Jonah Feldman

Larotrectinib (Vitrakvi) continued to demonstrate favorable efficacy and survival outcomes with low toxicity, according to extended follow-up for 2 trials of patients with lung cancerand

 fusions presented at the 2022 World Conference on Lung Cancer.

Investigators observed an objective response rate (ORR) of 83% (95% CI, 61%-95%) in 23 evaluable patients with 

 fusion–positive disease. The 24-month progression-free survival (PFS) rate was 67% (95% CI, 44%-90%) while the 24-month overall survival (OS) rate was 72% (95% CI, 48%-97%).

“Larotrectinib demonstrated rapid and durable responses, extended survival, and a favorable long-term safety profile in patients with advanced lung cancer harboring 

 gene fusions,” the investigators stated in their poster.

The results were based on the phase 2 NAVIGATE (NCT02576431) trial and phase 1 LOXO-TRK-14001 trial (NCT02122913) of patients with fusions in the 

 genes. Patients with cancer types including lung, thyroid, salivary, and colorectal cancers were enrolled on these trials, but this analysis included only those with advanced lung cancer. Both trials administered larotrectinib at a dose of 100 mg twice daily. The primary end point was ORR.

Larotrectinib was also investigated as an NTRK inhibitor in the SCOUT trial (NCT02637687). Across all 3 trials and disease types, this drug exhibited an overall response rate of 75% (95% CI, 61%-85%) by independent review committee (IRC) and 80% by investigator assessment (INV) in 55 patients with predominantly grade 1 adverse events (AEs).

 In 2018, based on SCOUT, NAVIGATE, and LOXO-TRK-14001, it was approved by the FDA for all solid tumors harboring an 

 fusion in adults and children with metastatic disease or those who cannot receive surgery and have no satisfactory alternative treatments.

At the previous data cutoff of July 20, 2020, 15 patients with advanced lung cancer were evaluated, with an ORR of 87% as assessed by an IRC and 73% by INV.

 With an additional year of follow-up, the ORR was still 87% by IRC, termed Group 1 in this analysis.

 They also presented data for Group 2, which consisted of these 15 plus an additional 11 patients. Both groups were evaluated at a data cutoff of July 20, 2021.

For Group 1, the median DOR was not reached; the median PFS was 33.0 months; and median OS was 40.7 months at a median follow-up of 24.0, 35.8, and 35.8 months, respectively.

Investigators found that of the 23 evaluable patients in Group 2, there were 2 complete responses, 17 partial responses (PR), and 4 patients with stable disease (SD). No patients had progressive disease. The median PFS and DOR in all 26 patients were not reached, while the median OS was 40.7 months (95% CI, 19.4–not estimable [NE]). The 24-month rate of DOR was 72%. The median follow-up for DOR was 12.9 months, while for PFS it was 14.6 months and for OS it was 12.9 months.

When including all 26 patients, the median age was 51.5 years (range, 25.0-76.0). Patients had received a median of 2 prior therapies (range, 0-6), with 46% having received 3 or more prior therapies.

Ten evaluable patients had baseline central nervous system metastases. They had an ORR of 80% (95% CI, 44%-97%) including 8 PRs and 2 with SD. For these patients, the median DOR was 9.5 months (95% CI, 3.6–NE), while the median PFS was 9.9 months (95% CI, 5.3–NE), and the median OS was 19.4 months (95% CI, 7.6–NE) at a median follow-up of 9.3, 11.0, and 12.0 months, respectively.

There were no new safety signals for Group 1, which previously reported mainly grade 1 and 2 AEs. Group 2 also reported mainly grade 1 and 2 treatment-related AEs. The most common treatment-related AEs included elevated alanine aminotransferase and aspartate aminotransferase (AST) levels (38.5% and 30.8%, respectively), followed by myalgia (26.9%) and constipation (23.1%). The most common grade 3 or higher AEs related to larotrectinib were increased AST (7.7%) and weight gain (7.7%). No patients discontinued treatment due to AEs.

