Resistance to Therapy Clouds Treatment Successes in EGFR-, ALK-Positive NSCLC

D. Ross Camidge, MD, PhD

Although researchers and physicians have made advances in treatment options for patients withEGFR- andALK-positive non—small cell lung cancer (NSCLC), a true understanding of the development of resistance to therapy is yet to emerge, according to D. Ross Camidge, MD, PhD.

Camidge, director of Thoracic Oncology at the University of Colorado, said osimertinib (Tagrisso) is the best frontline therapy choice for patients with advancedEGFR-positive disease. InALK-driven NSCLC, frontline treatment with alectinib (Alecensa) should be the standard of care.

Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), gained FDA approval in the frontline setting in April 2018 based on data from the phase III FLAURA study, in which frontline osimertinib reduced the risk of progression or death by 54% versus standard TKI therapies erlotinib (Tarceva) and gefitinib (Iressa). The median progression-free survival (PFS) was 10.2 months for standard therapy and 18.9 months with osimertinib (HR, 0.46; 95% CI, 0.37-0.57;P<.0001).¹

For patients withALK-positive NSCLC, alectinib improved PFS by 47% compared with crizotinib (Xalkori) (HR, 0.53; 95% CI, 0.38-0.73;P<.0001) in the phase III ALEX study, which led to the FDA approval of alectinib in the frontline setting in November 2017.²

In an interview withTargeted Therapies in Oncology, Camidge discussed the crowded landscape of oncogene-driven NSCLC at the 13th Annual New York Lung Cancers Symposium hosted by Physicians&rsquo; Education Resource^&reg;, LLC.

TARGETED ONCOLOGY:What have been some of the most significant findings in the EGFR space?

Camidge:InEGFRmutations, the field is pretty much solidified in that osimertinib, a third-generation TKI, is your initial choice. People are looking at adding bevacizumab [Avastin] to osimertinib [or] adding chemotherapy. These are both hard sells, though. If you have a pill that is going to control your disease for a number of years, you want a short leash in the infusion center. Another thing we have to understand is why people eventually progress on osimertinib and what [the] rational combinations [are] to overcome this. If you try to do them more up front, maybe it applies only to a subgroup.

TARGETED ONCOLOGY:Is there any insight into why patients become resistant to these targeted agents?

Camidge:If you biopsied somebody who initially responded to osimertinib and then progressed, we [would] understand some of the mechanisms. [For example,] you can develop an additional mutation called C797S. [Investigators] are looking at adding antibodies to this, such as cetuximab [Erbitux]. This will bring in added toxicity, but [it may] control the disease for a significant period of time. [Investigators] are looking to [develop] a drug specifically targeting C797S.

The other actionable area is MET amplification. We knew this was a resistance mechanism to first- and second-generation TKIs. It could be [occurring in] up to 30% of patients on osimertinib. The one challenge is that it is a continuous variable. Where do we determine that MET is a true second driver and that you need combination therapy?

TARGETED ONCOLOGY:Where do you see the newly approved EGFR inhibitor dacomitinib (Vizimpro) fit in?

Camidge:Dacomitinib is a second-generation, irreversible inhibitor in the same class as afatinib [Gilotrif]. The ARCHER 1050 trial led to this FDA approval, and technically it was a positive study.³Median PFS was [14.7 versus 9.2 months in patients treated with gefitinib]. This is a very toxic drug, [and 66% of] patients needed dose reductions.⁴

TARGETED ONCOLOGY:Immunotherapy has not made much of an impact in this space. Will it have a role one day?

Camidge:InEGFR-positive NSCLC, immunotherapy is going through some growing pains. Initially, in second-line studies [examining] pembrolizumab [Keytruda], nivolumab [Opdivo], and atezolizumab [Tecentriq] compared with pretty poor chemotherapy regimens such as docetaxel; [the checkpoint inhibitors] could not even beat docetaxel. We are seeing response rates as high as 12% and as low as 3% or 4%.⁵

There is a very small subset of patients who areEGFR-positive who will benefit from immunotherapy, but it is obviously less than the general lung cancer population. The patients who benefit may also have severe [adverse] effects.

TARGETED ONCOLOGY:What does the landscape look like for ALK-driven therapies?

Camidge:There are 3 different categories here. One is somebody who is already on crizotinib. Post crizotinib, the response rates under the next-generation inhibitors all look pretty much the same. Where they differ is in the median PFS. Brigatinib [Alunbrig] is the standout winner. We may not understand why, and the preclinical modeling suggests this should not be happening. But that tells us the model is not perfect.

The second group [comprises patients] withALK-positive disease. What do they start therapy on? The drugs with a first-line license are crizotinib, ceritinib [Zykadia], and alectinib. We already know alectinib beats crizotinib head-to-head.⁶Ceritinib has been tested against chemotherapy [only], and it did better than chemotherapy. I think it is clear that alectinib is the first-line choice.

The third category is [for those patients who progress] on a next-generation inhibitor. Very recently, lorlatinib [Lorbrena] got a license for patients who progress on 1 or more next-generation inhibitors.

The really exciting thing about this field is that these hazard ratios can mature over time. We now understand why. The maturation is coming from controlling differences in extra CNS penetration. It takes 7 or 8 months to even start out separating the curves.

References:

1. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Presented at: 2017 ESMO Congress; Madrid, Spain; September 9-12, 2017. Abstract LBA2_PR.
2. FDA Approves Genentech&rsquo;s Alecensa (Alectinib) as First-Line Treatment for People with Specific Type of Lung Cancer [news release]. Genentech website. Published November 6, 2017. http://bit.ly/2zmLda7?rel=0" . Accessed November 6, 2017.
3. Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase 3 trial.J Clin Oncol.2017;35(suppl; abstr LBA9007).
4. Passaro A, de Marinis F, Dacomitintib in EGFR-positive non—small cell lung cancer: and attractive but broken option.Transl Lung Cancer Res.2018;7(Suppl 2):S100-S102. doi: 10.21037/tlcr.2018.02.09.