Lung Cancer Investigators Expand Upon Indications of Standard Therapeutic Agents

Benjamin Levy, MD, is a thoracic medical oncologist and clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center in Washington, DC, as well as cochair of the 39th Annual CFS®, hosted by Physicians’ Education Resource, LLC (PER®).

Over the past decade, increased survival times have been tied to the emergence of targeted and checkpoint blockade therapies as the standard of care for most patients with metastatic non–small cell lung cancer (NSCLC). Given advancements in this setting, investigators have been exploring ways to bring these life-saving treatments to more patients with lung cancer across additional settings.

“In terms of the changes, the [breakthroughs] that have happened over the past 5 years are indicative of how quickly we’re moving in the field,” Benjamin Levy, MD, a thoracic medical oncologist and clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center in Washington, DC, said in an interview. “When I started, a lot of the talks were just on chemotherapy and potentially immunotherapy, and now we’ve got such a huge charge to cover all the new approvals for all the new drugs.”

Levy, who is also co-chair of the 39th Annual CFS® hosted by Physicians’ Education Resource®, LLC (PER®), sat down with ONCOLOGY® to discuss lung cancer research he is excited about and feels has the potential to transform the lung cancer treatment paradigm.

Q: What are some new targeted therapies for which you are excited to see newly reported data?

A: You can’t talk about new targeted therapies without talking about the recent approval of sotorasib [Lumakras] for KRAS G12C[–mutant NSCLC]. This mutation was once thought to be undruggable. We now have a novel oral therapy that was approved [recently to treat tumors with] this mutation and [saw data recently presented] on the outcomes of patients receiving sotorasib who have KRAS G12C[–positive] NSCLC [NCT0360083].^1,2

The second drug is called amivantamab [Rybrevant], which was also recently approved for [the treatment of patients with] EGFR exon 20 mutations, a very hard mutation to treat and drug. We now have an approval for that study [NCT02609776] [and for] that genotype as well.³

Finally, if you’re thinking about novel targets, HER2 mutations, the evolving role of trastuzumab deruxtecan [Enhertu] [could lead to an] approval by November for HER2-mutated lung cancer. I think those are 3 exciting drugs that we have. Two [are] now approved, 1 [will be] potentially approved, and the list keeps getting longer and longer with some of these drugs.

Q: Can you discuss some novel applications of immunotherapy in the lung cancer space?

A: Immunotherapy [has] been solidified in the advanced-stage setting [for NSCLC]. Multiple trials show that when you add immunotherapy to chemotherapy, or you compare immunotherapy with chemotherapy, there are improvements in outcome for stage IV [disease], and there’s probably a tail of the [Kaplan-Meier] curve for [this population]. Now, what has happened over the past 6 months [with] recent data is that we’re learning to understand how to leverage immunotherapy for a cure. [When] looking at immunotherapy—potentially in the neoadjuvant space prior to surgical resection, and then, based on the most recent data that were presented at ASCO 2021, looking at it in the adjuvant setting—that will be a focus of [interest going forward], to discuss the potential role of neoadjuvant therapies for cure and early-stage disease.

Q: Circulating tumor DNA (ctDNA) is constantly evolving. What do you think we might soon learn about these assays?

A: We know that ctDNA can be used as a 1-time static event where we can accurately genotype patients with lung cancer. In the past 6 to 12 months, we’ve learned 2 new ways that it may be used. One is for longitudinal assessment, [where we look] at changes in ctDNA when patients are on a drug, either targeted therapy or immunotherapy, as an early indicator of response or lack of response. The other strategy is looking at it and the minimal residual disease setting for patients who are cured and are being followed and surveilled by CT scan. The question is, can you use ctDNA to detect recurrences earlier than a CT scan [can], and can that then inform treatment decisions?

Q: Are you anticipating results of any particular studies?

A: Charu Aggarwal, [MD, MPH], from Penn Medicine, and colleagues recently] published data with immunotherapy in JCO Precision Oncology.³ They look at longitudinal assessment of ctDNA for patients treated with immunotherapy and show that drops correlate with response and lack of drops portend worse outcome. This is not just touching the field for targeted therapy but for immunotherapy, as well.

Q: Can you discuss new approvals for small cell lung cancer (SCLC)?

A: Historically, [SCLC is] a very aggressive disease. We’ve [seen many] approvals in the past couple of years. One was atezolizumab [Tecentriq], one was durvalumab [Imfinzi],^4,5 and a second-line [agent] was approved over the past 6 months—lurbinectedin [Zepzelca].⁶ Data are emerging with other therapies that may be promising.

Q: What are some questions that need clarification in NSCLC?