These results confirm the long-term response and efficacy of larotrectinib in patients with advanced lung cancer who are identified as harboring 

 fusions. “These results support testing for 

 gene fusions in patients with lung cancer,” the investigators concluded in their poster.

1. Moreno V, Lin JJ, Tan DSW, et al. Extended follow-up of efficacy and safety of larotrectinib in patients with TRK fusion lung cancer. Presented at: IASLC 2022 World Conference on Lung Cancer; August 6-9, 2022; Vienna, Austria. Abstract EP08.020-148.

2. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448

3. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. December 14, 2018. Accessed August 4, 2022. https://bit.ly/3Sve4AX

4. Drilon A, Tan DSW, Lassen UN, et al. Efficacy and safety of larotrectinib in patients with tropomyosin receptor kinase fusion-positive lung cancers. JCO Precis Oncol. 2022;6:e2100418. doi:10.1200/PO.21.00418

Articles

Larotrectinib continued to demonstrate favorable efficacy and survival outcomes with low toxicity, according to extended follow-up for 2 trials of patients with lung cancer and NTRK fusions.

Larotrectinib Shows Continued Efficacy in NTRK-Positive Lung Cancer

Cancer immunotherapy has dramatically changed the landscape of medical oncology by offering more tolerable and effective alternatives to chemotherapy, according to David L. Bartlett, MD. Over the past 10 years, immune checkpoint inhibitors (ICIs) were introduced and gradually became adopted, even as first-line treatment for some diseases.

While immunotherapies offer safe treatment options for many disease types compared with the toxicities of chemotherapies, they have their own unique types of toxicities that must be managed carefully in the real-world setting.

Research into prognostic biomarkers and combination therapies have improved the efficacy of immunotherapy, while alternative approaches that utilize the immune response to treat cancer such as monoclonal antibodies and cell therapies are showing promise. Focused study of immunotherapy for cancer has generated a greater understanding of the tumor microenvironment. This research is leading to more advanced cell therapies that can target tumor-specific antigens and formulate new therapies that can be tailored to multiple disease types effectively.

During an interview with Targeted Oncology

, Bartlett, chair of the Allegheny Health Network Cancer Institute in Pittsburgh, Pennsylvania, discussed the adoption of key immunotherapies and how exploration of the tumor microenvironment and immune environment is opening new approaches to treatment.

: How has immunotherapy changed over the last 10 years?

 I think it is interesting to see how cancer immune therapy has evolved over the last 10 years. It's been quite dramatic. If you think about 10 years ago, we just had 1 agent, the anti-CTLA-4 agent [ipilimumab (Yervoy)], which had just been approved.

 There was excitement around that as a new class of agents. But then if you look at what's happened since then, it's just been an explosion of immunotherapy agents that have been approved and changed the way we manage cancers: all of the anti­–PD-1 and anti–PD-L1 [agents], bispecific antibodies, and oncolytic viral therapies, and then finally, the cell therapies including CAR [chimeric antigen receptor] T-cell and tumor-infiltrating lymphocyte [TIL] therapies. So it's been this massive evolution around cancer treatment over the last 10 years. It's hard to imagine it's only been that long given how much we've learned about the immune system during that time.

What ongoing or published trials of immunotherapy do you think have been the most practice changing?

Over the years, there have been a lot of key trials that have transformed our thinking about immune therapy, from the first TIL trials that have demonstrated a cure rate between 10% and 20% in melanoma,

 to the CAR T-cell trials which have shown cures in B-cell hematologic malignancies,

 to the large, randomized trials showing the impact of anti–PD-1 and ICI therapy.

The evolution of those trials is to now look at combination therapies and finally, combining chemotherapy and immune therapy together, using immunotherapy in the adjuvant setting, and moving from third- and fourth-line therapies up to first-line therapies. So much has gone on in terms of the clinical trials in immune therapies.

