Novel Therapies for NSCLC: Management of Disease Beyond Progression

Course Director

Jyoti D. Patel, MD

Jyoti D. Patel, MD
Feinberg School of Medicine
Northwestern University
Chicago, Illinois

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Part 2 of a 2-part series

Dr. Patel 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 benefiting from optimal first-line therapy. In the second part of this series, Dr. Jyoti Patel answers questions submitted by US oncologists regarding current therapeutic strategies for progressive NSCLC.


This activity is supported by educational grants from Genentech and Lilly USA, LLC. Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
Jyoti D. Patel, MD, has a financial interest/relationship or affiliation in the form of:
Consultant for Genentech, Inc.
Grant/Research Support from Eli Lilly and Company.
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Annette Wiggins
Answers in CME, Inc.
Annette Wiggins has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

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This is a case concerning an 82-year-old male with adenocarcinoma. He responded well to initial therapy with cisplatin/gemcitabine; he now presents with residual mild effusion. His EGFR mutational status is unknown, due to lack of cells. Would you re-biopsy to assess EGFR status? What treatment would you recommend?

Dr. Patel: This is a very interesting case. The fact is that almost half [50%] of our patients are over 70 [years of age], and there are unique treatment considerations for these patients.

Clearly, this patient was well enough to get about four cycles with a very nice response. He now has recurrence of a mild effusion. So we have a lot of treatment options, assuming that his performance status is well-preserved. I think that we could consider single-agent docetaxel, single-agent pemetrexed, or erlotinib—if he is quite well, doesn’t have a lot of lingering toxicity from the [first-line] therapy, and he's had responsive disease, that second-line therapy would provide not only a survival advantage, but probably a clinical benefit by keeping the effusion from returning.

If he had disease that was easily accessible through a biopsy, I would very much advocate for repeat biopsy. I would be more likely to do this if he had a modest or never-smoking history. I know we can't select [for] mutations clinically, but if my pretest suspicion is that he has an EGFR mutation in the second-line setting, I'd probably do the biopsy. This has relevance in terms of prognostic significance, and would help us plan and certainly personalize therapy.

So, if he had an [EGFR] mutation, the answer is easy: I'd treat him with erlotinib. Particularly in the elderly who have sensitizing mutations, treatment with tyrosine kinase inhibitors [TKIs] can have a dramatic response.1 If the tissue was more difficult to assess, then in all likelihood, I would treat this patient with single-agent pemetrexed until he had significant toxicity or progression of disease. So, pemetrexed every three weeks, with imaging every two or three cycles, again, until toxicities precluded further therapy.

There are some investigational therapies that many of us are interested in [some of which I will briefly outline here]. In this gentleman with adenocarcinoma, statistically he's got a 30% chance of having a [K-]ras mutation. We will have some data from recent clinical trials looking at MET inhibition with TKIs in this disease,2 and a more interesting “golden grail” is whether this gentleman would benefit from immunotherapy, looking at agents that target programmed death: ligand-1, PD-L1, as well as PD-1.3 These are antibodies that remove checkpoints and let the body's own immune system scavenge for these antigenic cells that cause cellular death. What's been really remarkable about these approaches is they haven't been fraught with as much autoimmunity as some of the earlier approaches with drugs like ipilimumab—they’ve generally been well-tolerated and particularly interesting is their activity across a broad range of histologic types.

Narrator: Ipilimumab is not an approved treatment option for NSCLC.

Dr. Patel: Most trials in 2013 may require the correlation of tissue to help predict response to certain drugs and to help us better understand the biology. So that, alone, might push me to rebiopsy this patient, to really tailor even a clinical trial option [that would be] in his best interest

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Which is better for maintenance therapy in advanced NSCLC, bevacizumab or pemetrexed?

Dr. Patel: Both of these drugs would be applicable only to nonsquamous NSCLC, so [that's] a vast majority of lung cancer in the United States, but certainly not all patients with lung cancer.

