The Chance to Make a Difference Made Herbst a Lung Cancer Pioneer

Roy S. Herbst, MD, PhD

Roy S. Herbst, MD, PhD, was inspired to become an oncologist during his first week as an MD/PhD candidate at Cornell University and The Rockefeller University, thanks in part to Ralph L. Nachman, MD, longtime chair of Weill Department of Medicine at Weill Cornell Medical College.

Herbst can remember going on rounds with Nachman as a young physician, seeing patients with Hodgkin lymphoma and review-ing the micrographs at teaching rounds. He knew then he was interested in cancer.

Treating patients with cancer became personal when Herbst’s mother developed an early-stage breast cancer during his second year of medical school. She would send a giant packet of pathology slides from her home in Florida to him in New York and he would review them with experts in breast pathology at Cornell and Memorial Sloan Kettering Cancer Center (MSK). At the time, Herbst was working in the laboratory of James E. Darnell Jr, MD, a pioneer in the study of RNA processing and cytokine signaling. The young physician found that oncology fit his research and clinical interests. Plus, he felt good helping his mother navigate through her cancer diagnosis and treatment, a joy he now experiences with his patients.

Herbst enjoyed working in hematology and initially considered specializing in leukemia and lymphoma, but that was a crowded field. He also considered specializing in breast or gastrointestinal cancers, but those fields also didn’t leave much room for an ambitious young investigator.

Arthur T. Skarin, MD, his clinical mentor at MSK, recommended Herbst to the late, legendary Emil “Tom” Frei III, MD, former director and physician-in-chief at Dana-Farber Cancer Institute, and they both encouraged Herbst to pursue lung cancer. It was the mid-1990s and decades had passed since the last major advance in the field. Frei told the younger physician there was no place to go but up in lung cancer and that he had the opportunity to make a significant difference.

Herbst saw an opportunity to bring science from the laboratory to the clinic and began seeing patients under the direction of the late thoracic surgeon David J. Sugarbaker, MD. His mentor and fellowship director Robert J. Mayer, MD, a 2015 Giants of Cancer Care^® award winner in the gastrointestinal cancer category and vice president for faculty affairs at Dana-Farber, also gave Herbst’s career a boost. Mayer nominated him for the first class of the newly established clinical investigator training program at the Harvard-MIT Program in Health Sciences and Technology, where Herbst would go on to earn a master’s degree in human clinical investigation.

“There wasn’t much competition for the job in lung cancer back then,” he said. “Now it’s very competitive to work in this field.”

Certainly, Herbst, a pioneer in designing novel clinical trials and developing new therapies, has helped turn the lung cancer treatment landscape into one of the most active in oncology today. Along the way, Herbst has worked at some of the best medical centers in the world, first at Dana-Farber, then at The University of Texas MD Anderson Cancer Center, and now back at his undergraduate alma mater of Yale University. There, he is Ensign Professor of Medicine (medical oncology) and professor of pharmacology, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, and associate director for translational science at Yale Cancer Center. He also serves as an undergraduate adviser and enjoys working with the trainees and junior physicians.

His friend Thomas J. Lynch Jr, MD, a 2013 Giants of Cancer Care^® award winner for lung cancer who is now president and director at Fred Hutchinson Cancer Research Center, formerly served as director of Yale Cancer Center and recruited Herbst back to Yale. Herbst’s wife and daughter are longtime Texans—his wife is a graduate of The University of Texas and their daughter was born there—so they weren’t thrilled with trading Houston for New Haven, Connecticut. Now, the family is thriving in the Northeast.

“They love it here. It’s a good community,” he said. “We live right in the heart of New Haven—the university is a mile and a half away. The Yale Bowl where they play football is 2 blocks away and we often walk over there to see a game or walk the dog. I can even walk to the office on a nice day. We enjoy every aspect of life.”

"Shovel-Ready" Data for the Clinic

As an innovative investigator in the lung cancer arena, Herbst enjoys communicating with his colleagues about emerging treatment strategies and best practices. He has been involved with the International Lung Cancer Congress^® (ILCC) since it was founded 22 years ago except for 2005, when he missed the meeting for the birth of his daughter. In 1999, conference founder Chandra P. Belani, MD, invited him to address the inaugural congress.

Several years later, Herbst joined the steering committee for the meeting, which is hosted by Physicians’ Education Resource^®, LLC (PER^®). He and David R. Gandara, MD, emeritus professor of medicine and director of the Thoracic Oncology Program at UC Davis Comprehensive Cancer Center and the 2017 Giants of Cancer Care^® award winner for lung cancer, have cochaired the conference for more than a decade.