My interest being in gastrointestinal [GI] cancers, we're finally seeing immune therapy play a role in many of the GI cancers, and those have been game changing. For instance, the trials looking at atezolizumab [Tecentriq] and bevacizumab [Avastin] in the hepatocellular cancer [HCC] inthe IMbrave [150 (NCT03434379)] study, microsatellite instability [MSI]-high colorectal cancers and using pembrolizumab [Keytruda] upfront in the KEYNOTE-177 study [NCT02563002], and frontline immune therapy or checkpoint inhibition for colon cancers. Then, finally, with gastric junction cancers and gastroesophageal cancers, [investigators looked] at the combination of pembrolizumab and chemotherapy in a large, randomized trial showing an advantage over chemotherapy alone.

I think what we're what we're finally seeing is that the immune therapies that have been so effective in what we consider to be hot, inflamed tumors like melanoma, renal cell cancer, and lung cancer are now being moved into a GI space where we didn't really appreciate that before. This is just going to continue to evolve with all the thousands of studies that are out there now.

How have immunotherapies been adopted as standard of care or as frontline options?

I think the standard immune therapies have become standard of care for many different malignancies, and it's a matter of whether we're using them as first-line or we're using them as salvage therapy after the failure of standard chemotherapies. [Agents] like atezolizumab/bevacizumab are now a frontline therapy for HCC. It's so much better tolerated and more effective than the previous agents, and it's a game changer for that. I think, similarly, using immune therapy and ICIs as frontline for MSI-high tumors, regardless of the histology, in colon cancer or pancreas cancer as upfront therapy has also been a game changer.

Which newer targets do you feel like are important for upcoming immunotherapies?

There are so many targets. If you think about all the ICIs, there's dozens of checkpoints that have been identified, all of which may have an impact when inhibited. We now know how to inhibit those checkpoints using antibodies. There are dozens of targets that we can go after that [researchers] are looking into right now. And it's exciting that a LAG-3 inhibitor [relatlimab-rmbw; Opdualag] was just approved.

So you can just see this continuing to evolve. [In] bispecific-antibody therapies, where you engage T cells, activate T cells, and put them in close proximity with tumor antigens, we've identified many tumor antigens that it could be effective for. So the sky's the limit there as well. I think, by the same token, as we learn more about CAR T-cell therapy and how to get cell therapy into solid tumors, the targets are infinite in terms of the neoantigens and tumor antigens that we can look at.

What should more community oncologist understand about treating patients with immunotherapy?

Immune therapy has a different set of complications and adverse events [AEs] that I think most physicians are becoming more and more familiar with. But each agent is going to have its own unique AE profile that's going to have to be kept in mind. I think the issue of autoimmunity that's being stimulated by these immune therapy agents provides a unique spectrum of toxicities that have to be kept into account, how we manage those toxicities through other immune suppressants and steroids, and what impact those will have on the cancer response. I think all we're still evolving in that understanding. But those are all things that have to be kept in mind as we're using these agents.

It's also important for everybody to keep up with what's being reported because thousands of clinical trials are active. We're constantly learning more, and more therapies are being approved, and that will continue to happen. So stay tuned, be aware, and become comfortable with the AE profiles of these unique agents and combinations of agents.

What upcoming research into immunotherapy is important to highlight?

I am very interested in cell therapy with TILs; expanding lymphocytes from the tumor microenvironment itself and in a variety of ways of activating those cells ex vivo and giving them back to patients. In our laboratory, we've been interested in developing what we consider a pre-TIL approach, where we use oncolytic viruses to transform the tumor microenvironment in a way that we can then harvest T cells that are very specific to tumor antigens, expand those T cells ex vivo and then give them back as a therapeutic agent.

So it's about combining complex therapies—oncolytic viral therapy and T-cell therapy—through TILs to achieve a dramatic response. That all works very well in the laboratory. Now we're just looking at ways to bring that into the clinical realm. But I think it's just another example where we should be able to, through combinations and understanding the immune environments, enhance these immune therapy approaches. Treatments like that are agnostic to tumor type. In other words, it should work as well in colon cancer as it does in lung cancer or melanoma or sarcoma. I think that's where the future lies: all these different ways that we can manipulate the immune system and take advantage of the immune system to treat these cancers. I think this will continue to evolve for another couple of decades.

How can physicians support the progress of immunotherapy in clinical trials?

