Managing Disease Progression in Advanced NSCLC

Corey J. Langer, MD:Brain metastases are quite common in patients withEGFRmutations. Historically, up until the era of personalized therapy, we typically treated these individuals with whole brain radiation. Then, more recently, with stereotactic radiation. But you can make a case, in those individuals who have relatively low-volume brain metastases who do not have symptoms, who do not have much in the way of vasogenic edema, for simply observing their progress on TKIs alone.

In fact, that has been looked at. A retrospective analysis by Schuler and colleagues, published in theJournal of Thoracic Oncologyin 2016, looked at overall progression-free survival in LUX-Lung 3 and LUX-Lung 6. The bottom line is, the PFS benefits seem to track the overall population, including those without brain metastases. In LUX-Lung 3, PFS was over 11 months for the group with brain metastases, compared with roughly 5.3 or 5.4 months for the control group. We see a similar benefit—8 or more months versus 4.7 months—in LUX-Lung 6.

It’s a little dicey. You are taking a population with known brain metastases. There is a potential for further growth and evolution in these brain metastases, as well as the possibility for developing vasogenic edema and generating intracranial symptoms, headaches, nausea and vomiting, seizures, and stroke-like symptoms. So, these individuals need to be followed very closely. If we do not initiate brain-specific treatment, I’ll generally get MRIs every 2 to 3 months, at a minimum. Obviously, should there be evidence of CNS progression, then you need to intervene. Increasingly, in 2018 and beyond, we are applying stereotactic radiation or Gamma Knife to these individuals for several reasons.

The smaller lesions will often recede with the use of TKIs. Also, Gamma Knife spares cognitive dysfunction. We have found that if you can use multiple converging beams selectively, on individual lesions, the risk of CNS toxicity goes down.

Unfortunately, disease progression, in patients with anEGFRmutation, is almost always inevitable. It may take 2, 3, 4, or 5 years, or beyond. I do have some patients, in my practice, who have been fortunate enough to remain free of progression beyond 5 years. But, by and large, the majority of patients will experience disease progression.

If we look at LUX-Lung 3, which is probably the most representative population that we deal with in North America, the median PFS exceeds 13 months. This patient has been on treatment, now, for about 9 to 10 months. So, it’s conceivable that in another 3 to 4 months, she may experience disease progression. Remember, that’s a median—50% have disease progression beyond the median. Sometimes it can be years out.

At the time when disease progression is established, at least in individuals who are receiving first-line or second-line TKIs—first-generation or second-generation TKIs, be it erlotinib, gefitinib, or afatinib—it’s imperative to test forT790M. IfT790Mis disclosed—it is found in about 50% to 60% of patients withEGFRmutations who develop disease progression—the standard of care, in that group, is to use osimertinib, which is specifically designed againstT790Mand the originalEGFRmutations. Thirty percent to 40%, or more, will not exhibitT790Mmutations. In that group, it’s a bit more problematic. The standard approach remains to use chemotherapy as second-line treatment.

In general, we will institute a platinum-based combination—often, platinum and pemetrexed. Or, if there’s no contraindication, we may institute platinum, pemetrexed, and bevacizumab; or platinum, a taxane, and bevacizumab. Very frequently, these patients will go on to enjoy another prolonged disease-free interval, at least progression-free interval, before they face the prospect of additional or third-line treatment.

That’s an area that’s really unexplored. There are some studies that are now looking at going back to a different TKI in that setting—if a patient received erlotinib or gefitinib, they are looking at trying afatinib or osimertinib; or, they are looking at reinstituting the original treatment with the premise that the original clone that harbored the mutation may have expanded in that interval, and the patient may retain some sensitivity.

There’s 1 very important trial that has actually tested the concept of continuing the initial TKI through chemotherapy—that was the IMPRESS trial. This trial looked at patients who had been on gefitinib and had experienced disease progression and compared a standard chemotherapy combination—platinum and pemetrexed—either alone or with continuation of gefitinib beyond progression. Intriguingly, the group that got all 3 agents, the TKI plus chemotherapy, actually did worse.

There was no increase in response rate. If anything, the PFS was a little bit worse. The survival was significantly worse. So, there’s big concern that chemotherapy and TKIs, when given concurrently, may antagonize each other. I’ve really taken the message from that study to heart. I’ll continue to give chemotherapy. I’ll usually suspend the TKI a few days before I start the chemotherapy. If the chemotherapy stops working, then I’ll entertain resumption of the TKI or some other protocol that would be appropriate in that individual. Only in very select cases will I continue a TKI while I institute salvage chemotherapy.

Transcript edited for clarity.

June 2017

• A 61-year-old Caucasian woman presented with persistent cough and shortness of breath
• Patient history:
  • Never smoked
  • Mild hypertension, controlled on diuretic
  • No major cardiovascular disease or diabetes
  • Worked at local jazz club until symptoms forced her to resign
• Physical exam and imaging:
  • No palpable masses
  • CT reveals multiple tumors in right lung and brain metastases
  • ECOG PS: 1
• Biopsy and mutation analysis:
  • Adenocarcinoma
  • EGFRexon 19 deletion
  • No ALK rearrangement
• Started treatment with afatinib 40 mg once daily
  • Developed diarrhea that necessitated dose interruption
  • Recovered and resumed treatment at 30 mg once daily

March 2018

• Patient remains on afatinib, with no apparent progression