Predominant Lung Cancer Investigator Welcomes a New Era of Research

Julie Brahmer, MD, MSc

Early efficacy data in a phase 1 trial of the agent now known as nivolumab (Opdivo) were not enough to convince Julie Brahmer, MD, MSc, about the potential of the investigative agent.¹ It was only when patients with non–small cell lung cancer (NSCLC) continued responding in readouts from the phase 2 trial that she was sure she was working on something important, an intuition confirmed by the results from the phase 3 CheckMate 057 trial (NCT01673867) and subsequent approval of the PD-1 inhibitor.²

Brahmer, who is codirector of the Upper Aerodigestive Cancer Department at Johns Hopkins Medicine’s Bloomberg~Kimmel Institute for Cancer Immunotherapy in Baltimore, Maryland, has remained at the cutting edge of immunotherapy research and lung cancer treatment ever since. She has worked on dozens of trials and authored or coauthored nearly 200 papers, all while continuing to see patients in clinical practice.

Brahmer is also a cochair of the 19th Annual Winter Lung Cancer Conference^®, which will take place February 4-6, 2022, virtually and on site at the Eden Roc Miami Beach hotel in Florida. The 3-day event hosted by Physicians’ Education Resource^® (PER^®), LLC, will provide a practical overview of recent advances in the landscape of lung cancer treatment.

During the conference, experts will discuss trial results that have changed or have the potential to change standards of care. Leaders in thoracic oncology joining Brahmer include cochairs Rogerio C. Lilenbaum, MD, director of Banner MD Anderson Cancer Center in Phoenix, Arizona, and Mark A. Socinski, MD, executive medical director at AdventHealth Cancer Institute in Orlando, Florida.

Faculty will discuss a wide range of recently published data from ongoing trials, debate controversial topics via Medical Crossfire^® exchanges, and open the floor to discussions that address practical strategies for treating complex clinical cases. Topics of interest include:

• integrating and optimization of molecular testing throughout the continuum of disease,
• leveraging the growing therapeutic armamentarium for oncogene-driven NSCLC,
• navigating options for first-line immunotherapy-based regimens in metastatic NSCLC,
• applying consolidation immunotherapy in locally advanced NSCLC, and
• using surgery and radiation oncology for patients with thoracic malignancies.

Brahmer recently sat down for an interview with OncologyLive® to preview the conference in greater depth, share her thoughts about the major trends in lung cancer, and discuss some of the major work she has done over the course of her career. “This is a very exciting time in lung cancer care,” she said. “A number of significant trial results have appeared in the past year or so, and a large number of very interesting trials are under way.”

Ongoing Research Sparks New Directions in Care

Expanding PD-L1 inhibitors beyond expression

Among the most important results presented this year came from the phase 3 IMpower010 trial (NCT02486718), which supported the decision by the FDA to expand the approval of the PD-L1 inhibitor atezolizumab (Tecentriq). The agent’s indication now includes the adjuvant treatment of patients with stage II to IIIA NSCLC, whose tumors express PD-L1 following surgery and platinum-based chemotherapy. The approval is the first adjuvant indication in NSCLC for an immunotherapy.³ The FDA also approved the VENTANA PD-L1 (SP263) Assay for use as a companion diagnostic device.

Data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting in June and the European Society for Medical Oncology Annual Congress 2021 in September showed that the end point of disease-free survival (DFS) was met in the all-randomized stage II to IIIA population with a benefit demonstrated for those with PD-L1 expression of at least 1%.^4,5

For those in the all-randomized stage II to IIIA population, at a median follow-up of 32.2 months (range, 0-57.5), the median DFS in patients who received atezolizumab (n = 442) was 42.3 months (95% CI, 36.0-not estimable [NE]) vs 35.3 months (95% CI, 30.446.4) in patients who received best supportive care (n = 440; HR, 0.79; 95% CI, 0.64-0.96; P = .02). The 36-month DFS rates were 55.7% vs 49.4%, respectively.

At a median follow-up of 32.8 months (range, 0.1-57.5), the median DFS for patients with PD-L1 expression of at least 1% on tumor cells who received atezolizumab (n = 248) was NE (95% CI, 36.1-NE) vs 35.8 months (95% CI, 29.0-NE) for those who received best supportive care (n = 228; HR, 0.66; 95% CI, 0.50-0.88; P = .004).