The key to all of the evolution of immune therapy is the engagement of all of our oncologists in the clinical trial process and working wherever you are to be able to get those clinical trials up and running and to accrue patients to those trials so that we can get these questions answered as quickly as possible. I would encourage everybody to work with their patients to understand how important these trials are and to continue to accrue to these trials.

1. FDA approves Yervoy™ (ipilimumab) for the treatment of patients with newly diagnosed or previously-treated unresectable or metastatic melanoma, the deadliest form of skin cancer. Bristol-Myers Squibb. Published March 25, 2011. Accessed June 8, 2022. https://bit.ly/3xkebWa

2. Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res. 2011;17(13):4550-4557. doi:10.1158/1078-0432.CCR-11-0116

3. Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019;380(1):45-56. doi:10.1056/NEJMoa1804980

4. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med. 2017;377(26):2531-2544. doi:10.1056/NEJMoa1707447

5. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396(10254):839-852. doi:10.1016/S0140-6736(20)31366-0

6. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-771. doi:10.1016/S0140-6736(21)01234-4

7. FDA approves Opdualag for unresectable or metastatic melanoma. FDA. Published March 18, 2022. Accessed June 8, 2022. https://bit.ly/3tp3YGR

8. Giehl E,Kosaka H, Liu Z, et al. In vivo priming of peritoneal tumor-reactive lymphocytes with a potent oncolytic virus for adoptive cell therapy.Front Immunol. Published online February 18, 2021. doi:10.3389/fimmu.2021.610042

David L. Bartlett, MD, discussed the adoption of key immunotherapies and how exploration of the tumor microenvironment and immune environment is opening new approaches to treatment in an interview with Targeted Oncology.

Cancer Immunotherapy Month: Greater Understanding of Immune System Leads to Advanced Targeted Treatments

Sophia Kamran, MD, a radiation oncologist at Massachusetts General Hospital and assistant professor of radiation oncology at Harvard Medical School, discusses potential toxicities limiting the addition of immunotherapy to trimodal therapy for patients with urothelial cancer.

Trimodal therapy combines trans-urethral resection with chemotherapy and radiotherapy. According to Kamran, hypofractionated radiotherapy delivers a larger dose of radiation to shorten the length of radiotherapy treatment by a week or multiple weeks. She says patients prefer to undergo hypofractionated radiation therapy for a shorter time with fewer trips to a radiation center, and in addition, it is more cost-effective.

However, early data have shown unacceptable toxicity risks when combined with immune checkpoint inhibitors (ICIs). This includes a phase 1 trial [NCT03620435] of trimodal therapy plus atezolizumab (Tecentriq) from McGill University in which 4 out of 8 patients with muscle-invasive bladder cancer developed grade 3 gastrointestinal toxicities, including 2 who had received a lower dose of atezolizumab.

The ongoing large phase 3 randomized SWOG NRG 1806 trial (NCT03775265), which is comparing trimodal therapy plus atezolizumab versus trimodal therapy with chemotherapy alone in patients with localized muscle-invasive bladder cancer, did not include hypofractionation for this reason. Kamran says this is an important area of research to determine whether hypofractionated radiation can be used safely with ICIs.

Another challenge that we're running into, or just needs to be further investigated, is when we use ICIs—because we are now incorporating that into our treatment—whether or not we can safely hypofractionate treating the bladder when we use that. The reason why I bring that up is because hypofractionated radiation therapy, which really involves getting a larger dose of treatment per day of radiation so we can actually shorten the treatment duration overall by maybe a week, or a couple of weeks, just depending on what regimen you use. That has been very popular, particularly in the [United Kingdom], and it’s been used in the United States as well. However, there [have] been some early data showing that if you use hypofractionated radiation therapy in combination with these ICIs, some of the data [show] that there’s some unacceptable toxicity risks, particularly related to gastrointestinal toxicity.

