Getting Ready for the Next Chapter in Lung Cancer

David R. Gandara, MD

David R. Gandara, MD

David R. Gandara, MD, an esteemed lung cancer specialist and 2017 Giants of Cancer Care^® award winner, views himself not only as a physician-scientist, but also as an educator and communicator. He has mentored more than 50 oncologists in his career, along with PhD candidates and medical students. He also enjoys sharing his scientific knowledge with laypeople and prides himself on his ability to break down complex information for patients in language they can understand.

That’s part of the reason that Gandara regularly takes to Twitter (@drgandara) to share a mix of clinical data, medical news, and the occasional joke. “There is so much bad information on the internet, I feel like it is part of my moral obligation to do what I can to speak on a factual basis, and if there’s something that is misinformation, to point it out,” he said in an interview with OncologyLive^®.

These days, Gandara, director of Thoracic Oncology and senior adviser to the director at the University of California Davis Comprehensive Cancer Center in Sacramento, intersperses informational and inspirational messages about coronavirus 2019 disease (COVID-19) in his Twitter feed.

As the public health threat from COVID- 19 grew more pressing in late March, Gandara took to Twitter to ask practicing oncologists whether they would arbitrarily postpone treatment for patients with advanced NSCLC because of pandemic conditions. Of 357 respondents, 67% said they would treat patients on schedule, assuming the patient does not have an active COVID-19 infection. Approximately 20% said they would delay chemotherapy, 5% would postpone immunotherapy, and 10% would hold off on both.

“I also had a number of patients who independently responded in terms of their views, and every single one of them said, in effect, ‘I know that COVID may kill me, but lung cancer untreated will kill me.’ They said, ‘Please treat us like you are treating us in normal times.’ So although there is considerable debate about this issue, and some institutions are holding therapy, my own belief and that at our institution is we should treat patients with standards of care if we can do it safely,” Gandara said.

Taking a Think Tank Approach

Although providing care for patients with lung cancer during the pandemic will be a continuing concern, Gandara is moving forward with plans for 21st Annual International Lung Cancer Congress^® (ILCC) that Physician’ Education Resource, LLC (PER^®) is hosting. The meeting will be a live webcast, taking place July 23 through 25. (For information, visit GoToPER.com).

Gandara serves as one of the program directors for the meeting, along with Roy S. Herbst, MD, PhD, Ensign Professor of Medicine, professor of pharmacology, chief of medical oncology, and associate cancer center director for translational research at the Yale Cancer Center in New Haven, Connecticut, and Heather A. Wakelee, MD, professor of medicine (oncology) at Stanford University Medical Center in California. They are organizing a program that will deliver the latest data on novel agents, clinical practice, and new developments with the potential to shape the future of lung cancer therapy. Because the conference is held shortly after the 2020 American Society for Clinical Oncology Annual Meeting in May, Gandara said attendees have the unique opportunity to hear world-renown experts interpret data.

“I’ve always referred to our meeting as a think tank, because it’s much more like that than a regular meeting,” he added. “It has not only classic lectures, but it has a number of panel discussions and casebased discussions with multidisciplinary experts, including all the disciplines that are involved in lung cancer or thoracic malignancy care.”

Gandara said many of the presentations at this year’s conference will explore newly approved agents for the treatment of lung cancer, a field that has seen rapid expansion of targeted agents and immune checkpoint inhibitor therapies during the past decade.

In the realm of targeted therapies, recent developments include FDA approvals for 2 new drugs and expanded indications for several others—all during May 2020.

On May 6, the agency authorized capmatinib (Tabrecta) for patients with non—small cell lung cancer (NSCLC) whose tumors harbor a MET exon 14 skipping mutation. Two days later, the FDA approved selpercatinib (LOXO-292; Retevmo) for patients with RET alteration—positive NSCLC, medullary thyroid cancer, and other thyroid cancers. On May 22, brigatinib (Alunbrig), which had been approved in a second-line setting, gained a frontline indication for patients with ALK-positive metastatic NSCLC.¹