Atezolizumab performed particularly well in patients with high PD-L1 expression. In a prespecified secondary subgroup analysis of patients with stage II to IIIA NSCLC with a PD-L1 tumor cell expression of 50% or higher (n = 229), the HR for DFS vs best supportive care was 0.43 (95% CI, 0.27-0.68). In results of an exploratory analysis, patients with a PD-L1 tumor cell expression ranging from 1% to 49% (n = 247), the HR for DFS was 0.87 (95% CI, 0.60-1.26).⁵

The most frequently reported adverse effects were increased aspartate aminotransferase, increased blood creatinine, and increased alanine aminotransferase. Other toxicities included hyperkalemia, rash, cough, hypothyroidism, pyrexia, fatigue/ asthenia, musculoskeletal pain, peripheral neuropathy, arthralgia, and pruritus. The recommended atezolizumab dose for this indication is 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks for up to 1 year.

“It’s great to be able to see immunotherapy [affect] patients in early-stage disease for NSCLC. It is another demonstration that lung cancer is a cancer that’s affected by the immune system and that the immune system plays a role in disease control,” Brahmer, who believes the new treatment option will be adopted quickly on the strength of the trial results, said. “It’s early on, but the data we’re seeing show increased chances of cure or at least increased disease-free survival in these patients with early-stage disease.”

KRAS G12C

Atezolizumab was not the only drug to earn a lung cancer approval in 2021. In May, the FDA granted accelerated approval to sotorasib (Lumakras) as a second-line treatment for patients with NSCLC with KRAS G12C mutations based on data from the phase 2 CodeBreaK 100 trial (NCT03600883).⁶

In published findings from CodeBreaK 100, sotorasib elicited an objective response rate (ORR) of 37.1% (95% CI, 28.6%-46.2%) among 124 patients with KRAS G12C–mutated NSCLC who had progressed following treatment with an immunotherapy and/ or chemotherapy. The median duration of response (DOR) with the treatment was 11.1 months (95% CI, 6.9-NE), and the disease control rate was 80.6% (95% CI, 72.6%-87.2%).7 The median progression-free survival (PFS) was 6.8 months (95% CI, 5.1-8.2), and the median overall survival (OS) was 12.5 months (95% CI, 10.0-NE).

Findings from exploratory biomarker analyses revealed that sotorasib demonstrated clinical activity across a range of biomarker subsets, including those with PD-L1–negative or –low status, and those with tumors that exhibited STK11 mutations.⁸

Sotorasib is the first drug approved for patients with KRAS G12C mutation in NSCLC, and Brahmer thinks it will be interesting to see when the targeted drug will be used in such patients relative to other treatment options.

“Right now, at least in patients with driver- mutated tumors who are never smokers, we typically start with the tyrosine kinase inhibitor [TKI],” she said. “Where it gets a little bit harder right now is in patients with KRAS G12C inhibitors, where immune checkpoint inhibitors as a single agent have a decent response rate, somewhere between 30% and 40%. That is where we need head-tohead comparison studies to see what is best to give these patients first,” said Brahmer, who added that there are reasons beyond treatment efficacy to prefer trying TKIs before immunotherapy.

“A lot of us are a bit hesitant when we’re giving immunotherapy first in patients who will receive TKIs next because there’s concern about increased adverse effects. It takes [time] for the immunotherapy antibody to get out of [the patient’s] system, and the effects on a patient’s immune system can last for months to years. Sometimes when we add a TKI to immunotherapy or start a TKI after immunotherapy, we can see more unusual adverse effects or increased adverse effects, and that’s always a concern.”

Adverse Effects Come Into Focus

Managing adverse effects from immuno-therapy will be a major point of emphasis at the conference because strategies for treat-ment selection and toxicity management continue to evolve.

“For the most part, oncologists are now getting comfortable treating patients on with this class of medication, but there are always nuances in dealing with the toxicities,” Brahmer said. “The guidelines help give us a framework to treat or mitigate the adverse effects, and we’ll discuss those. I also think we’re learning more about who we can safely treat and how to best use these therapies in patients with preexisting autoimmune diseases as well. At the conference, we hope to focus on some complex cases that we see occasionally in the clinic to give the providers in attendance a framework in thinking about these toxicities.”

Molecular Testing Solidifies Role in NSCLC

Another area of emphasis at the conference will be strategies for using molecular tests to guide caregiver decisions, both before treatment and as treatment continues. The number of molecular tests has ballooned in recent years along with the number of medications targeted at new mutations.

This year, for example, the FDA approved 2 diagnostic tests designed to evaluate eligibility for 2 novel agents—amivantamab-vmjw (Rybrevant) and mobocertinib (Exkivity)—both of which were approved for patients with NSCLC with EGFR exon 20 insertion mutations (Table^9,10). They are the first treatments for these rare mutations, which are associated with aggressive cancer growth.