At this time, in that very large phase 3 randomized trial…SWOG NRG 1806, we do not allow for hypofractionation, so patients get the standard fractionations. It is kind of a prolonged treatment and we like hypofractionated radiation because patients like it better, they do not have to come in so many times to the radiation center, they can really shorten the duration, it's cost effective, etc. But, at this time, there needs to be a little bit more investigation because it just appears that there [are] some dose-limiting toxicities when you're combining the 2 in the hypofractionated setting.

Videos

Sophia Kamran, MD, discusses potential toxicities limiting the addition of immunotherapy to trimodal therapy for patients with urothelial cancer.

Hypofractionated Radiotherapy Plus ICI for Bladder Cancer Limited by Toxicity

Patients with renal cell carcinoma (RCC) with poor performance status did not demonstrate significant differences in efficacy based on receiving frontline pembrolizumab (Keytruda) plus axitinib (Inlyta) or nivolumab (Opdivo) plus ipilimumab (Yervoy), according to results of a retrospective study presented at the 2022 International Kidney Cancer Symposium: Europe in Antwerp, Belgium.

No significant differences were found between the 2 regimens in terms of overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) for patients with an ECOG performance score of 2 or greater. The retrospective analysis also identified a correlation between lung immune prognostic index (LIPI) and ORR, PFS, and OS among these patients with poor prognosis.

Pembrolizumab plus axitinib and nivolumab plus ipilimumab have been approved by the FDA for first-line treatment of advanced or metastatic RCC based on the KEYNOTE-426 (NCT02853331) and CheckMate 214 (NCT02231749) trials, respectively.

However, both studies only enrolled patients with a Karnofsky performance status of 70% or greater, equivalent to an ECOG performance score of 0 or 1, so the outcomes for higher-risk patients are unknown.

The retrospective analysis identified 70 patients across 14 institutions, 45 of whom were treated with nivolumab/ipilimumab and 25 of whom were treated with pembrolizumab/axitinib.

There were 45 patients (64%) with poor-risk disease based on International Metastatic RCC Database Consortium criteria and 25 (36%) withvintermediate-risk disease. The median age ofvpatients at diagnosis was 63 years, and 51 (73%) were male. Seventeen patients (24%) had prior nephrectomy, and 50 (71%) had synchronous metastatic disease at diagnosis.

At the time of analysis, at a median followup of 11.1 months, the ORR for patients who received pembrolizumab/axitinib was 42% vs only 23% for those who received nivolumab/ipilimumab, but this difference was not statistically significant (

 = .379). The combined ORR for all patients was 31%. The disease control rate for pembrolizumab/axitinib vs nivolumab/ipilimumab was 63% vs 43% (

The median PFS for those receiving pembrolizumab/ axitinib was 6.0 months vs 3.8 months with nivolumab/ipilimumab (

 = .842); this was also not statistically significant. Median PFS across both subgroups was 5.4 months.

At the time of follow-up, 41% of patients had died. Median OS was not reached for the pembrolizumab/axitinib group vs 9.8 months for the nivolumab/ipilimumab group (

= .286). Median OS across both groups was 16 months.

The rate of grade 3 or higher treatment-related adverse events was also assessed. The incidence rate was 20% with pembrolizumab/axitinib vs 25% with nivolumab/ipilimumab, showing no signifi cant difference in toxicity (

However, LIPI status did show significant associations with effi cacy outcomes. Of the 42 patients who were able to be evaluated for LIPI, 20 patients (48%) had good LIPI scores, 15 (36%) had an intermediate LIPI score, and 7 (17%) had a poor LIPI score. LIPI was associated with ORR (

= .045). IPI was significantly associated with ORR (

 = 0.045) and with PFS (poor hazard ratio [HR], 7.6; 

 = .018) and OS (poor/intermediate HR, 3.5; 

In their conclusion, the investigators recommended that prospective real-world studies are needed to confirm these results.

1. Carril-Ajuria L, Colomba E, Romero-Ferreiro C, et al. Efficacy of frontline combination therapy in metastatic renal cell carcinoma (mRCC) patients (pts) with poor performance status (PS). Presented at: 2022 International Kidney Cancer Symposium: Europe; April 22-24, 2022; Antwerp, Belgium.

