Spectacular Progress in Lung Cancer Care

OncologyONCOLOGY Vol 35 Issue 1

ONCOLOGY® recently sat down with Jennifer W. Carlisle, MD, of Emory University’s Winship Cancer Institute, to discuss the many advances made during the last year for patients with lung cancer along with her hopes for further significant milestones in the year to come.

The coronavirus disease 2019 (COVID-19) pandemic stole the medical spotlight in 2020, and rightfully so. But what was sometimes lost in the never-ending news cycle and the coverage of the worldwide race for a vaccine was that advances in other diseases—particularly cancer—continued on.

Against the difficult and trying backdrop of the pandemic, cancer investigators persisted, and for patients with lung cancer, that persistence paid off in spectacular ways. With several new FDA approved treatments, as well as 2 new targetable mutations in non–small cell lung cancer (NSCLC), 2020 was a banner year in the overall lung cancer space.

ONCOLOGY® recently sat down with Jennifer W. Carlisle, MD, of Emory University’s Winship Cancer Institute, to discuss the many advances made during the last year for patients with lung cancer along with her hopes for further significant milestones in the year to come.

Q: How would you characterize 2020 in terms of the advancements made for patients with lung cancer?

Carlisle: I would say 2020 has been remarkable. We’ve had 10 FDA approvals: Some were novel treatments and some were new uses for regimens we’ve already had for NSCLC. I think that is particularly impressive amidst the COVID-19 pandemic. And it’s important to note that all of these advances are the result of patients enrolling on clinical trials, including during this pandemic. We’ve learned from a lot of different registries, [particularly] the TERAVOLT registry, about just how high-risk our patients with lung cancer are for severe effects of COVID-19. So, the fact that we continue to make these advances amidst this global pandemic is remarkable.

Some of the TERAVOLT registry results to highlight are that our patients older than 65 years, those who have medical comorbidities, and those with an ECOG performance status of 2 or greater are all at the highest risk [for COVID-19 complications], and our treatments may or may not contribute to this risk. We saw higher deaths associated with patients on chemotherapy or chemotherapy/immunotherapy but not immunotherapy alone.

Q: Of all the 2020 advancements made to treat patients with lung cancer, do any stand out as having the greatest impact?

Carlisle: I wouldn’t say so in terms of the number of patients, but I think the biggest impact has been in adding to our nuanced understanding of lung cancer, [continuing to realize] that not all lung cancers are the same. As of late 2019, we had 5 targetable mutations—EGFR, ALK, RAS, [a] BRAF, and NTRK— but [a year later], we now have 3 new drugs approved for 2 completely new targets in NSCLC.

The first target is [composed of] the RET fusions, which we can see in 1% to 2% of patients with NSCLC, as well as some other malignancies, most commonly papillary thyroid cancer. While we’ve known about RET fusions in lung cancer for 8 years or so, the drugs that we previously had for this were repurposed multikinase inhibitors that didn’t have the best RET activity. But within the past 3 years, we’ve seen studies for 2 selective RET inhibitors, selpercatinib (Retevmo) and pralsetinib (Gavreto), and they are now FDA approved. Both agents showed good responses in patients who were treatment naive and previously treated alike, and both showed good data with respect to brain metastases, indicating good central nervous system penetration.

The second main target is [composed of] MET exon 14 skipping alterations, seen in 3% to 4% of patients with lung cancer. This target is unique, because it’s not the typical driver pathway. MET exon 14 actually encodes a binding domain for ubiquitin-mediated degradation. When you lose this docking site, essentially you can’t recycle MET and it stays more active in the cell membrane, and this is what causes the cancer to grow. So, a study looking at capmatinib (Tabrecta) looked at patients with both MET exon 14 skipping alterations as well as MET amplifications, and [the researchers] found that specifically in the skipping alteration category, patients had a very robust response, with an objective response rate of more than 60% in the first-line setting. Learning about these 2 new targets, bringing the total to 7, has moved the lung cancer field along. And, [knowing about] these 7 alterations reinforces the need to do multiplex testing, ideally with broad-panel next-generation sequencing, so that we don’t miss some of these rare but important targets. Finding one of these has a huge impact for patients to be able to go on a pill and avoid systemic or intravenous treatments for later on in their treatment course.

Q: We hear the term precision medicine a lot. Is finding the utility of these additional targets an indication that we are getting closer to realizing the full promise of precision medicine?

Carlisle: Well, our methodology is getting more sensitive. Previously, we were just spot-looking for the targets that we knew most about, and we were missing other parts of the genome. Now that we have so many places to look, we look at more of the genetic code of the tumor. This has led to looking at possible biomarkers like tumor mutation burden (TMB), although I don’t think [using TMB] has totally found its way yet because we still use PD-L1 to stratify patients for immunotherapy treatment options. But [these additional targets indicate] that now, with better sequencing and broader panels, we can look deeper and see not just driver alterations at the time of diagnosis, but resistance mechanisms that come up on treatment that we may also be able to target. These are also very important.

Q: We know the positive that came out of 2020 for patients with lung cancer, but were there any disappointments?

Carlisle: Maybe I’m a glass-half-full person, but I think there are far more positive [than negative] things to talk about. For instance, there are 4 new FDA approvals for immunotherapy agents that we already had but can now use in new settings. To start, atezolizumab (Tecentriq) now has an indication in PD-L1–high patients. We can now use ipilimumab (Yervoy) and nivolumab (Opdivo) either as a chemotherapy-sparing agent, [due to results] from CheckMate 227, or we can use nivolumab plus 2 cycles of chemotherapy, [due to results] from CheckMate 9LA. This gives us more options, which is only better for patients.