The amivantamab approval—which was joined by an approval for a companion diag-nostic, the Guardant360 CDx liquid biopsy assay and the QIAGEN therascreen KRAS RGQ PCR kit—was based on data from the phase 1 CHRYSALIS trial (NCT02609776). Results showed that amivantamab elicited an ORR of 40% (95% CI, 29%-51%) among 81 pretreated patients whose NSCLC had EGFR exon 20 insertion mutations. The median DOR was 11.1 months (95% CI, 6.9-NR) with 63% of responders maintaining a response for at least 6 months.^9,11

Among those who responded to amivan-tamab, 3 achieved complete response and 29 had partial responses. Variations in EGFR exon insertion mutations that were detectable in circulating tumor DNA did not seem to affect response to treatment. The median PFS for patients who received amivantamab was 8.3 months (95% CI, 6.5-10.9), and the median OS was 22.8 months (95% CI, 14.6-NR).^9,11

Almost all participants experienced treat-ment-related adverse effects (TRAEs). Some 16% experienced TRAEs that were grade 3 or higher, 9% percent of patients reported serious TRAEs, and 4% had toxicities that resulted in discontinuation.⁹

The mobocertinib approval—which also came with the approval of a companion diag-nostic, Thermo Fisher Scientific’s Oncomine Dx Target Test—was based on results from a phase 1/2 trial (NCT02716116) on a cohort of 114 patients with EGFR exon 20 inser-tion–positive NSCLC who had received prior platinum-based therapy.¹⁰

Results showed that mobocertinib elicited an ORR of 28% (95% CI, 20%-37%) and a DOR of 17.5 months (95% CI, 7.4-20.3). The median PFS was 7.3 months (95% CI, 5.5-9.2), and the median OS was 24.0 months (95% CI, 14.6-28.8).^12,13 Further, the ORR in the cohort of patients who received prior platinum-based therapy was 35% (95% CI, 26%-45%) with a median DOR of 11.2 months (95% CI, 5.6-NE). The confirmed disease control rate in this cohort per investigator assessment was 78% (95% CI, 69%-85%).¹³

The most common TRAEs included diarrhea, rash, nausea, stomatitis, vomiting, and decreased appetite. The prescribing information for mobocertinib includes a box warning for heart-rate corrected QT prolongation and Torsades de pointes, in addition to warnings and precautions for interstitial lung disease/pneumonitis, cardiac toxicity, and diarrhea.¹⁴

“We’ll certainly be going over all of these new inhibitors that are being approved by the FDA on what almost seems like a monthly basis, focusing on some of the new FDA approvals for KRAS G12C mutations, EGFR exon 20 mutations, as well as HER2 mutations,” Brahmer said. “I’m excited to be able to offer [participants] a time to discuss some of these new treatment options and to figure out how best to integrate them into practice.”

As Brahmer spoke of the new targeted agents, she returned to the topic of molecular testing. “As targetable mutations proliferate, testing obviously becomes more important, so we want to go over testing: who to test, what tests are best,” Brahmer said. “In the metastatic setting, we always struggled with the issue of getting enough tumor tissue and in trying to get those results as quickly as possible so that we can get the patients on the right treatment as quickly as possible. Certainly, we do use blood-based cell-free DNA testing platforms in order to try to get those results more quickly.”

Turning Personal Experience Into a Career Passion

Brahmer grew up in rural Nebraska, the daughter of a sixth-generation farmer and a nurse. She became interested in oncology during her high school years, after her grandfather died of lymphoma. After completing her undergraduate degree at Creighton University in Omaha, she graduated from the University of Nebraska Medical School, where she conducted her first cancer research under the tutelage of Julie Vose, MD, MBA, a past president of ASCO.

After serving her internship and residency at The University of Utah in Salt Lake City, Brahmer accepted an oncology/hematology fellowship at Johns Hopkins Medicine, where she has remained. “I specifically got interested in lung cancer at Johns Hopkins after meeting David S. Ettinger, MD, who is a giant in our field,” Brahmer said. “He opened my eyes to the opportunities and the need for research in lung cancer back in 2000, and I’ve been in this field ever since, blessed to have amazing mentors and colleagues.”

Among Brahmer’s interests were earlystage trials, often first-in-human uses for potential lung cancer treatments. The overwhelming majority of these agents never went beyond the tiny preliminary trials, and even those that showed some early promise tended to fizzle out, which was why Brahmer controlled her enthusiasm when she saw strong responses in that first nivolumab trial. Still, there was a part of her that thought she might be involved with something important.