2. FDA approves pembrolizumab plus axitinib for advanced renal cell carcinoma. FDA. Updated April 22, 2019. Accessed May 20, 2022. https://bit.ly/3wv1Csa

3. FDA approves nivolumab plus ipilimumab combination for intermediate or poor-risk advanced renal cell carcinoma. FDA. Updated April 16, 2018. Accessed May 20, 2022. https://bit.ly/3yJJpZo

Following a study of frontline pembrolizumab plus axitinib or nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma, investigators recommended that prospective real-world studies are needed to confirm the results.

Minimal Difference in Efficacy Shown for Immunotherapy Combos in Poor-Performance Metastatic RCC

A stronger chemotherapy regimen that included irinotecan combined with the targeted EGFR inhibitor panitumumab (Vectibix) failed to show significant benefit over an active comparator plus panitumumab in patients with metastatic colorectal cancer (mCRC) with unmutated 

, according to results presented at the 2022 American Society for Clinical Oncology Annual Meeting.

In the phase 3 TRIPLETE study (NCT03231722), the mFOLFOX6 (modified folinic acid, 5-fluorouracil, oxaliplatin) regimen plus 

panitumumab had an objective response rate (ORR) of 76%

 versus 73% with mFOLFOXIRI (modified folinic acid, 5-fluorouracil, oxaliplatin, irinotecan) plus panitumumab (odds ratio [OR], 0.87; 95% CI, 0.56-1.34, 

“The intensification of the upfront chemotherapy backbone with mFOLFOXIRI does not increase the ORR as compared with FOLFOX6 in combination with panitumumab in [patients with] 

 wild-type mCRC,” said Chiara Cremolini, associate professor at the University of Pisa, Italy, in her presentation.

FOLFOX (folinic acid, fluorouracil, and oxaliplatin) and FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) plus one of the anti-EGFR monoclonal antibodies panitumumab or cetuximab (Erbitux) are upfront treatment options for mCRC with unaltered 

. The combined regimen of FOLFOXIRI has shown promising efficacy in early-stage trials, and a modified schedule of FOLFOXIRI plus panitumumab showed improved efficacy versus FOLFOXIRI alone in the phase 2 VOLFI trial (NCT01328171).

The TRIPLETE trial enrolled 435 previously-untreated patients with wild-type 

 whose mCRC was unresectable.1 Patients could not have received adjuvant oxaliplatin and could only receive adjuvant fluoropyrimidine monotherapy if 6 months passed between the end of adjuvant therapy and first relapse.

Stratification factors were ECOG performance status 0 or 1 versus 2, primary tumor location (right or left), and whether metastases were only in the liver. Patients were randomized 1:1 to receive induction therapy with panitumumab plus either mFOLFOXIRI or mFOLFOX6 for up to 12 cycles, followed by maintenance with 5-fluoruracil, folinic acid, and panitumumab until disease progression. The trial took place in 57 treatment centers from September 2017 to September 2021.

The median age in both arms was 59 years. In the FOLFOX arm, 43% of patients had a resected primary tumor, versus 51% in the FOLFOXIRI arm. Only 2% had received adjuvant chemotherapy in the mFOLFOX6 arm and only 6% in the mFOLFOXIRI arm.

The schedule of FOLFOXIRI was modified to have lower doses of 5-fluororacil and irinotecan due to the high rate of grade 3 and 4 gastrointestinal toxicities previously observed. Irinotecan was given at a dose of 150 mg/m

 for 48-hour infusion. Panitumumab was given at 6 mg/kg in both arms.

The primary end point was ORR. Cremolini said in her presentation that this end point was justified for a phase 3 study. “First…we deem ORR a clinically relevant end point in the vast majority of mCRC cases. Second, due to the lack of reliable signs of efficacy for progression-free survival [(PFS) and] overall survival [OS] when assessing upfront chemotherapy plus anti-

The end point was based on the expected comparator arm’s ORR of 60% and targeted an increase of at least 15% in the experimental arm. Secondary end points included early tumor shrinkage, depth of response, PFS, and OS.