And, on May 29, the FDA expanded the indication for ramucirumab (Cyramza), a VEGF inhibitor already approved in combination with docetaxel for progressive metastatic NSCLC, to include its use as frontline therapy in conjunction with erlotinib (Tarceva) for patients with EGFR exon 19 deletions or exon 21 L858R mutations.¹

These approvals follow the August 15, 2019, approval of the oral kinase inhibitor entrectinib (Rozlytrek) for adults and adolescents with solid tumors that harbor NTRK gene fusions and for adults with ROS1-mutated metastatic NSCLC.¹

In the immunotherapy arena, the FDA has issued multiple approvals in the past 14 months. On March 30, 2020, the agency expanded the indication for the anti—PD-L1 monoclonal antibody durvalumab (Imfinzi) in combination with chemotherapy to include first-line treatment for patients with extensive-stage small cell lung cancer (SCLC). The FDA also approved expanded SCLC indications for atezolizumab (Tecentriq), a PD-L1 inhibitor, and pembrolizumab (Keytruda), a PD-1–targeting agent, in 2019.¹

Meanwhile, on May 15, 2020, the FDA approved the dual immunotherapy combination of nivolumab (Opdivo), an anti—PD-1 antibody, and ipilimumab (Yervoy), which targets CTLA-4, for the first-line treatment of patients with PD-L1–positive (≥1%) metastatic or recurrent NSCLC with no EGFR or ALK aberrations.¹ In data from the phase 3 CheckMate 227 trial (NCT02477826), the combination resulted in a median overall survival (OS) of 17.1 months compared with 14.9 months with chemotherapy in patients with tumor PD-L1 expression of 1% or higher (HR, 0.79; 97.72% CI, 0.65-0.96; P = .007).²

Less than 2 weeks later, the FDA approved the 2 immunotherapies in combination with 2 cycles of platinum doublet chemotherapy as a frontline treatment for patients with metastatic or recurrent NSCLC without EGFR or ALK aberrations, regardless of PD-L1 expression levels. The immunotherapy-containing regimen demonstrated a median OS of 14.1 months versus 10.7 months with chemotherapy alone (HR, 0.69; 96.71% CI, 0.57-0.86; P = .006) in the phase 3 CheckMate 9LA trial (NCT03215706).³

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These advances are not just in one area or the other, they’re in multiple areas,” Gandara said. “Again, what that means is a practicing oncologist has to stay on top of the field, and the best way to do that is by CME education such as we’re providing in the ILCC.”

He is particularly excited about discussing emerging drugs that target KRAS mutations in patients with NSCLC. Leading the pack is AMG 510, a small-molecule inhibitor of KRAS G12C that is being developed under the FDA’s fast track designation for patients with previously treated metastatic disease that harbors the mutation.⁵

Another agent that targets KRAS G12C, MRTX849, also has demonstrated promising early clinical findings.⁶ Additionally, phase 1 testing began in 2019 on a pan-KRAS inhibitor, BI 1701963 (NCT04111458), and on mRNA-5671 (V941), a KRAS vaccine (NCT03948763). Another pan-KRAS inhibitor, BBP-454, is in preclinical testing and investigators also are exploring blocking KRAS activation by targeting SOS1.

“At ILCC each year, we have a session on new drugs, new drugs that are coming out, new classes of drugs that are available. That will be one of the highlights of this meeting,” Gandara said. “In particular, although there are several drug classes where there are new findings, one that is brand new is the development of drugs for KRAS G12C mutation. KRAS―and I’ve always said this myself― has been an undruggable target because of the difficulty in developing a drug which could inhibit that mutation. But now there are drugs, and there are 5 of them in development, and we’ll be hearing about them at ILCC.”

Diagnostics Drive Changes

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At present, the National Comprehensive Cancer Network recommends molecular testing for patients with advanced or metastatic NSCLC for 4 oncogene-driven NSCLCs: EGFR mutations (category 1), ALK (category 1), ROS1 rearrangements, and BRAF point mutations. Other molecular targets described as emerging in the guidelines: NTRK fusions, MET amplification or exon 14 skipping mutation, RET rearrangements, and ERBB2 (HER2) mutations.⁷ Gandara expects KRAS G12C mutations to be added for molecular testing.