This year’s meeting, scheduled for July 29 to 31, will be a hybrid conference that includes both virtual and in-person sessions in Huntington Beach, California. Herbst said he will attend in person “by hook or by crook.”

“I really like the in-person interaction, so I will figure out a way to get there,” he said, adding it that will be nice to get away and see some colleagues in person. “I’m vaccinated and ready to go. The idea of reviewing data about lung cancer, discussing cases and having knowledge exchanged between academic and community physicians—I look forward to it every year.”

Herbst is cochairing this year’s meeting with Gandara and Heather A. Wakelee, MD, a professor of medicine at Stanford University Medical Center in Palo Alto, California. They were still working on the agenda when Herbst spoke about the conference in April, but he said the meeting would include sessions on early and metastatic disease, targeted therapy, immune checkpoint inhibitor (ICI) therapy, radiation, surgery, and multimodal therapy. There also will be a series of debates and case discussion panels, which are always a highlight of the meeting.

“We’re very excited this year because we’re going to have an increased number of discussion sections, we’ll be very case focused,” he said. “We’re expecting new adjuvant data to be out by the meeting, so we can discuss those data. Dr Wakelee has been involved with that research. In every panel, we’ll have cases with audience questions and response, then we’ll discuss it in a multimodality way.

“I am excited about creative ways to interact with both the in-person and virtual attendees,” Herbst added. “This is certainly the way we will be doing these types of meeting in the future.”

He noted that ILCC faculty members will discuss data presented at meetings hosted by the American Society of Clinical Oncology (ASCO), the International Association for the Study of Lung Cancer (IASLC), and the American Association for Cancer Research (AACR). Specifically, Herbst is looking forward to examining findings for non–small cell lung cancer (NSCLC) from trials including IMpower010 (NCT02486718), Lung-MAP (NCT02154490), and CheckMate 816 (NCT02998528).

Figure. A Closer Look at Lung-MAP

The phase 3 IMpower010 study compared atezolizumab (Tecentriq), a PD-L1 inhibitor, with best supportive care (BSC) as adjuvant therapy for patients with stage II to IIIA NSCLC who had received surgery and chemotherapy. The study randomized 1005 patients to up to 16 cycles of atezolizumab vs BSC.¹

Atezolizumab demonstrated a statistically significant improvement in disease-free survival, the primary end point of the study, according to Genentech, the company developing the drug.1 Wakelee and colleagues are scheduled to present primary results from the trial during the 2021 ASCO Annual Meeting, which will be held virtually June 4 to 8.²

In Lung-MAP, which began in 2014, investigators have been using an umbrella design to conduct molecular testing on the tumors of patients with NSCLC to match them with targeted therapies. The study, for which Herbst serves as the founding and current PI, has recruited more than 3660 patients who have been treated at 800 centers with novel therapies during 13 substudies.³

The protocol represents a milestone for precision medicine not only in trial design but also in the amount of information that has been compiled. “Lung-MAP now has one of the largest collections of data and biospecimens ever gathered for lung cancer,” Herbst, who chairs the study, said in a statement.³

In January, translational discoveries from the study were presented at the virtual 2020 World Conference on Lung Cancer. Findings showed that higher tumor mutational burden was associated with better survival rates and longer disease-free periods; that mutations in a previously undetected set of 3 genes, PARP4, NFE2L2, and KEAP1, may play an important role in driving squamous cell lung cancers; and that analysis of plasma circulating tumor DNA shows high sensitivity and specificity as a screening tool for genomic aberrations.³

At the 2021 AACR Annual Meeting in April, investigators shared data from the phase 3 CheckMate 816 trial testing the combination of nivolumab (Opdivo) plus platinum doublet chemotherapy vs chemotherapy alone as neoadjuvant therapy for patients with resectable stage IB to IIIA NSCLC. The At the 2021 AACR Annual Meeting in April, investigators shared data from the phase 3 CheckMate 816 trial testing the combination of nivolumab (Opdivo) plus platinum doublet chemotherapy vs chemotherapy alone as neoadjuvant therapy for patients with resectable stage IB to IIIA NSCLC. The addition of nivolumab increased the rate of pathologic complete response (pCR) to 24% compared with 2.2% with chemotherapy alone (odds ratio, 13.94; 99% CI, 3.49-55.75; P < .0001). Among those who subsequently underwent resection, the pCR rate was 30.5% with nivolumab compared with 3.2% for chemotherapy alone.⁴

Herbst said that, like other meetings organized by PER^®, ILCC will focus on delivering information physicians can quickly apply to clinical practice. “Everything about our meeting is practical. We discuss the data, then discuss how to apply them with cases and in patients.”