In addition to the inferior ORR for mFOLFOXIRI, the complete response rate for both arms was 7%, while the partial response rate was 69% for mFOLFOX6 and 66% for mFOLFOXIRI. The percentage of patients with no macroscopic or microscopic residual tumor was 29% in the mFOLFOX6 arm versus 25% in the mFOLFOXIRI arm (OR, 0.81; 95% CI, 0.53-1.23; 

 = .317). The median change in depth of response was 48% with mFOLFOXIRI versus 47% with mFOLFOX6 (

 = .845). Similarly, there was no difference in early tumor shrinkage.

At median follow-up of 26.5 months, the median PFS was 12.3 months for mFOLFOX6 versus 12.7 months for mFOLFOXIRI (HR, 0.88; 95% CI, 0.70-1.11; 

 = .277). OS results were not yet mature.

Subgroup analysis showed 2 distinct differences in ORR. “It seemed that especially female patients and those with right-sided primary tumor could derive more benefit from the use of the traditional control strategy instead of the experimental arm,” said Cremolini. ORR favored mFOLFOX6 with female patients (OR, 0.43; 95% CI, 0.21-0.88; 

 = .014) and with right-sided tumors (OR, 0.26; 95% CI, 0.08-0.85; 

 = .030). She noted that these findings did not correlate when analyzing outcomes by PFS.

The mFOLFOXIRI arm was associated with higher grade 3 or 4 adverse events, especially diarrhea at 23% versus only 7% in the comparator arm and neutropenia at 32% versus 20% in the comparator arm. Grade 3 or 4 skin rash was more frequent in the mFOLFOX6 arm at 29% versus 19% with mFOLFOXIRI.

The null hypothesis of a 60% ORR for the mFOLFOX6 comparator arm was significantly inaccurate. Cremolini suggested that the ORR of 76% could be explained by primary tumor location, as 88% of patients had left-sided tumors.

“In conclusion, FOLFOXIRI plus panitumumab should not be recommended as upfront therapy for RAS and BRAF wild-type mCRC patients,” Cremolini stated. “When the use of targeted agents is optimized in a clinically and molecularly [selected] population, there is no added value from the intensification of the associated chemotherapy backbone.”

1. Rossini D, Antoniotti C, Lonardi S, et al. Upfront modified fluorouracil, leucovorin, oxaliplatin, and irinotecan plus panitumumab versus fluorouracil, leucovorin, and oxaliplatin plus panitumumab for patients with RAS/BRAF wild-type metastatic colorectal cancer: the phase III TRIPLETE study by GONO. 

. 2022;40(suppl 17):LBA3505. doi:10.1200/JCO.22.00839

2. Modest DP, Martens UM, Riera-Knorrenschild J, et al. FOLFOXIRI plus panitumumab as first-line treatment of RAS wild-type metastatic colorectal cancer: the randomized, open-label, phase II VOLFI study (AIO KRK0109). 

. 2019;37(35):3401-3411. doi:10.1200/JCO.19.01340

FOLFOXIRI plus panitumumab should not be recommended as upfront therapy for RAS and BRAF wild-type mCRC patients. according to investigators of the phase 3 TRIPLETE study.

Intensified Chemotherapy Does Not Improve Efficacy With Panitumumab in mCRC

Nivolumab (Opdivo) plus ipilimumab (Yervoy) exhibited long-term durable benefit in the frontline versus chemotherapy in patients with metastatic non–small cell lung cancer (mNSCLC), according to 5-year analysis of the CheckMate 227 trial (NCT02477826) presented at the 2022 American Society for Clinical Oncology Annual Meeting.

The 5-year rate of overall survival (OS) was 24% in patients who received nivolumab/ipilimumab who had PD-L1 expression of at least 1%, and 19% in those with PD-L1 expression less than 1%, versus 14% and 7%, respectively, in patients who received chemotherapy. The immunotherapy combination also had a significantly higher duration of response (DOR) of 24.5 months for those with positive PD-L1 expression and 19.4 months for those with negative PD-L1 expression versus 6.7 months and 4.8 months with chemotherapy, respectively.