“I had been the principal investigator on a lot of phase 1, first-in-human trials that just never went anywhere,” she said. “So even the phase 1 trial was exciting because in patients who responded well the disease would just melt away and not come back for months or years.” Brahmer added that many observers were so sure immunotherapy would not work for lung cancer that they assumed these early trial results were coincidences.

“That feeling continued among the oncology community as a whole until the phase 3 study, and even at that point, a lot of [practitioners] still felt it was a fluke,” Brahmer said. “So now, all these years later, seeing that there are groups of patients within lung cancer—as well as in other cancers—benefiting from these treatments, it’s very exciting and gratifying. It’s gratifying to know that I played a small part in the development of this thing that has extended so many lives among patients who did not have many treatment options till then.”

Brahmer has continued to study the use of immunotherapies in lung cancer treatment, and she and other investigators have made many discoveries over those years that have increased the benefits of such medications. Still, many questions remain unanswered.

“We’d really like to learn to predict who can get away with receiving just singleagent immunotherapy and just keep on responding. We’d basically need tests that are as accurate as the ones we have for driver mutations, tests that would allow us to do precision immunotherapy. We’re not there yet, but we’re making progress,” Brahmer said. “We’re also getting a better idea of which combinations which patients should receive. There’s obviously a bunch of different potential combinations, checkpoint inhibitors being tested with cellular therapies. We also want to learn more about predicting which patients still need to rely on chemotherapy to get their disease under control, and we are making steps toward figuring that out. Short term, I think we’ll learn more about how best to sequence treatments. Should we be giving everything up front to these patients to give their best chance of response? If we do, does that affect their long-term disease control? The list of questions is long, but we’re making progress on many fronts. It’s a very rewarding time to be in cancer research.”

References

1. Brahmer JR, Tykodi SS, Chow LQM, et al. Safety and activity of anti-PD-L1 antibody in fgs with advanced cancer. N Engl J Med. 2012;366(26):2455-2465. doi:10.1056/NEJMoa1200694
2. Kazandjian D, Suzman DL, Blumenthal G, et al. FDA approval summary: nivolumab for the treatment of metastatic non-small cell lung cancer with progression on or after platinum-based chemotherapy. Oncologist. 2016;21(5):634-642. doi:10.1634/theoncologist.2015-0507
3. FDA approves atezolizumab as adjuvant treatment for non-small cell lung cancer. FDA. October 15, 2021. Accessed November 24, 2021. bit.ly/3lHUgvQ
4. 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
5. Felip E, Vallieres E, Zhou C, et al. IMpower010: sites of relapse and subsequent therapy from a phase 3 study of atezolizumab vs best supportive care after adjuvant chemotherapy in resected stage IB-IIIA NSCLC. Ann Oncol. 2021;32(suppl 5):S1319. doi:10.1016/j.annonc.2021.08.2120
6. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed November 24, 2021. bit.ly/3c172Ah
7. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med. 2021;384(25):2371-2381. doi:10.1056/NEJMoa2103695
8. Bauml JM, Li BT, Velcheti V, et al. Clinical validation of plasma cell-free DNA (cfDNA) sequencing in the phase 2 trial of sotorasib in patients (pts) with KRAS p.G12C mutated NSCLC. Cancer Res. 2021;81(suppl 13):CT181. doi:10.1158/1538-7445.AM2021-CT181
9. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed November 24, 2021. bit.ly/3G28grS
10. FDA grants accelerated approval to mobocertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. FDA. Updated September 16, 2021. Accessed November 24, 2021. bit.ly/3EFY1tm
11. Sabari JK, Shu CA, Park K, et al. Amivantamab in post-platinum EGFR exon 20 insertion mutant non-small cell lung cancer. J Thorac Oncol. 2021;16(3):S108-S109. doi:10.1016/j.jtho.2021.01.284
12. Takeda’s Exkivity (mobocertinib) approved by U.S. FDA as the first oral therapy specifically designed for patients with EGFR exon20 insertion+ NSCLC. News release. Takeda Pharmaceutical Company. September 15, 2021. Accessed November 24, 2021. bit.ly/3HO9Xux
13. Ramalingam SS, Zhou C, Kim TM, et al. Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study. J Clin Oncol. 2021;39(suppl 15):9014. doi:10.1200/JCO.2021.39.15_suppl.9014
14. Exkivity. Prescribing information. Takeda; 2021. Accessed November 24, 2021. bit.ly/39rF2nK