This year, Herbst said, the most pressing clinical questions include: “How do you use adjuvant therapy? Do you use neoadjuvant therapy based on pathologic complete response rate? What combinations are more impactful for immune resistance? How do you define immune resistance? How do you use biomarkers and immune resistance? I think all of that will be very important.”

New Therapies Result in Improved Survival

Herbst has been a leader in clinical research for nearly 25 years. When he started his career in 1994, lung cancer was no place for an ambitious, young scientist to focus. The only treatment option for metastatic disease was cytotoxic chemotherapy, which put patients through significant adverse effects with very little benefit. In 2001, the 2-year survival rate was 26% for men with NSCLC and 35% for women. Today, those numbers are 35% and 44%, respectively.⁵

Since then, multimodality treatments, targeted therapy, and immunotherapy have improved outcomes for patients. Lung cancer-specific mortality declined 3.2% annually for men from 2006 to 2013. From 2013, when the FDA approved the EGFR-directed therapies in the first line, to 2016, mortality declined 6.3% every year. For women, mortality declined by 2.3% from 2006 to 2014 and by 5.9% from 2014 to 2016.⁵

Since then, multimodality treatments, targeted therapy, and immunotherapy have improved outcomes for patients. Lung cancer-specific mortality declined 3.2% annually for men from 2006 to 2013. From 2013, when the FDA approved the EGFR-directed therapies in the first line, to 2016, mortality declined 6.3% every year. For women, mortality declined by 2.3% from 2006 to 2014 and by 5.9% from 2014 to 2016.⁵

Herbst modestly jokes that witnessing such drastic improvements in survival just means he’s getting old, but he has played a significant role in pushing lung cancer care forward. He began his research career focusing on developing novel targeted agents for the treatment of lung cancer, especially therapies targeting the EGFR and VEGF signaling pathways such as gefitinib (Iressa), erlotinib (Tarceva), axitinib (Inlyta), cetuximab (Erbitux), and bevacizumab (Avastin).

“Some of my most impactful early work was to lead the first phase 1 studies for the use of EGFR inhibitors in lung cancer, understanding their use, their toxicity, their response, bringing those drugs to the clinic, and understanding biomarkers involved in their use. And then, of course, bringing them all the way to phase 3 in untreated patients as adjuvant therapy with a highly positive results,” he said.

Moreover, Herbst has been instrumental in developing ICIs directed at PD-1/PD-L1, including the development of PD-L1 as a prospective biomarker. “[In] the early studies on IO [immuno-oncology] inhibitors, whether it be at atezolizumab or pembrolizumab [Keytruda], we carefully explored PD-L1 as a biomarker, which has turned out to be very important,” Herbst said. “Those [are] all things that have been successes that I’ve been involved with…developing new combination therapies when possible to do so with biomarker targets.”

Herbst was the lead author for the phase 1 trial investigating the first-generation EGFR tyrosine kinase inhibitor (TKI) gefitinib.⁶ He later served as principal investigator (PI) on the phase 3 INTACT 2 trial, the results of which supported FDA approval in May 2003 for gefitinib for treating patients with locally advanced or metastatic NSCLC.^7,8

In December 2020, the FDA approved the third-generation EGFR-inhibitor osimertinib (Tagrisso) as adjuvant treatment following tumor resection for patients with resected NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations. The agency granted approval based on data from the ADAURA trial (NCT02511106).^9,10

Herbst was the senior and corresponding author for ADAURA, in which 682 patients with resectable (stage IB-IIIA) NSCLC were assigned to 80 mg once-daily oral osimertinib or placebo following recovery from surgery and/or standard adjuvant chemotherapy. The primary end point was median disease-free survival (DFS) in patients with stage II to IIIA disease.

In patients with stage II to IIIA disease, the median DFS was not reached in the osimertinib arm (95% CI, 38.8-not estimable [NE]) compared with 19.6 months (95% CI, 16.6-24.5) with placebo (HR, 0.17; 95% CI, 0.12-0.23; P < .0001). In the overall study population, which comprised patients with stage IB to IIIA disease, median DFS was not reached in patients in the osimertinib arm (95% CI, NE-NE) compared with 27.5 months (95% CI, 22.0-35.0) for placebo (HR, 0.20; 95% CI, 0.15-0.27; P < .0001).¹⁰ The 83% improvement in DFS with osimertinib with significantly decreased metastatic disease to the brain was paradigm changing.