We have learned that maintenance therapy can improve survival and progression-free survival, which is a meaningful endpoint for our patients with advanced disease. Maintenance therapy with bevacizumab came from ECOG 4599: [For] patients who received carboplatin and paclitaxel, bevacizumab was given for up to six cycles with therapy and then [they] continued bevacizumab until progressive disease. This trial was positive on all counts: Improvements in response rate, progression-free survival, and overall survival.4

Pemetrexed is a little bit more nuanced. It has been approved as continuation therapy, as well as switch maintenance therapy.5 Many people look at switch maintenance as early second-line treatment; the idea is that patients get platinum and some other agent for four cycles. At the completion of that, they switch to a new class-resistant drug and continue that until progressive disease or symptoms. Pemetrexed has also been extensively studied as an initial therapy, and then dropping the platinum doublet and then continuation of pemetrexed.

The last strategy is a combination of pemetrexed and bevacizumab. We compared, in a phase 3 study called the PointBreak study,6 [ECOG] 4599 carboplatin, paclitaxel, and bevacizumab with bevacizumab maintenance versus our regimen of carboplatin, pemetrexed, bevacizumab and pemetrexed/bevacizumab maintenance. This phase 3 study, which was powered to show superiority of the pemetrexed arm, failed to meet that endpoint and saw that both of these regimens resulted in the exact same survival. Interestingly, in [a] preplanned analysis [that] looked at progression-free survival in the maintenance population, we found an improvement in survival with two drugs.7 My take on it is that, if you're giving bevacizumab upfront with carboplatin and paclitaxel, you should probably give it as [the] 4599 [regimen] and continue bevacizumab. A very reasonable alternative is carboplatin, pemetrexed, and bevacizumab. And I tend to give both because that's how it's been studied and that survival is equivalent to the other regimen.

Although the overall survival is exactly the same on both studies, the toxicity profiles were a little bit different. So patients who received paclitaxel had more neuropathy; they had alopecia; they had more febrile neutropenia and neutropenia. Patients who received pemetrexed had more thrombocytopenia and more fatigue. And so these different toxicity profiles become very important when we're talking about palliative regimens.

We will have some interesting data from ASCO [2013]. AVAPERL is a study from Europe looking at cisplatin with pemetrexed in the maintenance setting, alone or pemetrexed and bevacizumab together. In that study, the progression-free survival almost doubled in patients who received both drugs rather than bevacizumab alone. We'll hear about overall survival results in a short time.8

Another option for switch therapy is giving erlotinib, based on SATURN, and that has led to improvements in survival and progression-free survival.9 We also have data from ATLAS, looking at the combination of bevacizumab and erlotinib. So, patients who were getting a bevacizumab-containing regimen have had an improvement in progression-free survival with the addition of erlotinib to the bevacizumab.10

One of the most exciting trials that’s going on right now is ECOG 5508: Over 1,000 patients who received carboplatin/paclitaxel and bevacizumab [are] re-randomized to one of three arms—bevacizumab alone, pemetrexed alone, and the combination of pemetrexed and bevacizumab. And this is an overall survival study.11 This will be the definitive study to answer the question.

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What are best options for a patient with EGFR-positive NSCLC who has progressed on first-line chemotherapy and maintenance erlotinib?

Dr. Patel: We're all very excited when a patient who has an EGFR-mutated lung cancer receives erlotinib; we all expect sort of dramatic responses and nice times of controlled disease. The unfortunate part is almost all patients will eventually develop acquired resistance. I usually will try to rebiopsy the primary lesion at the time the patient has progressed.