A: We’ve learned that when we wed targeted therapies to the right genotype, patients do quite well, [but] there are outstanding questions. For instance, what do you do for all these genotypes when they’re on a targeted therapy? What do you do when resistance develops? What are those mechanisms of resistance, and how should we act on them? That’s a big question for targeted therapy.

Another question is, are there optimal combination strategies with these targeted therapies? Should we be giving targeted therapies alone or should we be giving targeted therapies plus a novel therapy or chemotherapy upfront to our patients? [There] is clearly an unmet need for
patients with the right genotype.

[The] same is true for immunotherapy. What are the optimal immunotherapies? We’ve [got] great drugs to give patients without a target, [and] immunotherapy combinations [can produce effects that are] durable and meaningful. The question is, what do you do when there’s disease progression? What are the mechanisms of resistance, and how do we act on those, moving forward? We’ve sorted out what to do first for both the patients with targets and patients without. The question becomes, what do you do next when those treatments no longer work? Are the tumors growing? Those are really unmet needs.

Q: Are ongoing trials addressing the questions of resistance with targeted therapies?

A: [With] EGFR, one of the most common mutations, tremendous efforts are going on across the country, looking at and sorting out mechanisms of resistance and then what to do when you discover [such] a mechanism.

For instance, I’m involved in a trial called SAVANNAH [NCT03778229], looking at patients who are EGFR positive and on a targeted therapy of osimertinib [Tagrisso]. When they have disease progression, if you do a biopsy and it shows that they have another pathway involved called MET, we add a particular MET-directed therapy. That is where we’re heading. Multiple studies like this are going on, looking at mechanisms of resistance, and understanding those mechanisms of resistance is critical.

One of my areas of research is trying to understand what to do for some of these patients who are on a targeted therapy and develop disease progression—to understand the mechanisms of resistance, then come up with novel therapies. I also ask the question, “What’s the role of chemotherapy? Is there a role [for] just giving chemotherapy?” Those are examples of unmet needs and questions that we’re asking. Another question is, “Should chemotherapy be given just as with a nonselect therapy for patients who have disease progression on a targeted therapy, or should we be looking for mechanisms of resistance? Based on those mechanisms, [should we be] leveraging another novel therapy?” These are still unmet needs for patients with genotype[-driven disease].

Q: How are checkpoint inhibitors being moved further into the frontline, even before targeted therapy, for driver mutations?

A: I don’t think we yet understand the true role of immunotherapy for patients with driver mutations. We feel that this field is dichotomized into those who get targeted therapies and those who get immunotherapies. [The attempt] to understand how to leverage the immunotherapy and targeted therapy spaces is ongoing. We’re still trying to learn.

Q: You’ve previously mentioned recently published studies. Do you think any of those will be practice changing in the future?

A: One question is whether the IMpower010 study [NCT02486718]⁷ will change practice by November. We saw a disease-free survival hazard ratio of 0.66 for patients with stage II and III NSCLC who have PD-L1 expression greater than 1% [who were treated with atezolizumab]. I would be comfortable considering using that. This is an unmet need. These patients have historically aggressive diseases, and we need to do better.

What to do after progression on osimertinib [is another area of growth]. We have a data set with amivantamab, now already approved [for EGFR exon 20 insertion mutations] in combination with lazertinib (NCT02609776), that looked good post osimertinib.⁸ We have data with [patritumab deruxtecan; HER3-DXd; NCT03260491] that also look good.⁹ That’s where we’re starting to learn more and more.

References

1. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed July 16, 2021. https://bit.ly/2Un3Ol0
2. Spira AI, Wilson FH, Shapiro G, et al. Patient-reported outcomes (PRO) from the phase 2 CodeBreaK 100 trial evaluating sotorasib in KRAS p.G12C mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(Suppl 15):9057. doi:10.1200/JCO.2021.39.15_suppl.9057
3. Thompson JC, Carpenter EL, Silva BA, et al. Serial monitoring of circulating tumor DNA by next-generation gene sequencing as a biomarker of response and survival in patients with advanced NSCLC receiving pembrolizumab-based therapy. Published online March 19, 2021. JCO Precis Oncol. doi:10.1200/PO.20.00321
4. FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA. March 18, 2019. Accessed July 19, 2021. https://bit.ly/3ridklI
5. FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. March 27, 2020. Accessed July 19, 2021. https://bit.ly/36PkhkN
6. FDA grants accelerated approval to lurbinectedin for metastatic small cell lung cancer. FDA. June 15, 2020. Accessed July 19, 2021. https://bit.ly/3ewPPjw
7. Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(Suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500
8. Bauml J, Cho BC, Park K, et al. Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response. J Clin Oncol. 2021;39(Suppl 15):9006. doi:10.1200/JCO.2021.39.15_suppl.9006
9. Janne PA, Baik CS, Su W-C, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(Suppl 15):9007. doi:10.1200/JCO.2021.39.15_suppl.9007