A decade before the success of osimertinib, Herbst made his mark on the lung cancer field as a PI of the BATTLE clinical trial, along with his late mentor Waun Ki Hong, MD, the 2018 Giants of Cancer Care^® award winner for lung cancer, and other team members from his section of thoracic medical oncology at MD Anderson. BATTLE was the first completed, prospective, biopsy-mandated, biomarker-based, adaptively randomized trial in patients with heavily pretreated lung cancer. The study required tumor profiling with “real-time” biopsies, integrating molecular laboratory findings for identifying patient populations for individualized treatment and representing a substantial step toward personalized lung cancer therapy.¹¹

Results from the study demonstrated the feasibility of performing biopsies and real-time biomarker analyses, identifying interactions between treatments and markers that could be used when making treatment decisions, and confirming that treatment efficacy in the presence of individual markers relates to the treatments’ mechanism of action. Findings from BATTLE paved the way for larger ongoing trials such as Lung-MAP.

“It’s fantastic,” Herbst said. “It really speaks to how we are bridging the gap and helping people live longer with this disease. That’s what gets me up every morning— seeing the science translated to the patient and seeing patients doing well.

“Sadly, many become resistant to the targeted therapies and we have to figure out what to do next. But I’ve been proud that I’ve been part of teams—I’ve built some of the teams, I’ve been a member of others—I’ve contributed to a large number of publications and helped the field. I’ve cared for and hopefully helped a tremendous number of patients, both in Houston and New Haven.”

Custom Immunotherapy for Every Patient

Moving forward, Herbst would like to apply some of the lessons from his targeted therapy studies to immunotherapy. “I really would like to now lead a team to undertake personalized immunotherapy. I’d like to find the right biomarkers.” he said. “We did the BATTLE trial and I’d very much like to do the same thing with immunotherapy—pick the right markers and the right drugs, truly target immunotherapy in the best way.”

Immunotherapy has long been one of Herbst’s clinical interests as he searches for ways to make care more personalized. He works closely with some of the most prominent leaders in the field, including Lieping Chen, MD, PhD, a 2018 Giants of Cancer Care^® award winner in the immuno-oncology category; Scott Gettinger, MD; Mario Sznol, MD; and Harriet M. Kluger, MD.

He and his colleagues at Yale were among the first to understand and describe how the presence of PD-L1 correlated with response in patients receiving atezolizumab. This led to a biomarker-driven first-in-human trial, one of the first to demonstrate in human biopsies the concept of adaptive immunity.^12,13

Herbst and his collaborators later showed the value of PD-L1 as a prospective biomarker in the randomized phase 2/3 KEYNOTE-010 trial (NCT01905657), in which investigators examined pembrolizumab in the second line setting for patients with NSCLC. Findings from KEYNOTE-010 and KEYNOTE-024 (NCT02142738) contributed to the FDA approval in 2016 for pembrolizumab, the first approved anti–PD-1 agent, as first-line treatment of patients with NSCLC with high PD-1 expression.^14,15

Immunotherapy has resulted in incredible gains in survival for patients with NSCLC; data from KEYNOTE-024 showed that pembrolizumab doubled median overall survival (OS) compared with chemotherapy (26.3 vs 13.4 months).¹⁶ Findings published in 2020 showed that immunotherapy improves survival compared with chemotherapy for patients with metastatic NSCLC regardless of line of treatment.¹⁷

Additionally in 2020, Herbst and his colleagues published new data from the phase 3 IMpower110 trial (NCT02409342) demonstrating that patients with high PD-L1 expression who received atezolizumab had a median OS of 20.2 months compared with 13.1 months for those who received chemo-therapy (HR, 0.59; P = .01).

The findings led to FDA approval for atezolizumab as first-line therapy for patients with high PD-L1 expression (PD-L1 staining on ≥ 50% of tumor cells or ≥ 10% of tumor- infiltrating immune cells) and with no EGFR or ALK genomic tumor aberrations.^18,19

Additionally in 2020, Herbst and his colleagues published new data from the phase 3 IMpower110 trial (NCT02409342) demonstrating that patients with high PD-L1 expression who received atezolizumab had a median OS of 20.2 months compared with 13.1 months for those who received chemo-therapy (HR, 0.59; P = .01). The findings led to FDA approval for atezolizumab as first-line therapy for patients with high PD-L1 expression (PD-L1 staining on ≥ 50% of tumor cells or ≥ 10% of tumor- infiltrating immune cells) and with no EGFR or ALK genomic tumor aberrations.^18,19

Unmet Needs

However, for all the improvements in lung cancer treatment, survival still need to be improved. According to Cancer.net, the overall 5-year survival rate is 21%, 17% for men and 24% for women.²⁰