“Nivolumab and ipilimumab led to increased 5-year survivorship among these 5-year survivors and regardless of PD-L1 expression level,” Julie R. Brahmer, MD, director of the thoracic oncology program and professor of oncology at Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center, said in her presentation. “Responses were maintained for greater than 5 years in over 40% of those who responded.”

The phase 3 CheckMate 227 stratified patients with stage IV or recurrent NSCLC who had no prior systemic therapy and were negative for 

 alterations by positive or negative PD-L1 expression. In the PD-L1-positive subgroup, 1189 patients were randomized 1:1:1 to receive nivolumab/ipilimumab, nivolumab alone, or up to 4 cycles of chemotherapy. In the PD-L1-negative subgroup, 550 patients were randomized 1:1:1 to receive nivolumab/ipilimumab, chemotherapy, or nivolumab plus chemotherapy.

Chemotherapy consisted of pemetrexed plus cisplatin or carboplatin every 3 weeks for patients with nonsquamous disease or gemcitabine plus cisplatin or carboplatin every 3 weeks for patients with squamous disease.

The primary end points were OS for the PD-L1–positive population and progression-free survival (PFS) in patients with a high tumor mutational burden. The OS was previously reported at a minimum follow-up of 29.3 months with a median of 17.1 months for nivolumab/ipilimumab versus 14.9 months with chemotherapy, with 2-year OS rates of 40.0% and 32.8%, respectively.

 With the 5-year analysis, OS benefit continued to be observed with a hazard ratio of 0.77 favoring nivolumab/ipilimumab (95% CI, 0.66-0.91).

With all patients having stopped receiving immunotherapy for at least 3 years, the efficacy versus chemotherapy has persisted in patients regardless of positive or negative PD-L1 expression.Combined 5-year OS, PFS, and DOR rates were 22%, 11%, and 27%, respectively, for those who received nivolumab/ipilimumab versus 12%, 2%, and 3% for chemotherapy.

Among patients who survived for 5 years, median PFS was 59.1 months for PD-L1–positive patients and 60.7 for PD-L1–negative patients who received immunotherapy, versus 9.5 months and 24.9 months respectively for those who received chemotherapy. The median duration of response was not reached (52.6-NA) for PD-L1–positive patients and 59.4 months (18.0-NA) for PD-L1–negative patients, compared with 12.4 (5.6-24.4) and 15.2 (2.7-NA) for those who received chemotherapy.

“In patients that survived 5 years, improved outcomes were universally observed with nivolumab and ipilimumab versus chemotherapy irrespective of PD-L1 expression,” said Brahmer in her presentation. “The majority of patients treated with nivolumab and ipilimumab did not receive subsequent therapy, with approximately two-thirds of patients remaining treatment free 3 years after discontinuing treatment.”

In contrast, among those who received chemotherapy and survived for 5 years, only 22% of PD-L1–positive patients and 17% of PD-L1–negative patients received no subsequent systemic therapy.

No new safety signals were seen in this analysis. Quality of life (QOL) was measured by an EQ-5D assessment, which showed that 5-year survivors who received nivolumab/ipilimumab reported a QOL similar to the general United States population of 79.3, significantly above the lung cancer norm of 68.0.

“These long-term results from CheckMate 227 further support nivolumab and ipilimumab as an effective first-line treatment for patients with mNSCLC regardless of tumor PD-L1 expression level,” Brahmer concluded.

1. Brahmer JR, Lee JS, Ciuleanu TE, et al. Five-year survival outcomes with nivolumab (NIVO) plus ipilimumab (IPI) versus chemotherapy (chemo) as first-line (1L) treatment for metastatic non–small cell lung cancer (NSCLC): Results from CheckMate 227. 

. 2022;40(suppl 17):LBA9025. doi:10.1200/JCO.2022.40.17_suppl.LBA9025

2. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. 

. 2019;381(21):2020-2031. doi:10.1056/NEJMoa1910231

The 5-year analysis of the CheckMate 227 study shows long-term survival benefit for nivolumab plus ipilimumab versus chemotherapy in patients with metastatic non–small cell lung cancer.