In addition, the advancements in lung cancer don’t apply just to NSCLC; advances were made in small cell lung cancer (SCLC) as well. Chemotherapy plus durvalumab (Imfinzi) for extensive-stage SCLC was studied in the CASPIAN trial and is now an approved regimen. We also have lurbinectedin (Zepzelca), which was granted FDA accelerated approval back in June, for patients whose SCLC cancer progressed after platinum-based chemotherapy. While this is a standard cytotoxic agent, it utilizes a new mechanism of action: It inhibits transcription by binding to certain regions of the DNA, stopping the polymerase and leading to DNA breaks that result in cell death. It showed a good response rate of 35% in 105 patients treated, with a median duration of response of 5 months. These new options for SCLC and these new immunotherapy targets [add up to] really just more good news from 2020 in lung cancer.

Q: When it comes to utilizing these existing immunotherapies in new or different settings, how do we find the patient populations or proper combinations to elicit these positive results?

Carlisle: [The answer is] due diligence: needing to try each of these agents in the specific cohort that they’ll be used in. While we think of checkpoint inhibitors—agents targeting PD-1 or PD-L1—as all very similar and working on the same pathway, there are nuanced differences [among them]. We really need to do the studies and not assume results. It just takes time to get those done.

Another really promising [development] this year has been more long-term follow-up data. We now have 5-year survival rates from patients with high PD-L1 expression on pembrolizumab (Keytruda) monotherapy. PD-L1–high disease is seen in 30% of patients with NSCLC, and the 5-year survival rate from some of the initial trials is up to 32%. This is [very] important. When I meet a patient with newly diagnosed stage IV NSCLC, I [can] say this isn’t curable, but it’s treatable, and in some cases, it can become like a chronic disease.

A big question that remains moving forward is understanding how long we need to treat these patients. Some reports show that stopping [treatment] at 1 year causes more recurrences than does continued treatment with a PD-1 inhibitor. But I think we need more data to determine how long to treat people, and additional biomarkers to know who is more likely to have a long-term response.

We also have additional data for patients with stage III NSCLC. We have 4-year follow-up data on 1 year of durvalumab, following chemotherapy and radiation, and the survival rate from those data is now 47%: about double what it was before the addition of immunotherapy. All of this information is really helpful for patients and families to have, to give them kind of concrete numbers showing that some people are living longer.

Q: What are you hoping for in 2021 in terms of further lung cancer treatment advances?

Carlisle: From a research perspective, I’m hoping for approvals for a couple of additional new targets. One of the most exciting areas is targeting KRAS, specifically KRAS G12C. We’ve known about KRAS [mutations] in lung adenocarcinoma for decades, and we know that various [KRAS] mutations affect about 30% of patients with lung adenocarcinoma, but we haven’t been able to target them. Recently, though, it was noted that specifically the G12C mutation creates [a] binding pocket, and now a couple of inhibitors specifically target KRAS G12C. One, AMG 510, which was recently reported, showed confirmed response rates of 32% and a disease control rate of nearly 90% in patients with lung cancer. While we’re still waiting for longer-term data, and this is not as high of a response as we’re used to seeing with targeted therapy, it [represents] proof of principle that we can target these KRAS alterations. Hopefully, we’ll be able to target other mutant alleles and reach a larger proportion of the population with KRAS alterations, including those with other tumor types, like colon cancer.

The second target I’m hopeful about is HER2, which people commonly know about in breast cancer. However, 3% to 4% of patients with lung cancer can have HER2 kinase domain mutations or insertions. While a lot of the tyrosine kinase inhibitors that also can inhibit HER2 haven’t been effective, we’ve seen some very exciting data about antibody-drug conjugates—specifically, [a study about] trastuzumab deruxtecan (Enhertu), which works by using an antibody to bring a cytotoxic agent or payload to cells that express HER2. In this study, the response rate was more than 60%. So, I’m hoping that in 2021 we can see [these] 3% to 4% of patients with HER2-mutated NSCLC have an FDA-approved treatment option, and another 13% of patients with KRAS G12C mutations have a targeted therapy [option].

Another wish I have for 2021 is that we use data that we already know about: the lung cancer screening data, which are unfortunately underutilized. We have the long-awaited results from the NELSON study, a screening trial that looked at low-dose CT scans and lung cancer mortality. Specifically, it looked at scans at baselines of 1, 3, and 5 years in patients who were aged 50 to 70 years and were current or former smokers. This showed [that proper screening leads to] a clear decrease in lung cancer–specific mortality. So, there are broadened screening guidelines, and really, we know that the earlier lung cancer is diagnosed, the easier it is to treat.

In 2021 I hope we’ll also see more data about using immunotherapy in earlier lines of lung cancer treatment, and about incorporating targeted therapy options earlier in the disease course. This year, we saw some impressive data from the ADAURA trial looking at EGFR adjuvant treatment with osimertinib (Tagrisso), with a remarkably low hazard ratio for disease recurrence. While we’re still awaiting long-term overall survival data, we’ve learned so much in patients with advanced disease that may benefit patients with earlier-stage disease, so I hope to see some of those data come out next year as well.

Finally, going back to 2020, we did get data from the American Cancer Society reported back last January, which showed the largest single-year decrease in cancer mortality, a drop largely attributed to reduction in lung cancer deaths: I think it went down 2.2% from 2016 to 2017. Some of this is related to fewer people smoking, but it’s also certainly related to all these targeted therapy options and longer-term survival with immunotherapy, so what we’re doing is actually making an impact.

Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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