According to findings from The Cancer Genome Atlas research network, KRAS (32%) is the most common mutation in lung adenocarcinoma, the most prevalent NSCLC subtype, followed by EGFR (11%) and BRAF (7%). Each of the remaining mutations recognized in the guidelines is found in 2% or fewer tumors.⁸ Investigators estimate than almost 50% of patients harbor a genomic alteration that could be druggable.⁹

Gandara is anticipating new data for agents targeting EGFR-mutated tyrosine kinase inhibitor (TKI)-resistant NSCLC. Although TKI therapy is well established for this population, nearly all patients with EGFR-mutated NSCLC will develop resistance to first-line therapy and overcoming that resistance is key to extending survival in these patients.¹⁰

The third-generation TKI osimertinib (Tagrisso) was developed to overcome both EGFR sensitizing and T790M resistance mutations. The FDA approved the agent in November 2015 to treat patients with EGFR T790M mutation—positive NSCLC who progressed following previous EGFR TKI therapy. That indication was expanded in April 2018 to include frontline use for patients with NSCLC who have tumors harboring EGFR exon 19 deletions or exon 21 L858R mutations.¹¹

Gandara noted that investigators are also targeting RET alterations. Previous multitargeted agents may have been active against RET, but the new generation of drugs in development specifically home in on the aberration.

In addition to the newly approved selpercatinib, pralsetinib (formerly BLU-667), a selective inhibitor of RET fusions and mutations, is being developed for patients with RET-positive NSCLC under a breakthrough therapy designation. The FDA is reviewing data submitted for a new drug application based on findings for patients previously treated with platinum-based chemotherapy.¹²

“So how does a practicing oncologist then test for all of these oncogenes in a timeefficient manner, with good sensitivity, good specificity, and have a turnaround time of 1 to 2 weeks, so that they can treat the patient with a personalized or precision medicine approach rather than empiric?” Gandara said. “We now have that ability—and liquid biopsy can now complement tissue next-generation sequence testing, enabling a personalized approach in even more patients.”

A Pioneering Investigator

Gandara has been a leader in clinical research for decades, playing key roles in the development of erlotinib (Tarceva), the first widely used EGFR TKI in the United States, and the immune checkpoint immunotherapies that have entered clinical practice since 2015. He helped set the direction of research in the field as chair of the lung committee for the Southwest Oncology Group (SWOG), a post he held for 17 years before stepping down to become a senior adviser with the research consortium in 2016.

In 2014, he played a pivotal role in developing and launching Lung-MAP, a unique public-private partnership for a master protocol incorporating molecular screening to match patients to investigational new treatments for NSCLC. Initial substudies of Lung-MAP include investigation of palbociclib (Ibrance) for patients with stage IV squamous cell lung cancer harboring cell-cycle mutations, taselisib for those with previously treated PIK3CA-positive stage IV squamous cell lung cancer, and selpercatinib for those with RET fusion-positive stage IV or recurrent NSCLC.

Gandara said his work on atezolizumab is among the major accomplishments of his career. In the phase 3 OAK trial (NCT02008227), investigators evaluated atezolizumab versus docetaxel in patients with stage IIIb or IV NSCLC who experienced progressive disease after 1 or 2 previous chemotherapy regimens, including at least 1 platinum-based regimen.¹³

The group published efficacy findings in 2017 demonstrating that atezolizumab improved median OS compared with docetaxel in all patients (13.8 vs 9.6 months; HR, 0.73; 95% CI, 0.62-0.87; P = .0003), regardless of PD-L1 level.

Atezolizumab also improved median OS versus docetaxel among patients who expressed 1% or greater PD-L1 on tumor cells or tumor-infiltrating immune cells (15.7 vs 10.3 months, respectively; HR, 0.74; 95% CI, 0.58-0.93; P = .0102) and among patients in the PD-L1 low or undetectable subgroup (12.6 vs 8.9 months; HR, 0.75; 95% CI, 0.59-0.96). The FDA approved atezolizumab in second-line treatment for patients with NSCLC in October 2016, based in part on data from the OAK study.