It is, I think, no longer anecdotal to find that a patient has had small-cell transformation; this happens even in never-smokers.12 If that's the case, you want to treat them with a small-cell regimen. Most likely we'll find that these patients have T790 mutations. Our approach is to direct these patients primarily to clinical trials. So, a trial that we've just completed here at Northwestern is Dr. Melissa Johnson's study of Hsp90 inhibitor, AUY-922, in combination with erlotinib.13 We have completed the phase 1 and phase 2 trials and [have] seen some nice responses and stabilized disease in patients who develop the T790 mutation. Another approach is using a combination of a third-generation EGFR TKI, afatinib, in combination with the monoclonal antibody cetuximab.14 The vast majority of patients responded to this treatment, [but] afatinib comes at the price of more fatigue, more rash, [and] more diarrhea—and cetuximab causes rash and diarrhea, and so you have overlapping toxicities. There are other newer-generation TKIs that are overcoming this resistance.

If a patient is not eligible for a trial, then we have a couple of strategies. I think one is to look if there's just a dominant area of progression—so if a patient has progression maybe in just one bony lesion, I tend to keep those patients on erlotinib and then just provide local therapy with palliation by radiation or radiofrequency ablation to that disease site. If a patient has progression in multiple sites and has already been through front-line therapy with a platinum doublet, I'd take the patient off of the erlotinib [and] initiate [most likely] pemetrexed. And then, depending on disease response and tolerability of therapy, I may even add the erlotinib back to the pemetrexed, if the patient's having a nice response and tolerating therapy.

A new area is patients who carry an ALK translocation who are treated initially on crizotinib. The classic patient scenario that we've seen is we have a patient on crizotinib and they have a wonderful systemic response; then they have progression. There are some investigational approaches for patients who have progression on crizotinib. [There is a newer drug] called LDK-348, and it's more potent than crizotinib and it's more selective. Patients on the trial had very similar adverse events to crizotinib, but 80% of patients who had had crizotinib-resistant disease had a response.15 So, it's certainly very, very exciting. Similarly to Hsp90 inhibitors in EGFR-mutant lung cancers, Hsp90 inhibitors have been used in patients who harbor an ALK rearrangement—some include IPI-504 and STA-9090.16,17

So, certainly there's a lot of excitement [about] how we can resensitize these tumors to these TKIs that have been so successful. Generally, these drugs are much better tolerated than chemotherapy, so if they're working and even result in stable disease, you want to keep them going. Patients generally feel better on them than with cytotoxic agents, if the disease is controlled.

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  1. Rosell R et al. Lancet Oncol. 2012;13:239-246.
  2. Robinson KW, Sandler AB. Oncologist. 2013;18:115-122.
  3. Brahmer JR. J Clin Oncol. 2013;31:1021-1028.
  4. Ramalingam SS et al. J Clin Oncol. 2008;26:60-65.
  5. Gerber DE, Schiller JH. J Clin Oncol. 2013;31:1009-1020.
  6. Patel JD et al. Clin Lung Cancer. 2009;10:252-256.
  7. Patel JD et al. 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology. Abstract LBPL1.
  8. Rittmeyer A et al. American Society of Clinical Oncology 2013 Annual Meeting (ASCO 2013). Abstract 8014.
  9. Cappuzzo F et al. Lancet Oncol. 2010;11:521-529.
  10. Kabbinavar FF et al. American Society of Clinical Oncology 2010 Annual Meeting (ASCO 2010). Abstract 7526.
  11. Bevacizumab or Pemetrexed Disodium Alone or In Combination After Induction Therapy in Treating Patients With Advanced Non-Squamous Non-Small Cell Lung Cancer.
  12. Varghese AM et al. ASCO 2013. Abstract 7593.
  13. Johnson ML et al. ASCO 2013. Abstract 8036.
  14. Trial of BIBW 2992 (Afatinib) + Cetuximab in Non-Small Cell Lung Cancer.
  15. Shaw AT et al. European Society for Medical Oncology 2012 (ESMO 2012). Abstract 4400.
  16. Normant E et al. Oncogene. 2011;30:2581-2586.
  17. Shimamura T et al. Clin Cancer Res. 2012;18:4973-4985.

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Current and Emerging Therapies for the Treatment of Advanced NSCLC: Clinical Implications

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