reasonable to consider chemotherapy, but I would say that most experts would favor pursuing the treatment specifically for the driver mutation, if you’ve identified it.      

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  1. Quoix E et al. Lancet. 2011;378:1079-1088.
  2. Ramalingam SS et al. J Clin Oncol. 2008;26:60-65.
  3. Sandler A et al. N Engl J Med. 2006; 355:2542-2550.
  4. Zhu J et al. JAMA. 2012;307:1593-1601.
  5. Scagliotti GV et al. J Clin Oncol. 2008;26:3543-3551.
  6. Socinski MA et al. J Clin Oncol. 2012;30:2055-2062.
  7. Herbst RS et al. J Clin Oncol. 2005;23:5892-5899.
  8. Gatzemeier U et al. J Clin Oncol. 2007;25:1545-1552.
  9. Shaw AT et al. Lancet Oncol. 2011;12:1004-1012.
  10. Ardini E, Galvani A. Front Oncol. 2012;2:17. doi:10.3389/fonc.2012.00017.2.

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