Updated results published in 2018 showed that atezolizumab had a durable effect in the initial 850 patients after a minimum follow-up of 26 months (HR, 0.75; 95% CI, 0.64-0.89; P = .0006) and in the overall cohort after a minimum of 21 months (HR, 0.80; 95% CI, 0.70-0.92; P = .0012).14

In 2018, Gandara led a research team that conducted a retrospective analysis of the OAK data evaluating atezolizumab treatment beyond progression. Among patients who experienced progressive disease, the median post-progression OS was 8.6 versus 6.4 months in favor of the atezolizumab arm. At 18 months post progression, 26% of patients in the atezolizumab arm were still alive versus 18% in the docetaxel arm.¹⁵

New Assay Shows Promise

The work Gandara is most proud of is not a drug; it is a liquid biopsy assay that he and colleagues at Foundation Medicine and Roche-Genentech developed to measure tumor mutational burden in blood (bTMB). Approximately 30% of patients have inadequate tumor tissue to perform molecular testing, and there is evidence suggesting that circulating blood-derived DNA might provide an alternative source of diagnostic material for these patients. To validate the assay, investigators compared the results of comprehensive genomic profiling conducted on tumor tissue samples from patients who participated in the OAK study and the POPLAR trial (NCT01903993), which also involved patients with progressive NSCLC. They compared data gleaned from tumor tissue with information derived from pretreatment circulating tumor DNA in plasma from the same patients.

Investigators found that results obtained from bTMB correlated with those from tissue samples obtained via tissue and plasma. TMB greater than or equal to 16 was associated with a higher PFS benefit from atezolizumab therapy.¹⁶

“We went back to [OAK] and used blood specimens that had been collected to see if we could duplicate the predictive value that had been seen with tissue analysis of TMB, and, in fact, we could,” Gandara said. “That diagnostic test has now completed its phase 3 evaluation in a trial called B-FAST [NCT03178552]. We don’t know the results yet, but it is a trial randomizing to atezolizumab or platinum chemotherapy in patients with high blood TMB.”

A Writer At Heart

Many people who grow up to become physicians know they’re going to pursue medicine even as children. Gandara, however, wanted to be a writer. He planned to become the next Ernest Hemingway, a dream that ended abruptly after high school.

“Once I got into college, I said, ‘Oh, Journalism 101, this doesn’t interest me so much, maybe I should look at something else,’ and I decided to go into medicine,” he said. “But I have always kept my interest in writing, and I think I actually have fairly good writing skills.”

He loves putting clinical research into manuscript form and happily edits manuscripts for other investigators. Gandara is the former editor in chief of Clinical Lung Cancer and he has reviewed manuscripts for New England Journal of Medicine, Journal of the National Cancer Institute, Journal of Clinical Oncology, Oncogene, and Journal of Thoracic Oncology, among others.

“I have been able to blend my writing skills into my medical career,” he said. “I have published almost 400 peer-reviewed articles and hope to do more.”

Gandara does not restrict himself to the written word. He’ll make use of any medium available to talk about science and medicine.

The GO2 Foundation for Lung Cancer, a new organization created when the Bonnie J. Addario Lung Cancer Foundation merged with the Lung Cancer Alliance in 2019, hosts the Lung Cancer Living Room every month. The foundation invites lung cancer physicians and investigators to speak to advocates, survivors, patients, and their families about a wide range of topics including treatment options, molecular and genetic testing, clinical trials, drug discoveries, and up-to-date news about advancements.

The event is webcast around the world and Gandara makes a point to appear regularly. In a recent episode, Gandara used an analogy in which he compared the uniqueness of an individual’s fingerprint, different from all others, to the molecular “fingerprint” of their cancer as defined by next-generation sequencing.

He explained acquired resistance to targeted therapy this way: “Pretend you’re on a bus and it stops. The driver gets off and the person in the row behind him is the new driver. I say, ‘That’s what’s happening in your cancer. The back seat driver has taken over for your cancer, so we have to test to find out what it is and treat it appropriately.’ ” Gandara has worked to communicate with patients and patient advocates throughout his career and finds such analogies to be an effective way to get his point across. “That’s a communication skill that I feel is very important and I try to share it when I can,” he said.

