New Targeted Therapy Strategies on Horizon in NSCLC

Edward Kim, MD

TKIs have revolutionized treatment options for those with EGFR mutations or the ALK gene rearrangement. Anti-angiogenic agents have also shown great promise for patients with NSCLC.

OncLive sat down with Edward Kim, MD, chairman, Solid Tumor Oncology and Investigational Therapeutics, Levine Cancer Institute, Carolinas HealthCare System, to learn more about the impact of recent advances in NSCLC and what the future treatment paradigm might look like.

OncLive: How has lung cancer treatment evolved in recent years?

Kim: The field has changed quite a bit in the last five to seven years as we have identified EGFR mutations and now routinely test for those as well as ALK in patients with adenocarcinomas, and certainly others that have light- or never-smoking histories. This has led to EGFR TKIs in the frontline setting replacing chemotherapy in these patients, which has been a really remarkable turnaround in lung cancer for patients. Being able to take a pill for several years sometimes before even looking at chemotherapy is remarkable.

What do you expect to be the next big treatment advancement for those with EGFR mutations?

Obviously we are trying to build on these strategies in the front-line setting and determine ‘can we even do better than we are already?’ Those with EGFR containing tumors benefit tremendously from drugs such as erlotinib or afatinib. There are even other drugs out there like gefitinib, which may be making a return to the U.S, but is certainly used worldwide. These are very easy to take and they have manageable toxicities.

How can we build on those? One of the strategies is to use bevacizumab. We’ve tested bevacizumab or Avastin in other settings. There was the BeTa study, which was in second-line therapy, and we’ve shown some very promising data in the phase ll trials which led to a very large phase lll study, which did show some benefit, but didn’t cross that barrier of overall survival that was needed. This was a combination of Avastin and Tarceva (erlotinib). It was a drug combination that I thought was very promising; however, it was not in a selected cohort of patients with EGFR mutations.

The Japanese have now published data in the frontline setting in a phase ll manner that have shown benefit: increased response rate, increased progression-free survival, and potentially increased overall survival. This needs to be tested in a larger randomized form, but there is promise now that perhaps you can add another biologic to an existing platform and see if there is benefit. We are hopeful that this and other combinations could increase the overall effectiveness of drugs in the frontline setting. We would still call this a biologic approach to these patients and a non-cytotoxic approach.

What potential do you see for anti-angiogenic agents in the frontline and relapsed settings?

We’ve come a long way from platinum-based doublets and giving any one that you wanted to, to any type of patient with NSCLC. I still remember the days of ECOG 1594. However, our first change in pattern came with the ECOG 4599 study - this was the addition of bevacizumab to paclitaxel—carboplatin. It showed a 2-month improvement with the addition of giving bevacizumab to cytotoxic chemotherapy. This changed the way we thought about non-squamous NSCLC.

One, there were side effects that were associated in the squamous population, so they were excluded. There were other side effects that were included, such as some renal insufficiency, some bleeding, things that were associated with bevacizumab, that just took some time to manage. But clearly, it is very manageable now and the use of bevacizumab has spanned other tumor types, which made physicians more comfortable with this. That was the first big leap we had in NSCLC in a non-biomarker cohort. So it is still one of the staples that we use in frontline NSCLC for those patients that don’t have an EGFR mutation or ALK translocation.

We’ve also seen the introduction of other anti-angiogenic agents. One of these recently is ramucirumab, which is an antibody that targets VEGF. It was a drug that was FDA approved first in gastric cancer and has most recently gained approval in combination with docetaxel for second-line in NSCLC. This antibody is a little unique, in that it seemed not to have the same type of adverse events occurring in the squamous population, so it is one of the first anti-angiogenic agents that can be utilized in both the squamous and non-squamous population in lung cancer. It also has activity after using bevacizumab.

It’s a comparable compound, but it’s not a similar compound from that standpoint. It has added more tools to the oncologist toolkit. As we expand the life of patients with NSCLC, we now have more tools to utilize and try and treat patients as long as they can maintain a good performance status.

I think this field is still moving forward, although it is harder now to find biologic compounds and move them forward without specific biomarkers. We know that is one of the areas that have been a gap in anti-angiogenic agents. Everyone has been looking for that biomarker and it’s hard to find one. But I think there will be a role down the road to combine these drugs with other biologics or other cytotoxics and so that is research we still need to continue. At the same time, we need to be mindful of capturing the data in the tissue to see if we can indeed find a biomarker.

Looking to the future, how will physicians approach monitoring the emergence of T790M in patients on the first- and second-generation EGFR TKIs?

T790 mutations are the nature evolution to the utilization of EGFR TKIs as first- or second-line in those patients whose tumors have sensitizing EGFR mutations. We know that, especially in Asia, there are many people who qualify to take a TKI upfront because of the presence of an EGFR mutation. T790 has now become a very hot area, but it is a natural occurrence after being treated.

For example, a patient has a sensitizing mutation, they are treated with an EGFR TKI, eventually the drug stops working, and the tumor changes. The tumor changes by, at least half or 60% of the time, the development of a resistance mutation, which is T790. We now have specific inhibitors of T790, and these have shown a lot of promise in the clinic. One is made by AstraZeneca, and one is made by Clovis, so it has really established a really cool paradigm in these patients.

If you are going to have lung cancer, hope you are fortunate enough to have a sensitizing mutation, and get treated with an EGFR TKI. Then if it stops working and you happen to develop a T790 mutation, which more than half of patients will, you have another pill you can take. Theoretically, a patient with stage 4 NSCLC, who gets a sensitizing mutation and a resistant mutation, could be treated on pills for 3 to 5 years. That is unheard of, when our median survival with cytotoxic therapies just 10 years ago was 8-9 months.

I think it is amazing what has occurred. I think what we will be talking about in 3-4 years is resistance from the T790 and what emerges after that. It is a natural evolution.