Long-term results from the KEYNOTE-001 trial (NCT01295827) showed that the 5-year OS rate exceeded 25% among patients with a PD-L1 tumor proportion score of 50% or greater (PD-L1 high) who were treated with pembrolizumab monotherapy. This is a huge improvement over previous treatments but one that still leaves many patients without a survival benefit.²¹

Moreover, not all patients who are PD-L1 high respond to immunotherapy.²² Of those who do respond, up to 27% of patients with advanced NSCLC exhibit resistance to first-line ICIs with or without chemotherapy and up to 44% develop resistance to ICI monotherapy in the pretreatment setting.²³

“We have to look the nonresponders and understand what else is going on, identify what other immune regulatory mechanisms are in play. So we can then target them with precision combination therapies,” Herbst said.

Solving those mysteries, he continued, will require translational research bridging the lab and the clinic to bring the best science to bear on the problem. This will likely involve biopsies, combination studies, more preclinical lab work, and preclinical models.

He’s even more focused on under-standing how and why patients initially respond, then become refractory to treatment. Herbst leads the Lung Specialized Programs of Research Excellence (SPORE) in Lung Cancer at Yale Cancer Center that is currently conducting multiple trials, including evaluating approaches to prevent TKI-resistance in EGFR-mutant lung cancer and develop-ing ways to target lung cancer metastasis and drug resistance in the central nervous system. He is also working to bring new targets to the clinic, many of which were discovered in the laboratory of his friend and collaborator Chen.

“We’re constantly trying to understand how to treat these tumors. We are uncover-ing resistance mechanisms. We now know that [EGFR] C797S is a resistance mutation to some other targets, so we’ll hopefully find ways to target that,” Herbst said. “That is what keeps me going, trying to find new combinations, new immunotherapies, and always using biology to promote even better therapy.”

References

1. Pivotal phase III study shows Genentech’s Tecentriq helped people with early lung cancer live longer without their disease returning. Press release. Genentech. March 21, 2021. Accessed May 3, 2021. https://bit.ly/3thLnd9
2. Wakelee HA. 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). American Society of Clinical Oncology. Accessed May 3, 2021. https://bit.ly/3tbBw8t
3. Lung-MAP translational discoveries shared at 2020 World Conference on Lung Cancer. Press release. Lung Cancer Master Protocol (LUNG-MAP) Clinical Trials. January 28, 2021. Accessed May 3, 2021. https://bit.ly/3ti4yDo
4. Forde PM, Spicer J, Lu S, et al. Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment (tx) for resectable (IB-IIIA) non-small cell lung cancer (NSCLC) in the phase 3 CheckMate 816 trial. Presented at: American Association for Cancer Research Annual Meeting; April 10-15, 2021; Virtual. Abstract CT003. Accessed May 3, 2021. https://www.abstractsonline.com/pp8/#!/9325/presentation/5134
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6. Herbst RS, Maddox AM, Rothenberg ML, et al. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. J Clin Oncol. 2002;20(18):3815-3825. doi:10.1200/JCO.2002.03.038
7. Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial––INTACT 2. J Clin Oncol. 2004;22(5):785-794. doi:10.1200/JCO.2004.07.215
8. Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R. FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets. Oncologist. 2003;8(4):303-306. doi:10.1634/theoncologist.8-4-303
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10. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. December 18, 2020. Accessed May 3, 2021. https://bit.ly/2Rz8Rxc
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15. Pai-Scherf L, Blumenthal GM, Li H, et al. FDA approval summary: pembrolizumab for treatment of metastatic non-small cell lung cancer: first-line therapy and beyond. Oncologist. 2017;22(11):1392-1399. doi:10.1634/theoncologist.2017-0078
16. Brahmer JR, Rodriguez-Abreu D, Robinson AG, et al. KEYNOTE-024 5-year OS update: first-line (1L) pembrolizumab (pembro) vs platinum-based chemotherapy (chemo) in patients (pts) with metastatic NSCLC and PD-L1 tumour proportion score (TPS) ≥ 50%. Ann Oncol. 2020;31(suppl 4):S1181-S1182. doi:10.1016/j.annonc.2020.08.2284
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19. FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD-L1 expression. FDA. May 18, 2018. Accessed May 3, 2021. https://bit.ly/3aYZEVM 
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23. Walsh RJ, Soo RA. Resistance to immune checkpoint inhibitors in non-small cell lung cancer: biomarkers and therapeutic strategies. Ther Adv Med Oncol. 2020;12:1758835920937902. doi:10.1177/1758835920937902