Gandara said care of patients with lung cancer has been advancing at a breakneck pace over the past 10 years. These changes present both challenges and opportunities for health care providers. In particular, advances in molecular testing have driven developments in the field as investigators develop better diagnostic tools.

Also in May, the FDA granted a new indication for atezolizumab as first-line therapy for patients with metastatic NSCLC with high PD-L1 expression, defined as PD-L1 staining on 50% or greater on tumor cells or 10% or greater on tumor-infiltrating immune cells. In the IMpower110 study (NCT02409342), atezolizumab demonstrated a median OS benefit of 20.2 months in the PD-L1—high population compared with 13.1 months for those who received platinum-based chemotherapy (HR, 0.59; 95% CI, 0.40-0.89; P = .0106).⁴

References

1. Hematology/oncology (cancer) approvals & safety notifications. FDA. Updated May 29, 2020. Accessed June 1, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications
2. Hellmann MD, Paz-Ares L, Bernabe Carbo R, et al. Nivolumab plus ipilimumab in advanced non—small-cell lung cancer. N Engl J Med. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231
3. U.S. Food and Drug Administration approves Opdivo® (nivolumab) + Yervoy® (ipilimumab) combined with limited chemotherapy as first-line treatment of metastatic or recurrent non-small cell lung cancer. News release. Bristol Myers Squibb; May 26, 2020. Accessed May 27, 2020. https://news.bms.com/press-release/corporatefinancial-news/us-food-and-drug-administration-approves-opdivo-nivolumab-ye-2
4. FDA approves atezolizumab for first-line treatment of metastatic NSCLC with high PD- L1 expression. FDA. May 18, 2020. Accessed May 20, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-first-line-treatment-metastatic-nsclc-high-pd-l1-expression
5. Amgen announces new clinical data evaluating novel investigational KRAS(G12C) inhibitor in larger patient group at WCLC 2019. News release. Amgen; September 8, 2019. Accessed May 12, 2020. https://bit.ly/2kqnxi4
6. Jänne P. A phase 1 clinical trial evaluating the pharmacokinetics (PK), safety, and clinical activity of MRTX849, a mutant-selective small molecule KRASG12C inhibitor, in advanced solid tumors. Presented at: 2019 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; October 26-30, 2019; Boston, MA.
7. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2020. Accessed May 12, 2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
8. Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511(7511):543‐550. doi:10.1038/nature13385
9. Anguera G, Majem M. BRAF inhibitors in metastatic non-small cell lung cancer. J Thorac Dis. 2018;10(2):589‐592. doi:10.21037/jtd.2018.01.129
10. Santoni-Rugiu E, Melchior LC, Urbanska EM, et al. Intrinsic resistance to EGFR-tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: differences and similarities with acquired resistance. Cancers (Basel). 2019;11(7):923. doi:10.3390/cancers11070923
11. Tagrisso. Prescribing information. AstraZeneca Pharmaceuticals LP; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/208065s013lbl.pdf
12. Blueprint Medicines announces top-line data for pralsetinib and initiates rolling NDA submission to FDA for the treatment of patients with RET fusion-positive non-small cell lung cancer. News release. Blueprint Medicines Corporation; January 8, 2020. Accessed May 12, 2020. https://prn.to/37R0Juz
13. Rittmeyer A, Barlesi F, Waterkamp D, et al; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255‐265. Published correction appears in Lancet. 2017;389(10077):e5. doi:10.1016/S0140-6736(16)32517-X
14. Fehrenbacher L, von Pawel J, Park K, et al. Updated efficacy analysis including secondary population results for OAK: a randomized phase III study of atezolizumab versus docetaxel in patients with previously treated advanced non-small cell lung cancer. J Thorac Oncol. 2018;13(8):1156-1170. doi:10.1016/j.jtho.2018.04.039
15. Gandara DR, von Pawel J, Mazieres J, et al. Atezolizumab treatment beyond progression in advanced NSCLC: results from the randomized, phase III OAK study. J Thorac Oncol. 2018;13(12):1906‐1918. doi:10.1016/j.jtho.2018.08.2027
16. Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441-1448. doi:10.1038/s41591-018-0134-3