COMMENTARY

Lung Cancer Therapy Makes Major Advances

Suresh S. Ramalingam, MD

Disclosures

October 10, 2019

This transcript has been edited for clarity.

Hello. I'm Suresh Ramalingam, professor and deputy director of the Winship Cancer Institute of Emory University in Atlanta, Georgia.

This September, we have had two major meetings that are relevant for the lung cancer community, with both of them held in Barcelona: the World Conference on Lung Cancer and the European Society for Medical Oncology (ESMO) Congress. We've seen a number of exciting presentations through these meetings that have a direct impact on how we manage our patients with lung cancer, and I would like to talk about some of the key data.

Lung Cancer Patients With Targetable Mutations

Let's first talk about patients with lung cancer who have targetable mutations. There are two important updates that I would like to provide.

The first is for patients with EGFR mutations. In patients with EGFR mutations, we know that the FLAURA study documented significant improvement in progression-free survival (PFS) for osimertinib compared with erlotinib or gefitinib when used in the frontline therapy setting.[1] We know that the median PFS with osimertinib was 18.9 months and the control group had a median PFS of 10.2 months.

At the ESMO Congress, we reported the final overall survival results of this trial[2]; overall survival was a secondary endpoint. We showed that patients who received osimertinib had a clinically and statistically significant improvement, with a median overall survival of 38.6 months compared with 31.8 months in the control group. The hazard ratio was 0.799, and the P value was significant.

There was a high rate of crossover in the control group where patients with T790M mutations who progressed on erlotinib or gefitinib [received osimertinib]. About 47% of patients who had any second-line therapy received osimertinib [after progression], reflecting the real world. Despite this, the survival benefit was clinically significant, at a median of approximately 7 months.

The results of the FLAURA overall survival analysis clearly document the role of osimertinib in the frontline setting, and we posit that it is the new standard of care in parts of the world where it has not been adopted because of pending survival data. In the United States, osimertinib is already being used in the frontline setting.

Another area where we have seen some promising advances is in patients with the RET fusion gene, accounting for 1%-2% of lung cancers. We do not have any US Food and Drug Administration (FDA)-approved targeted therapies, but the good news is that there are at least two targeted agents that are likely to be approved in the near future. One of those two drugs is LOXO-292, a very specific RET inhibitor.

At the World Conference on Lung Cancer, we saw results with LOXO-292 in a cohort of approximately 105 patients with RET-positive lung cancer.[3] The response rates were really high. The overall response rate was 60%; for patients who were treatment naive, the response rate was over 80%. The median duration of response was over 20 months, and the median PFS was approximately 20 months. The drug was well tolerated with very minimal grade 2, 3, or 4 side effects, suggesting that LOXO-292 would be a highly effective therapy for patients with RET fusion–positive non–small cell lung cancer.

These are two exciting drugs that are either in the clinic, in the case of osimertinib, or very close to the clinic [LOXO-292].

Also, AMG 510 is a specific KRAS G12C mutation inhibitor that is currently in phase 1/ 2 studies. We saw at the World Conference on Lung Cancer that when given as a single agent, this orally administered therapy has a response rate of nearly 54% in patients with KRASG12C mutations.[4] Based on this, the drug is being developed very rapidly, and we hope to see more results. If these results hold up, this will be the first proven therapy for patients with a subset of KRAS G12C mutations. We know that KRAS G12C mutations are seen in approximately 12%-14% of lung adenocarcinomas, so it is of relevance to a big subgroup of patients with non–small cell lung cancer.

Taking all of these things together, it is important that we do molecular testing for non–small cell lung cancer patients with nonsquamous histology. I would suggest using next-generation sequencing approaches so you have a full profile from which to determine the specific targets a patient may have.

Immune Checkpoint Inhibition in Lung Cancer

Let's shift gears now. We know that immune checkpoint inhibitors in lung cancer are incredibly effective and have the ability to provide long-term results in a subset of patients.

At the ESMO Congress, we heard the results of the phase 3 trial of CheckMate 227,[5] which evaluated the combination of ipilimumab and nivolumab as frontline therapy for advanced-stage non–small cell lung cancer. The results, which were simultaneously published in the New England Journal of Medicine ,[6] show a statistically significant improvement in overall survival for patients who received ipilimumab plus nivolumab compared with chemotherapy, with a hazard ratio of 0.78 in PD-L1–positive patients. Interestingly, in PD-L1–negative patients, the hazard ratio with ipilimumab plus nivolumab was also favorable, at approximately 0.65 over chemotherapy alone. When you look at the entire cohort of lung cancer patients, regardless of PD-L1 expression, ipilimumab plus nivolumab improved overall survival, with a hazard ratio of 0.73, thus positioning this drug as an effective frontline therapy option.

As one of the coinvestigators on this trial and the senior author of the publication, what impressed me with these data was the durability of responses; they were really good with ipilimumab plus nivolumab, which could make this an attractive choice for a subset of patients.

We have pembrolizumab for our high–PD-L1 expressers. We have chemotherapy plus pembrolizumab or chemotherapy plus bevacizumab plus atezolizumab for frontline therapy. I believe that the ipilimumab plus nivolumab combination also belongs in that space. In the upcoming months, we will be talking about how to select the appropriate therapy from among these good choices we have for our patients.

We also heard the results of the IMpower110 study, which compared atezolizumab as monotherapy with platinum-based chemotherapy in the frontline space for PD-L1–positive patients.[7] We learned that for patients with the highest level of PD-L1 expression (referred to as TC3 positive/IC3 positive), there was an improvement in overall survival for atezolizumab over chemotherapy. For the low-expressing patients, we did not see a statistically significant improvement. These results are similar to what we saw from the KEYNOTE-024 study,[8] where with a PD-L1 [tumor proportion score] of 50% or greater, pembrolizumab had a survival advantage over chemotherapy.

Additionally, we saw a lot of information about tumor mutation burden as a biomarker. But I would say that the bottom line there is that we still do not know how to use tumor mutation burden in our decision-making, and I would not recommend it in routine practice.

Small Cell Lung Cancer

Lastly, I want to mention an important trial in small cell lung cancer.

We know that atezolizumab was approved recently by the FDA in combination with platinum-based chemotherapy for frontline treatment of small cell lung cancer.

At the World Conference on Lung Cancer, we saw the results of a phase 3 trial that evaluated durvalumab in combination with chemotherapy as frontline treatment of small cell lung cancer.[9] As you know, durvalumab is a PD-L1 antibody that is already approved for patients with stage III non–small cell lung cancer after they have had chemoradiotherapy. In the CASPIAN study, the randomization was chemotherapy with or without durvalumab for first-line treatment of extensive stage, small cell lung cancer. We found that the survival results favored durvalumab; the overall hazard ratio was approximately 0.73, and the PFS favored the use of durvalumab in combination with chemotherapy. The chemotherapy plus durvalumab regimen was also well tolerated.

The results from the CASPIAN study with durvalumab were very similar to what we had seen in the IMpower trial of chemotherapy plus atezolizumab that led to the approval of atezolizumab.

I believe that the CASPIAN results confirm the role of PD-1/PD-L1 inhibition as the frontline treatment of small cell lung cancer. We also look forward to other data from PD-1 inhibitors, such as pembrolizumab and nivolumab, from trials that have already been completed.

In summary, we continue to see major advances in the treatment of lung cancer patients. We have some good news for small cell lung cancer—and certainly great news coming for the subset of patients with KRAS G12C mutations. The results with osimertinib confirm it as the standard frontline therapy for patients with EGFR mutations.

Thank you for joining me.

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